</head> <body>Cancer Associated Fibroblast Cell map Cancer-associated fibroblasts (CAFs) are key non-immune players in tumor microenvironment which participate in tumor growth and drive metastatic process and local immunosuppression. The CAF map represent molecular interactions involved in the role of CAFs in tumoral microenvironment (TME). The map is divided into 11 functional modules: 'Integrin signaling pathways', 'Motility', 'Matrix regulation', 'Growth factors production', 'Interaction with tumoral cells', 'Markers of fibroblast activation', 'TReg modulators', 'Cytokines and chemokines production', 'Inflammatory signaling pathways', 'Core signaling', 'Growth factors signaling pathways'. The module 'Treg modulation' describes the regulatory T-cell key modulators described in literature, for some of which their specific role is only partially shown in fibroblasts. The map describes 681 chemical species (post-translational modifications of 303 proteins and 87 genes) connected by 581 reactions. The constructions of the map was based on 358 manually curated articles including 50 reviews, the majority of which are dated by the 2010-2016 period. </body> </html> </notes> <extension> <renderInformation backgroundColor="#ffffff" id="renderInformation" programName="cd2sbgnml" programVersion="0.1" xmlns="http://www.sbml.org/sbml/level3/version1/render/version1"> <listOfColorDefinitions> <colorDefinition id="color_7" value="#66ff66ff"/> <colorDefinition id="color_2" value="#cccc00ff"/> <colorDefinition id="color_5" value="#ccffccff"/> <colorDefinition id="color_10" value="#ccff66ff"/> <colorDefinition id="color_13" value="#808080ff"/> <colorDefinition id="color_6" value="#f7f7f7ff"/> <colorDefinition id="color_9" value="#ffccccff"/> <colorDefinition id="color_8" value="#ffff66ff"/> <colorDefinition id="color_11" value="#ffffccff"/> <colorDefinition id="color_15" value="#00ff00ff"/> <colorDefinition id="color_3" value="#cc99ffff"/> <colorDefinition id="color_14" value="#ff0000ff"/> 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id="s2_sa2" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 hgnc_id:HGNC:130 HGNC:130 ENTREZ:59 UNIPROT:P62736 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:INTEGRIN CASCADE:HGF CASCADE:HH PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. PMID:19747910, PMID:8515656 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:27111285 ILK/AKT pathway probably mediates TGF-β1-induced α-SMA expression and myofibroblast differentiation PMID:23673986 α-SMA expression in CAFs is a negative factor for patient survival. PMID:20129924 human corneal fibroblasts were transfected with small interfering RNA to alpha11, which decreased alpha-smooth muscle actin expression and myofibroblast differentiation PMID:11553712 Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA References_end </body> </html> </notes> <label text="ACTA2"/> <bbox w="80.0" h="40.0" x="6270.0" y="3900.0"/> </glyph> <glyph class="macromolecule" id="s4_sa4" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: chondroitin sulfate proteoglycan 4 HUGO:CSPG4 hgnc_id:HGNC:2466 HGNC:2466 ENTREZ:1464 UNIPROT:Q6UVK1 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:19211240; PMID:17106243 CSPG4 (NG2) is a marker of fibroblast activation References_end </body> </html> </notes> <label text="CSPG4"/> <bbox w="80.0" h="45.0" x="1980.0" y="4537.5"/> </glyph> <glyph class="macromolecule" id="s8_sa8" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: palladin, cytoskeletal associated protein HUGO:PALLD hgnc_id:HGNC:17068 HGNC:17068 ENTREZ:23022 UNIPROT:Q8WX93 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:23194363 PALLD is a marker of fibroblast activation References_end </body> </html> </notes> <label text="PALLD"/> <bbox w="80.0" h="40.0" x="1890.0" y="4580.0"/> </glyph> <glyph class="macromolecule" id="s9_sa9" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: podoplanin HUGO:PDPN hgnc_id:HGNC:29602 HGNC:29602 ENTREZ:10630 UNIPROT:Q86YL7 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:26828520; PMID:19556810 CAV1 and Podoplanin are markers of fibroblast activation Podoplanin expressed by CAFs seemed to have a protective role against cancer cell invasion. References_end </body> </html> </notes> <label text="PDPN"/> <bbox w="80.0" h="40.0" x="3230.0" y="3000.0"/> </glyph> <glyph class="phenotype" id="s19_sa19"> <label text="GROWTH_FACTORS_PRODUCTION"/> <bbox w="275.0" h="63.0" x="3712.5" y="5088.5"/> </glyph> <glyph class="phenotype" id="s20_sa20"> <label text="TUMOR_GROWTH"/> <bbox w="266.0" h="53.0" x="3427.0" y="5333.5"/> </glyph> <glyph class="macromolecule" id="s22_sa22" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: nerve growth factor HUGO:NGF hgnc_id:HGNC:7808 HGNC:7808 ENTREZ:4803 UNIPROT:P01138 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: PMID:25071162 References_end </body> </html> </notes> <label text="NGF"/> <bbox w="80.0" h="40.0" x="3990.0" y="4840.0"/> </glyph> <glyph class="phenotype" id="s27_sa27"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:19956757 Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model PMID:21051638 Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment. References_end </body> </html> </notes> <label text="IMMUNE_SYSTEME_MODULATION"/> <bbox w="213.0" h="67.0" x="523.5" y="4416.5"/> </glyph> <glyph class="macromolecule" id="s30_sa30" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL2 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. STAT3 inducec CLL2 expression downstream of this signaling. CCL2 derived from FAP+CAFs mediates their ability to promote tumor growth and MDSC infiltration CCL2 (MCP1) CAF express MCP-1/CCL2 when co-cultured with cancer cells [48] and [49]. Galectin-1 expression, which was shown to regulate CAF activation, also controls MCP-1 expression in the activated cells and MCP-1 in turn facilitates tumour invasion and metastasis. Although the mechanism of action described in the paper concentrated on the effects of MCP-1 on tumour cells, there is also a large body of evidence describing MCP-1's involvement in the recruitment of CCR2-positive immune cells such as monocytes, macrophages, dendritic cells and T cells. In 4T1 tumour bearing mice in which the Mcp-1 gene was deleted, a significant decrease of F4/80 positive macrophages was observed in the tumours PMID:23527025 The primary tumors of MCP-1(-/-) mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of MCP-1, and intravenous injection of 4T1 cells producing a high level of MCP-1 resulted in increased tumor foci in the lung of WT and MCP-1(-/-) mice. Thus, stromal cell-derived MCP-1 in the primary tumors promotes lung metastasis of 4T1 cells, but tumor cell-derived MCP-1 can also contribute once tumor cells enter the circulation. PMID:23943801 TAF-derived CCL2 and its downstream transcription factor, Ets-1, are prerequisites for TAF-induced FGFR4 upregulation. Furthermore, FGFR4-associated pathways are shown to be preferentially activated in colorectal tumor samples, and direct tumor metastasis in a mouse metastasis model. PMID:24531940 Cancer-associated fibroblasts (CAFs) have been described to play critical roles in initiation, progression and metastasis of various cancers. However, the involvement of CAFs in oral cancer (OC) has not been well addressed. In this study, we demonstrate that CAFs, when cocultured with OC cells (OCCs), produce high levels of chemokine (C-C motif) ligand 2 (CCL2) and, subsequently, enhance endogenous reactive oxygen species production in cells. Oxidative stress stimulates expression of cell cycle progression proteins in OCCs, leading to promotion of OCC proliferation, migration, invasion and, OC tumor growth. On the other hand, oxidative stress triggered the activation of nuclear factor-kappaB (NF-κB) and STAT3 in CAFs, resulting in accelerating CCL2 expression. PMID:23567181 CCL2, synthesized by both tumor cells and by CAFs, is a known chemoattractant of inflammatory monocytes, which express its receptor—CCR2 CCL5/RANTES and CCL2 secreted by CAFs isolated from human melanoma, breast and colon cancers mediated recruitment of Th17 cells from peripheral blood References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="80.0" h="40.0" x="1090.0" y="3584.0"/> </glyph> <glyph class="phenotype" id="s32_sa32"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:21324931 Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. PMID:22351925 The extracellular matrix: a dynamic niche in cancer progression. References_end </body> </html> </notes> <label text="ECM_REGULATION"/> <bbox w="221.0" h="43.0" x="6099.5" y="5108.5"/> </glyph> <glyph class="macromolecule" id="s34_sa34" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: matrix metallopeptidase 1 HUGO:MMP1 hgnc_id:HGNC:7155 HGNC:7155 ENTREZ:4312 UNIPROT:P03956 matrix metallopeptidase 2 HUGO:MMP2 hgnc_id:HGNC:7166 HGNC:7166 ENTREZ:4313 UNIPROT:P08253 matrix metallopeptidase 3 HUGO:MMP3 hgnc_id:HGNC:7173 HGNC:7173 ENTREZ:4314 UNIPROT:P08254 matrix metallopeptidase 7 HUGO:MMP7 hgnc_id:HGNC:7174 HGNC:7174 ENTREZ:4316 UNIPROT:P09237 matrix metallopeptidase 8 HUGO:MMP8 hgnc_id:HGNC:7175 HGNC:7175 ENTREZ:4317 UNIPROT:P22894 matrix metallopeptidase 9 HUGO:MMP9 hgnc_id:HGNC:7176 HGNC:7176 ENTREZ:4318 UNIPROT:P14780 matrix metallopeptidase 10 HUGO:MMP10 hgnc_id:HGNC:7156 HGNC:7156 ENTREZ:4319 UNIPROT:P09238 matrix metallopeptidase 11 HUGO:MMP11 hgnc_id:HGNC:7157 HGNC:7157 ENTREZ:4320 UNIPROT:P24347 matrix metallopeptidase 12 HUGO:MMP12 hgnc_id:HGNC:7158 HGNC:7158 ENTREZ:4321 UNIPROT:P39900 matrix metallopeptidase 13 HUGO:MMP13 hgnc_id:HGNC:7159 HGNC:7159 ENTREZ:4322 UNIPROT:P45452 matrix metallopeptidase 14 HUGO:MMP14 hgnc_id:HGNC:7160 HGNC:7160 ENTREZ:4323 UNIPROT:P50281 matrix metallopeptidase 15 HUGO:MMP15 hgnc_id:HGNC:7161 HGNC:7161 ENTREZ:4324 UNIPROT:P51511 matrix metallopeptidase 16 HUGO:MMP16 hgnc_id:HGNC:7162 HGNC:7162 ENTREZ:4325 UNIPROT:P51512 matrix metallopeptidase 17 HUGO:MMP17 hgnc_id:HGNC:7163 HGNC:7163 ENTREZ:4326 UNIPROT:Q9ULZ9 matrix metallopeptidase 19 HUGO:MMP19 hgnc_id:HGNC:7165 HGNC:7165 ENTREZ:4327 UNIPROT:Q99542 matrix metallopeptidase 20 HUGO:MMP20 hgnc_id:HGNC:7167 HGNC:7167 ENTREZ:9313 UNIPROT:O60882 matrix metallopeptidase 21 HUGO:MMP21 hgnc_id:HGNC:14357 HGNC:14357 ENTREZ:118856 UNIPROT:Q8N119 matrix metallopeptidase 23A (pseudogene) HUGO:MMP23A hgnc_id:HGNC:7170 HGNC:7170 UNIPROT:O75900 matrix metallopeptidase 23B HUGO:MMP23B hgnc_id:HGNC:7171 HGNC:7171 ENTREZ:8510 UNIPROT:O75900 matrix metallopeptidase 24 HUGO:MMP24 hgnc_id:HGNC:7172 HGNC:7172 ENTREZ:10893 UNIPROT:Q9Y5R2 matrix metallopeptidase 25 HUGO:MMP25 hgnc_id:HGNC:14246 HGNC:14246 ENTREZ:64386 UNIPROT:Q9NPA2 matrix metallopeptidase 26 HUGO:MMP26 hgnc_id:HGNC:14249 HGNC:14249 ENTREZ:56547 UNIPROT:Q9NRE1 matrix metallopeptidase 27 HUGO:MMP27 hgnc_id:HGNC:14250 HGNC:14250 ENTREZ:64066 UNIPROT:Q9H306 matrix metallopeptidase 28 HUGO:MMP28 hgnc_id:HGNC:14366 HGNC:14366 ENTREZ:79148 UNIPROT:Q9H239 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:16572188 Activated fibroblasts also secrete increased levels of ECM-degrading proteases such as matrix metalloproteinase 2 (MMP2), MMP3 and MMP9, facilitating increased ECM turnover and altered ECM composition. MMPs probably allow cancer cells to cross tissue boundaries and escape the primary tumour site. MMPs and other proteases also directly affect the motility and invasiveness of cancer cells. Such a direct effect has been elucidated for MMP3 (also known as stromelysin 1), which is highly expressed in fibroblasts. MMP3 directly cleaves the extracellular domain of E-cadherin, prompting normal mammary epithelial cells to disaggregate and undergo EMT, promoting cancer-cell invasiveness88. MMP1 also shows such a tumour-promoting effect. The protease-activated receptor PAR1, which is a tethered-ligand receptor, is activated by proteolytic cleavage of the extracellular domain by MMP1, promoting cancer cell migration and invasion through PAR1-dependent Ca2+ signals. PMID:20699369 activated fibroblasts through secretion of metalloproteinases elicit in cancer cells a clear epithelial-mesenchymal transition (EMT), as well as enhancement of tumor growth and development of spontaneous metastases. exposure of HPFs to CM from PC3 cells or to IL-6 treatment, but not to TGF-β treatment, elicits a strong increase in MMP-2 expression and the de novo appearance of MMP-9 (Fig. 3B). In addition, treatment of HPFs with IL-6–blocking antibodies during their exposure to CM from PC3 abrogates the upregulation of MMP expression (Fig. 3B). In keeping with our findings, we observed that the MMP inhibitor ilomastat reverts both the activation of the EMT process (Fig. 3C) and the proinvasive effect elicited by PCa-AFs on PC3 cells (Fig. 3D). In contrast, the EMT induction and the increase in PC3 invasiveness induced by MFs are insensitive to MMP inhibition PMID:22809838 CAF-induced cetuximab resistance is dependent on the matrix metalloproteinases References_end </body> </html> </notes> <label text="MMPs*"/> <bbox w="80.0" h="40.0" x="5360.0" y="4790.0"/> </glyph> <glyph class="phenotype" id="s35_sa35"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16572188 Normal stroma in most organs contains a minimal number of fibroblasts in association with a physiological ECM23. Reactive stroma is associated with an increased number of fibroblasts, enhanced capillary density, and type-I-collagen and fibrin deposition. References_end </body> </html> </notes> <label text="Reactive_stroma"/> <bbox w="237.5" h="91.0" x="5251.25" y="5304.5"/> </glyph> <glyph class="phenotype" id="s36_sa36"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:19937793 Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. References_end </body> </html> </notes> <label text="TUMOR_INVASION"/> <bbox w="168.0" h="75.0" x="3136.0" y="5412.5"/> </glyph> <glyph class="phenotype" id="s28_sa28"> <label text="CYTOKINE_CHEMOKINE_PRODUCTION"/> <bbox w="244.0" h="61.0" x="648.0" y="4239.5"/> </glyph> <glyph class="macromolecule" id="s44_sa43" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: lysyl oxidase HUGO:LOX hgnc_id:HGNC:6664 HGNC:6664 ENTREZ:4015 UNIPROT:P28300 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB PMID:19931152 Lysyl oxidase (LOX), a copper-dependent amine oxidase (Kagan and Li 2003) which initiates the process of covalent intra- and intermolecular crosslinking of collagen by oxidatively deaminating specific lysine and hydroxylysine residues located in the telopeptide domain. CAFs are expressing LOX, inhibiting LOX activity reduces collagen crosslinking, tempers tissue fibrosis, decreases focal adhesions, and impedes tumor progression to reduce breast tumor incidence. References_end </body> </html> </notes> <label text="LOX"/> <bbox w="80.0" h="40.0" x="5370.0" y="4380.0"/> </glyph> <glyph class="macromolecule" id="s46_sa45"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: sonic hedgehog HUGO:SHH hgnc_id:HGNC:10848 HGNC:10848 ENTREZ:6469 UNIPROT:Q15465 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:18754008 CAFs respond to Hh stimulation by increasing the production of ECM. Stromal hedgehog signalling can support tumour growth. subsets of colorectal, endometrial, ovarian and pancreatic cancers overexpressed Hh ligand mRNA (data not shown). Quantitative polymerase chain reaction with reverse transcription (RT–PCR) profiling of an independent set of human tissue specimens confirmed that the transcript levels of SHH and/or Indian hedgehog homologue (IHH) ligands were significantly upregulated in subsets of these cancers. PMID:24856585 Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth. Shh deletion results in greater vascular density and proliferation within pancreatic tumors PMID:22354771 SHH stimulates the release of ECM and induces fibrosis. SHH significantly increased the mRNA levels of COL1A1 and COL1A2 Myofibroblasts can be identified by the expression of α-SMA and the formation of stress fibers. Stimulation with SHH increased the protein levels of α-SMA in resting dermal fibroblasts in a dose-dependent manner, to a mean ± SEM of 807 ± 327% (P = 0.007) (Figures 5A and B). Consistent with the induction of α-SMA, SHH induced the formation of stress fibers in resting fibroblasts References_end </body> </html> </notes> <label text="SHH"/> <bbox w="80.0" h="40.0" x="6350.0" y="890.0"/> </glyph> <glyph class="macromolecule" id="s47_sa46"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: indian hedgehog HUGO:IHH hgnc_id:HGNC:5956 HGNC:5956 ENTREZ:3549 UNIPROT:Q14623 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:18754008 CAFs respond to Hh stimulation by increasing the production of ECM. Stromal hedgehog signalling can support tumour growth. subsets of colorectal, endometrial, ovarian and pancreatic cancers overexpressed Hh ligand mRNA (data not shown). Quantitative polymerase chain reaction with reverse transcription (RT–PCR) profiling of an independent set of human tissue specimens confirmed that the transcript levels of SHH and/or Indian hedgehog homologue (IHH) ligands were significantly upregulated in subsets of these cancers. References_end </body> </html> </notes> <label text="IHH"/> <bbox w="80.0" h="40.0" x="6440.0" y="930.0"/> </glyph> <glyph class="macromolecule" id="s48_sa47" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: GLI family zinc finger 1 HUGO:GLI1 hgnc_id:HGNC:4317 HGNC:4317 ENTREZ:2735 UNIPROT:P08151 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HH PMID:18754008 GLI1 and PTCH1 are expresed in fibroblast downstream of hedgehog (Hh) signalling. PMID:17638910 ; PMID:22354771 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 Double-staining for α-SMA and GLI1 or GLI2 demonstrated a prominent accumulation of both GLI transcription factors in myofibroblasts PMID:19081070 The vertebrate GliRepressor function is largely derived from Gli3 while the primary GliActivator activity is largely contributed by Gli2. Gli1 is a transcriptional target of Hh signaling and acts as a transcriptional activator to reinforce GliA function PMID:23031257 TGF-β1–Induced Fibroblast Differentiation Depends on SMO in Control Fibroblasts Expression of collagen and actin (alphaSMA) and FN1 are SMO and GLI1/GLI2 dependent References_end </body> </html> </notes> <label text="GLI1"/> <bbox w="80.0" h="40.0" x="5951.0" y="1840.0"/> </glyph> <glyph class="complex" id="s53_csa1" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:WWTR1:YAP1 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:25502501 yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1 (SERPINE1), which is regulated by matrix stiffness independent of transforming growth factor-β signaling. References_end </body> </html> </notes> <label text="s53"/> <bbox w="100.0" h="120.0" x="5070.0" y="2410.0"/> <glyph class="macromolecule" id="s51_sa50"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Yes associated protein 1 HUGO:YAP1 hgnc_id:HGNC:16262 HGNC:16262 ENTREZ:10413 UNIPROT:P46937 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY MODULE:CORE Maps_Modules_end References_begin: PMID:23708000 YAP is activated in cancer-associated fibroblasts in human disease YAP is required for cancer associated fibroblast function 6 out of the 14 genes with elevated mRNA levels in CAFs were found to be consistently transcriptionally regulated by YAP (AMOTL2, ANKRD1, ANLN, CTGF, DIAPH3, SDPR). ANLN, DIAPH3 and FLNA were required for CAFs to both remodel the ECM and promote invasion PMID:25502501 yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1 (SERPINE1), which is regulated by matrix stiffness independent of transforming growth factor-β signaling. PMID:26711338 Cdc42EP3 Is Required for Mechano-transduction and YAP activation References_end </body> </html> </notes> <label text="YAP1"/> <bbox w="80.0" h="40.0" x="5080.0" y="2420.0"/> </glyph> <glyph class="macromolecule" id="s52_sa51"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: WW domain containing transcription regulator 1 HUGO:WWTR1 hgnc_id:HGNC:24042 HGNC:24042 ENTREZ:25937 UNIPROT:Q9GZV5 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:25502501 yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1 (SERPINE1), which is regulated by matrix stiffness independent of transforming growth factor-β signaling. References_end </body> </html> </notes> <label text="WWTR1"/> <bbox w="80.0" h="40.0" x="5080.0" y="2460.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s54_sa52" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SERPINE1 Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="SERPINE1"/> <bbox w="90.0" h="25.0" x="2945.0" y="2367.5"/> <glyph class="unit of information" id="_2e015a5c-2478-459c-89bf-92cbb8442178"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2980.0" y="2362.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s55_sa53" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SERPINE1 Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:25502501 SERPINE1, which encodes PAI-1 and is a target of YAP/TAZ SERPINE1 and its protein product PAI-1 are well-known targets of TGF-β signaling. Exogenous TGF-β stimulates SERPINE1 expression on stiff matrices, but this effect was also attenuated by YAP/TAZ knockdown, suggesting a supportive role for YAP/TAZ in TGF-β-induced transcriptional effects References_end </body> </html> </notes> <label text="SERPINE1"/> <bbox w="70.0" h="25.0" x="2945.0" y="2297.5"/> </glyph> <glyph class="phenotype" id="s56_sa54"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:24856586 Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. References_end </body> </html> </notes> <label text="Fibrosis"/> <bbox w="170.0" h="70.0" x="5205.0" y="5025.0"/> </glyph> <glyph class="macromolecule" id="s60_sa59"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen HUGO:PLG hgnc_id:HGNC:9071 HGNC:9071 ENTREZ:5340 UNIPROT:P00747 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:20027185 Activated uPA cleaves the zymogen plasminogen, generating the protease plasmin, which reciprocally cleaves and activates pro-uPA2. References_end </body> </html> </notes> <label text="PLG"/> <bbox w="80.0" h="40.0" x="700.0" y="1380.0"/> </glyph> <glyph class="macromolecule" id="s61_sa60"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen HUGO:PLG hgnc_id:HGNC:9071 HGNC:9071 ENTREZ:5340 UNIPROT:P00747 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:20027185 Activated uPA cleaves the zymogen plasminogen, generating the protease plasmin, which reciprocally cleaves and activates pro-uPA2. References_end </body> </html> </notes> <label text="Plasmin"/> <bbox w="80.0" h="40.0" x="730.0" y="1530.0"/> <glyph class="unit of information" id="_bcde21f8-311d-4b12-9d4e-01b429c359cc"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="745.0" y="1525.0"/> </glyph> </glyph> <glyph class="phenotype" id="s62_sa61"> <label text="Matrix degradation"/> <bbox w="165.0" h="71.25" x="5497.5" y="5024.375"/> </glyph> <glyph class="phenotype" id="s63_sa62"> <label text="Angiogenesis"/> <bbox w="200.0" h="65.0" x="4040.0" y="5277.5"/> </glyph> <glyph class="macromolecule" id="s65_sa64" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-C motif chemokine ligand 5 HUGO:CCL5 hgnc_id:HGNC:10632 HGNC:10632 ENTREZ:6352 UNIPROT:P13501 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. PMID:21326202 CAFs may be the stromal source of the T cell attracting chemokine CCL5/RANTES, recruiting Treg cells into primary mammary tumors, which in turn stimulate metastatic progression CCL5 neutralization also inhibited recruitment of tumor-associated CD25+ cells in vivo Expression of CCR1, one of the cognate CCL5 receptors22, was strongly elevated in tumor CD4+ T cells relative to splenic CD4+ T cells of tumor-bearing or naïve mice. Notably, CD4+CD25+ tumor T cells expressed more Ccr1 mRNA than CD4+CD25− tumor T cells PMID:23567181 CCL5/RANTES and CCL2 secreted by CAFs isolated from human melanoma, breast and colon cancers mediated recruitment of Th17 cells from peripheral blood References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="80.0" h="40.0" x="1440.0" y="4050.0"/> </glyph> <glyph class="macromolecule" id="s67_sa66" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 14 HUGO:CXCL14 hgnc_id:HGNC:10640 HGNC:10640 ENTREZ:9547 UNIPROT:O95715 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:15261139 The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. PMID:23567181 prostate CAFs upregulate CXCL14 that functioned to promote CD68+ macrophage migration into prostate cancer xenografts References_end </body> </html> </notes> <label text="CXCL14"/> <bbox w="80.0" h="40.0" x="1060.0" y="4080.0"/> </glyph> <glyph class="macromolecule" id="s72_sa71" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: S100 calcium binding protein A4 HUGO:S100A4 hgnc_id:HGNC:10494 HGNC:10494 ENTREZ:6275 UNIPROT:P26447 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 TGFB upregulates FSP1 (S100A4) expression via Smad2 and smad3 PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1, BMP4, IL6, CXCL7, IL6R,IL6ST,CXCL5 PMID:7615639 Identification and characterization of a fibroblast marker: FSP1. PMID:20103644 Tumor infiltration of T lymphocytes is mediated in part through CAF-secreted S100A4/FSP-1 Moreover, S100A4 not only attracted T lymphocytes but also activated them, which was manifested by cytokine production: S100A4-stimulated T cells produced increased levels of distinct cytokines and growth factors including CCL5/RANTES, CXCL16, IL-4, G-CSF and MIP References_end </body> </html> </notes> <label text="S100A4"/> <bbox w="80.0" h="40.0" x="1810.0" y="4090.0"/> </glyph> <glyph class="macromolecule" id="s73_sa72" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: vimentin HUGO:VIM hgnc_id:HGNC:12692 HGNC:12692 ENTREZ:7431 UNIPROT:P08670 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:16322266, PMID:23194363 Vimentin is one of the markers of fibroblast activation References_end </body> </html> </notes> <label text="VIM"/> <bbox w="80.0" h="40.0" x="2240.0" y="4620.0"/> </glyph> <glyph class="phenotype" id="s75_sa75" compartmentRef="c5_ca5"> <label text="formation of basement membrane"/> <bbox w="275.0" h="57.5" x="5442.5" y="4481.25"/> </glyph> <glyph class="macromolecule" id="s79_sa79" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: secreted protein acidic and cysteine rich HUGO:SPARC hgnc_id:HGNC:11219 HGNC:11219 ENTREZ:6678 UNIPROT:P09486 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:17260013 SPARC prevents fibroblast activation in 293 xenografts, suggesting that the anti-cancer effects of SPARC may be due, at least in part, to the formation of tumor stroma that is not supportive of tumor growth. PMID:17235047 SPARC is a marker of fibroblast activation patients whose pancreatic cancer stromal fibroblasts expressed SPARC (median survival, 15 months) had a significantly worse prognosis than patients whose tumor stroma did not express SPARC (median survival, 30 months; In contrast, the expression of SPARC in pancreatic cancer cells was not associated with prognosis References_end </body> </html> </notes> <label text="SPARC"/> <bbox w="80.0" h="40.0" x="2140.0" y="3990.0"/> </glyph> <glyph class="macromolecule" id="s82_sa82" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: solute carrier family 16 member 4 HUGO:SLC16A4 hgnc_id:HGNC:10925 HGNC:10925 ENTREZ:9122 UNIPROT:O15374 Identifiers_end Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:22850421 CAFs have increased anaerobic glycolysis, as revealed by their increased basal glucose uptake CAFs show increased expression of MCT4 (SLC16A4), the passive lactate-proton symporter driving lactate efflux, thereby validating the idea that prostate CAFs increased their lactate production with respect to healthy HPFs. Protein level of MCT4 (SLC16A4) in CAFs is redox and HIF1 dependent. PMID:24486645 Catabolic cancer-associated fibroblasts enriched by MCT4 transfer energy and biomass to anabolic cancer cells, fueling tumor growth. PMID:23907124 Loss of Cav-1 in the stroma and gain of monocarboxylate transporter 4 (MCT4) expression in the stroma have been found to be involved in the progression of DCIS to IDC References_end </body> </html> </notes> <label text="SLC16A4"/> <bbox w="80.0" h="40.0" x="3350.0" y="4080.0"/> </glyph> <glyph class="macromolecule" id="s95_sa3" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tenascin C HUGO:TNC hgnc_id:HGNC:5318 HGNC:5318 ENTREZ:3371 UNIPROT:P24821 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:16572188 Fibroblasts can acquire an activated phenotype, which is associated with an increased proliferative activity and enhanced secretion of ECM proteins such as type I collagen and tenascin C, and also fibronectin that contains the extra domain a (EDA-fibronectin) and SPARC (secreted protein acidic and rich in cysteine). Phenotypically, activated fibroblasts are often characterized as expressing -smooth-muscle actin. Numerous growth factors such as transforming growth factor- (TGF), chemokines such as monocyte chemotactic protein 1 (MCP1), and ECM-degrading proteases have been shown to mediate the activation of fibroblasts. PMID:20833777 Tenascin-C deficiency attenuates TGF-ß-mediated fibrosis ans decrease protein level of collagen and aSMA in fibroblasts PMID:15059978 Proinvasive factors secreted by myofibroblasts are identified as TNC and SF/HGF, each of which is necessary but not sufficient for stimulation of invasion of human colon cancer cells References_end </body> </html> </notes> <label text="TNC"/> <bbox w="80.0" h="40.0" x="1770.0" y="4330.0"/> </glyph> <glyph class="macromolecule" id="s102_sa13"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: epidermal growth factor HUGO:EGF hgnc_id:HGNC:3229 HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:15175028 Epidermal growth factor induces fibronectin expression in human dermal fibroblasts via protein kinase C δ signaling pathway PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. PMID:18423981 EGF stimulates invasion of iHDF fibroblasts in collagen 3D-culture conditions, provbably via RAC activation. EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. PMID:19631971 Fibroblasts cultivated in cancer cell CM express different growth factors, bFGF mRNA and IL-1α mRNA was increased after 12 h, whereas mRNA for bFGF, HB-EGF, HGF, IGF-1, and IL-1α was increased after 24 h. EGF mRNA was not increased by the CM at any time point. PMID:21098712; TGFB induces EGF expression and secretion in fibroblasts References_end </body> </html> </notes> <label text="EGF"/> <bbox w="80.0" h="40.0" x="5120.0" y="580.0"/> </glyph> <glyph class="macromolecule" id="s103_sa10"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta 1 HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137 transforming growth factor beta 2 HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812 transforming growth factor beta 3 HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF PMID:21098712 Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:23784029, PMID:16572188, PMID:8515656 TGF-β1 treatment successfully transformed primary resting fibroblasts into CAFs PMID:19038247 TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3. Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1–3 and ERK inhibition reduces TGFβ-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGFβ [9]. Similarly, p38 MAPK has been shown to be central to TGFβ mediated-collagen and fibronectin expression in SSc fibroblasts [10]. PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:18423981 Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. PMID:23034983 Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects PMID:21041659 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts PMID:17768418 TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). ??? both TGF-β1 and TGF-β2 are up-regulated in CAFs PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, PMID:17979848 TGF-β promotes the generation and function of Treg cells TGF-β is able to convert CD4+CD25− non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3620.0" y="460.0"/> </glyph> <glyph class="macromolecule" id="s104_sa15"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 2 HUGO:FGF2 hgnc_id:HGNC:3676 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF CASCADE:FGF CASCADE:TGFB PMID:23123598 paracrine PDGF stimulation of CAFs induces production of the prototypical pro-angiogenic inducer fibroblast growth factor (FGF)-2 in both cervical carcinomas and melanoma [11] and [85]. PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling PMID:21098712; PMID:22652804; PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways PMID:9242465; PMID:19631971 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="80.0" h="40.0" x="4630.0" y="520.0"/> </glyph> <glyph class="nucleic acid feature" id="s106_sa90" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SLC16A4 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:22850421 Protein level of MCT4 (SLC16A4) in CAFs is redox and HIF1 dependent. References_end </body> </html> </notes> <label text="SLC16A4"/> <bbox w="90.0" h="25.0" x="3345.0" y="4027.5"/> <glyph class="unit of information" id="_d7a33e55-31d3-4c57-af5a-c6512fdaff3f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3380.0" y="4022.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s107_sa91" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SLC16A4 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:22850421 Protein level of MCT4 (SLC16A4) in CAFs is redox and HIF1 dependent. References_end </body> </html> </notes> <label text="SLC16A4"/> <bbox w="70.0" h="25.0" x="3355.0" y="3957.5"/> </glyph> <glyph class="macromolecule" id="s108_sa92" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: sirtuin 3 HUGO:SIRT3 hgnc_id:HGNC:14931 HGNC:14931 ENTREZ:23410 UNIPROT:Q9NTG7 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:22850421,PMID:21358671 SIRT3 is involved in the control of HIF1 expression, and redox signaling. A decrease in SIRT3 expression leads to increased superoxide dismutase 2 (SOD2) acetylation/inhibition, thereby causing ROS increase and HIF1 stabilization. SIRT3 is upregulated in normal fibroblasts and downregulated in CAFs. PMID:21109197 SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production (in vitro data) References_end </body> </html> </notes> <label text="SIRT3"/> <bbox w="80.0" h="40.0" x="2920.0" y="3300.0"/> </glyph> <glyph class="phenotype" id="s379_sa93" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:MACROPHAGE Maps_Modules_end References_begin: PMID:23204521 Mitochondrial reactive oxygen species regulate transforming growth factor-beta signaling PMID:22874531 Fibroblasts overexpressing the constitutively active TGF-β receptor kinase (RI; T204D) show increased autophagy and oxidative stress-induced aerobic glycolysis ROS production downstream of TGFB induces lactate secretion References_end </body> </html> </notes> <label text="ROS production"/> <bbox w="138.5" h="36.5" x="3200.75" y="4261.75"/> </glyph> <glyph class="nucleic acid feature" id="s109_sa95" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HIF1A Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:25732824 expression of HIF-1α was increased in CAFs, with no significant changes for HIF-2α or HIF-3α Stabilization of HIF-1α protein in induced CAF cells downstream of tgfb 5mRNA level is the same) References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="90.0" h="25.0" x="3285.0" y="3767.5"/> <glyph class="unit of information" id="_4f197b9b-0abb-46ee-9bee-fa3b78a2eb28"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3320.0" y="3762.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s110_sa94" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: hypoxia inducible factor 1 alpha subunit HUGO:HIF1A hgnc_id:HGNC:4910 HGNC:4910 ENTREZ:3091 UNIPROT:Q16665 Identifiers_end Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:22850421 Protein level of MCT4 (SLC16A4) in CAFs is redox and HIF1 dependent. PMID:20855962 HIF-1α drives Cav-1 degradation in CAFs and provides CAFs autophagy Autophagy in cancer associated fibroblasts promotes tumor cell survival: PMID:21051947 fibroblasts expressing activated HIF1α increased tumor mass by ∼2-fold and tumor volume by ∼3-fold, without an increase in angiogenesis.5 Similarly, HIF1α-transfected fibroblasts increased the lymph node metastasis of cancer cells. PMID:20535745 junD−/− fibroblasts exhibit features of carcinoma-associated myofibroblasts. The expression of the chemokine CXCL12 was increased in junD−/− fibroblasts HIF-1α protein accumulates in junD−/− fibroblasts and mice (Gerald et al, 2004; Laurent et al, 2008), the up-regulation of CXCL12 in junD−/− fibroblasts could be mediated, at least partly, through HIF. Specific inhibition of HIF-1α by siRNA strongly reduced HIF-1α mRNA levels (Fig S3A) and decreased the expression of its target gene, CXCL12 PMID:25732824 expression of HIF-1α was increased in CAFs, with no significant changes for HIF-2α or HIF-3α Stabilization of HIF-1α protein in induced CAF cells downstream of tgfb 5mRNA level is the same) References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="80.0" h="40.0" x="3290.0" y="3840.0"/> </glyph> <glyph class="nucleic acid feature" id="s111_sa96" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HIF1A Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:20535745 junD−/− fibroblasts exhibit features of carcinoma-associated myofibroblasts. The expression of the chemokine CXCL12 was increased in junD−/− fibroblasts HIF-1α protein accumulates in junD−/− fibroblasts and mice (Gerald et al, 2004; Laurent et al, 2008), the up-regulation of CXCL12 in junD−/− fibroblasts could be mediated, at least partly, through HIF. Specific inhibition of HIF-1α by siRNA strongly reduced HIF-1α mRNA levels (Fig S3A) and decreased the expression of its target gene, CXCL12 References_end </body> </html> </notes> <label text="HIF1A"/> <bbox w="70.0" h="25.0" x="3295.0" y="3707.5"/> </glyph> <glyph class="macromolecule" id="s113_sa98" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: solute carrier family 2 member 1 HUGO:SLC2A1 hgnc_id:HGNC:11005 HGNC:11005 ENTREZ:6513 UNIPROT:P11166 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:11120745 Glut1 promoter has HIF1 binding site PMID:25732824 HIF1 upregulates GLUT1 protein level SLC2A1 (GLUT1) is upregulated in CAFs. It provides enhanced glucose uptake by CAFs. References_end </body> </html> </notes> <label text="SLC2A1"/> <bbox w="80.0" h="40.0" x="3050.0" y="4760.0"/> </glyph> <glyph class="simple chemical" id="s117_sa102"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. LPA induces fibroblast proliferation. References_end </body> </html> </notes> <label text="lysophostatidic acid"/> <bbox w="70.0" h="25.0" x="5965.0" y="727.5"/> </glyph> <glyph class="nucleic acid feature" id="s118_sa103" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTA2 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HH CASCADE:HGF PMID:12702545, PMID:8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. References_end </body> </html> </notes> <label text="ACTA2"/> <bbox w="90.0" h="25.0" x="6257.75" y="3814.75"/> <glyph class="unit of information" id="_865f5f27-9b94-4001-9fc8-50ffa5a617db"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6292.75" y="3809.75"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s119_sa104" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTA2 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HGF CASCADE:HH PMID:12702545, PMID:8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. PMID:20129924 human corneal fibroblasts were transfected with small interfering RNA to alpha11, which decreased alpha-smooth muscle actin expression and myofibroblast differentiation. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation Nox4 mediates TGFB1–induced SMalpha actin in human cardiac fibroblasts. References_end </body> </html> </notes> <label text="ACTA2"/> <bbox w="70.0" h="25.0" x="6267.75" y="3753.75"/> </glyph> <glyph class="macromolecule" id="s120_sa105" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: calponin 1 HUGO:CNN1 hgnc_id:HGNC:2155 HGNC:2155 ENTREZ:1264 UNIPROT:P51911 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="CNN1"/> <bbox w="80.0" h="40.0" x="2530.0" y="4451.0"/> </glyph> <glyph class="nucleic acid feature" id="s121_sa106" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> calponin 1 HUGO:CNN1 hgnc_id:HGNC:2155 HGNC:2155 ENTREZ:1264 UNIPROT:P51911 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="CNN1"/> <bbox w="90.0" h="25.0" x="2525.0" y="4368.5"/> <glyph class="unit of information" id="_b91b7052-07f3-42f3-b277-436f962e8e80"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2560.0" y="4363.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s122_sa107" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> calponin 1 HUGO:CNN1 hgnc_id:HGNC:2155 HGNC:2155 ENTREZ:1264 UNIPROT:P51911 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="CNN1"/> <bbox w="70.0" h="25.0" x="2535.0" y="4313.5"/> </glyph> <glyph class="nucleic acid feature" id="s123_sa108" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:23031257 TGF-β1–Induced Fibroblast Differentiation Depends on SMO in Control Fibroblasts Expression of collagen and actin (alphaSMA) and FN1 are SMO and GLI1/GLI2 dependent PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="FN*"/> <bbox w="90.0" h="25.0" x="5485.0" y="4017.5"/> <glyph class="unit of information" id="_e713a11b-b3fe-43d2-bf75-2fb65ce67680"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5520.0" y="4012.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s124_sa109" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: HUGO:FN1 MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="FN*"/> <bbox w="70.0" h="25.0" x="5495.0" y="3937.5"/> </glyph> <glyph class="macromolecule" id="s125_sa110" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: endothelin 1 HUGO:EDN1 hgnc_id:HGNC:3176 HGNC:3176 ENTREZ:1906 UNIPROT:P05305 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="EDN1"/> <bbox w="80.0" h="40.0" x="2320.0" y="4451.0"/> </glyph> <glyph class="macromolecule" id="s126_sa111" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 12A HUGO:MYL12A hgnc_id:HGNC:16701 HGNC:16701 ENTREZ:10627 UNIPROT:P19105 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="MYL12A"/> <bbox w="80.0" h="40.0" x="2430.0" y="4451.0"/> </glyph> <glyph class="macromolecule" id="s127_sa112" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transgelin 2 HUGO:TAGLN2 hgnc_id:HGNC:11554 HGNC:11554 ENTREZ:8407 UNIPROT:P37802 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="TAGLN2"/> <bbox w="80.0" h="40.0" x="2000.0" y="4370.0"/> </glyph> <glyph class="macromolecule" id="s128_sa113" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: actin, gamma 2, smooth muscle, enteric HUGO:ACTG2 hgnc_id:HGNC:145 HGNC:145 ENTREZ:72 UNIPROT:P63267 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="ACTG2"/> <bbox w="80.0" h="40.0" x="6100.0" y="3910.0"/> </glyph> <glyph class="nucleic acid feature" id="s129_sa114" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTG2 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="ACTG2"/> <bbox w="70.0" h="25.0" x="6105.0" y="3747.5"/> </glyph> <glyph class="nucleic acid feature" id="s130_sa115" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTG2 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. References_end </body> </html> </notes> <label text="ACTG2"/> <bbox w="90.0" h="25.0" x="6095.0" y="3827.5"/> <glyph class="unit of information" id="_95872d1a-c6dc-4a77-bb79-a4d0fcc56c1d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6130.0" y="3822.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s131_sa116" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> myosin light chain 12A HUGO:MYL12A hgnc_id:HGNC:16701 HGNC:16701 ENTREZ:10627 UNIPROT:P19105 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="MYL12A"/> <bbox w="90.0" h="25.0" x="2427.75" y="4368.5"/> <glyph class="unit of information" id="_f307d909-573c-4df9-8ffd-78013a524ebf"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2462.75" y="4363.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s132_sa117" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> myosin light chain 12A HUGO:MYL12A hgnc_id:HGNC:16701 HGNC:16701 ENTREZ:10627 UNIPROT:P19105 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="MYL12A"/> <bbox w="70.0" h="25.0" x="2427.75" y="4313.5"/> </glyph> <glyph class="nucleic acid feature" id="s133_sa118" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> endothelin 1 HUGO:EDN1 hgnc_id:HGNC:3176 HGNC:3176 ENTREZ:1906 UNIPROT:P05305 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="EDN1"/> <bbox w="90.0" h="25.0" x="2315.0" y="4368.5"/> <glyph class="unit of information" id="_b6c13d82-f333-4f2d-aecc-5b17ff95a6ea"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2350.0" y="4363.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s134_sa119" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> endothelin 1 HUGO:EDN1 hgnc_id:HGNC:3176 HGNC:3176 ENTREZ:1906 UNIPROT:P05305 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="EDN1"/> <bbox w="70.0" h="25.0" x="2335.0" y="4313.5"/> </glyph> <glyph class="nucleic acid feature" id="s135_sa120" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TAGLN2 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="TAGLN2"/> <bbox w="90.0" h="25.0" x="1995.0" y="4297.5"/> <glyph class="unit of information" id="_73872750-6a8c-45f5-a4b0-14ac57f337bb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2030.0" y="4292.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s136_sa121" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TAGLN2 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end </body> </html> </notes> <label text="TAGLN2"/> <bbox w="70.0" h="25.0" x="2005.0" y="4217.5"/> </glyph> <glyph class="nucleic acid feature" id="s139_sa124" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FAP References_begin: CASCADE:HGF CASCADE:TGFB PMID:23034983 TGFb upregulates gene expression of FAP, probably via SMAD 3 PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA References_end </body> </html> </notes> <label text="FAP"/> <bbox w="90.0" h="25.0" x="2165.0" y="4277.5"/> <glyph class="unit of information" id="_b78bfdf9-9625-427e-a7f2-2402275029eb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2200.0" y="4272.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s140_sa125" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FAP References_begin: CASCADE:TGFB CASCADE:HGF PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:23034983; PMID:18423981 TGFb upregulates gene expression of FAP, probably via SMAD3 PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA References_end </body> </html> </notes> <label text="FAP"/> <bbox w="70.0" h="25.0" x="2175.0" y="4205.5"/> </glyph> <glyph class="macromolecule" id="s143_sa128" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: prostaglandin-endoperoxide synthase 2 HUGO:PTGS2 hgnc_id:HGNC:9605 HGNC:9605 ENTREZ:5743 UNIPROT:P35354 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to PMID:25987127; PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="80.0" h="40.0" x="1210.0" y="4270.0"/> </glyph> <glyph class="macromolecule" id="s146_sa132" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 32 HUGO:IL32 hgnc_id:HGNC:16830 HGNC:16830 ENTREZ:9235 UNIPROT:P24001 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:19509166 FGFR2, WNT2, WNT5A, WISP1, MMP1, MMP10, IGFBP2, IL8, FZD9, CD14, IL32, CXCL14, PKP2 are upregulated in CAFs, ISL1, HIST1H4K, BRCA2, BRCA1, CCNA2, CCNB2, and CDC2 are downregulated References_end </body> </html> </notes> <label text="IL32"/> <bbox w="80.0" h="40.0" x="480.0" y="3526.0"/> </glyph> <glyph class="macromolecule" id="s147_sa133" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Thy-1 cell surface antigen HUGO:THY1 hgnc_id:HGNC:11801 HGNC:11801 ENTREZ:7070 UNIPROT:P04216 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:20562849 CD90/THY1 is overexpressed in prostate cancer-associated fibroblasts and could serve as a cancer biomarker. References_end </body> </html> </notes> <label text="THY1"/> <bbox w="80.0" h="40.0" x="2110.0" y="4570.0"/> </glyph> <glyph class="macromolecule" id="s148_sa135" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: cardiotrophin like cytokine factor 1 HUGO:CLCF1 hgnc_id:HGNC:17412 HGNC:17412 ENTREZ:23529 UNIPROT:Q9UBD9 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:22962265 Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer growth in vivo. References_end </body> </html> </notes> <label text="CLCF1"/> <bbox w="80.0" h="40.0" x="730.0" y="3750.0"/> </glyph> <glyph class="macromolecule" id="s3_sa148" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 12 HUGO:CXCL12 hgnc_id:HGNC:10672 HGNC:10672 ENTREZ:6387 UNIPROT:P48061 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:CXCL12 CASCADE:TGFB CASCADE:HGF PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:15882617 CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15261139 The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. PMID:24277834 Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) PMID:21521526 Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response. References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="1020.0" y="3851.5"/> </glyph> <glyph class="macromolecule" id="s164_sa149" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 17A HUGO:IL17A hgnc_id:HGNC:5981 HGNC:5981 ENTREZ:3605 UNIPROT:Q16552 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:24323355 Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A References_end </body> </html> </notes> <label text="IL17A"/> <bbox w="80.0" h="40.0" x="680.0" y="3620.0"/> </glyph> <glyph class="macromolecule" id="s165_sa721" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 11 HUGO:IL11 hgnc_id:HGNC:5966 HGNC:5966 ENTREZ:3589 UNIPROT:P20809 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TGFB PMID:8133053 IL1a and TGFB induce gene expression and protein accamulation in fibroblasts. PMID:23153532; PMID:25074610 Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells and induces tumor invasion.. References_end </body> </html> </notes> <label text="IL11"/> <bbox w="80.0" h="40.0" x="710.0" y="3321.5"/> </glyph> <glyph class="macromolecule" id="s166_sa151" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: pro-platelet basic protein HUGO:PPBP hgnc_id:HGNC:9240 HGNC:9240 ENTREZ:5473 UNIPROT:P02775 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CXCL7"/> <bbox w="80.0" h="40.0" x="1230.0" y="3584.0"/> </glyph> <glyph class="macromolecule" id="s168_sa153" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 6 HUGO:CXCL6 hgnc_id:HGNC:10643 HGNC:10643 ENTREZ:6372 UNIPROT:P80162 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:24406209 CXCL6, like CXCL8, is involved in the recruitment of neutrophils. References_end </body> </html> </notes> <label text="CXCL6"/> <bbox w="80.0" h="40.0" x="1060.0" y="4000.0"/> </glyph> <glyph class="macromolecule" id="s169_sa154" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 8 HUGO:CXCL8 hgnc_id:HGNC:6025 HGNC:6025 ENTREZ:3576 UNIPROT:P10145 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:24406209 CXCL8 expressed by CAFs is involved in the recruitment of neutrophils. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. References_end </body> </html> </notes> <label text="CXCL8"/> <bbox w="80.0" h="40.0" x="1160.0" y="3851.5"/> </glyph> <glyph class="macromolecule" id="s170_sa155" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-C motif chemokine ligand 20 HUGO:CCL20 hgnc_id:HGNC:10619 HGNC:10619 ENTREZ:6364 UNIPROT:P78556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome References_end </body> </html> </notes> <label text="CCL20"/> <bbox w="80.0" h="40.0" x="1490.0" y="3584.0"/> </glyph> <glyph class="nucleic acid feature" id="s172_sa157" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL20 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome References_end </body> </html> </notes> <label text="CCL20"/> <bbox w="70.0" h="25.0" x="1485.0" y="3441.5"/> </glyph> <glyph class="nucleic acid feature" id="s173_sa158" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL20 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome References_end </body> </html> </notes> <label text="CCL20"/> <bbox w="90.0" h="25.0" x="1475.0" y="3517.0"/> <glyph class="unit of information" id="_6a63e4ed-314a-4fc7-9c02-0819ba330285"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1510.0" y="3512.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s174_sa159" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL8 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. References_end </body> </html> </notes> <label text="CXCL8"/> <bbox w="70.0" h="25.0" x="1165.0" y="3693.5"/> </glyph> <glyph class="nucleic acid feature" id="s175_sa160" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL8 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. References_end </body> </html> </notes> <label text="CXCL8"/> <bbox w="90.0" h="25.0" x="1155.0" y="3773.5"/> <glyph class="unit of information" id="_7ced4f16-9c88-4d62-a851-ae419d5d135d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1190.0" y="3768.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s176_sa161" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB PMID:24857661 TGF-β1-stimulated hDF was thus assessed by quantitative real-time PCR, that disclosed a 100-fold increase of LIF and 5-fold increase of IL6 mRNA steady-state levels. CASCADE:PGE PMID:8133053 IL1a and TGFB induce IL6 gene expression and protein accamulation in fibroblasts. References_end </body> </html> </notes> <label text="IL6"/> <bbox w="70.0" h="25.0" x="325.0" y="3168.5"/> </glyph> <glyph class="nucleic acid feature" id="s177_sa162" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:PGE PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB References_end </body> </html> </notes> <label text="IL6"/> <bbox w="90.0" h="25.0" x="315.0" y="3248.5"/> <glyph class="unit of information" id="_620c0494-d784-4d4f-a66a-f7baaeb3b5b9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="350.0" y="3243.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s178_sa163" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTGS2 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="90.0" h="25.0" x="1205.0" y="4207.5"/> <glyph class="unit of information" id="_d24fa7b8-0ceb-4235-a7b1-aebaac96923f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1240.0" y="4202.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s179_sa164" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTGS2 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome References_end </body> </html> </notes> <label text="PTGS2"/> <bbox w="70.0" h="25.0" x="1215.0" y="4117.5"/> </glyph> <glyph class="macromolecule" id="s180_sa165" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: indoleamine 2,3-dioxygenase 1 HUGO:IDO1 hgnc_id:HGNC:6059 HGNC:6059 ENTREZ:3620 UNIPROT:P14902 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:22182446 Increased levels of PGE2 were found in cocultured supernatants from HCC-derived fibroblasts, and up-regulated expression of IDO and COX-2 were detected in these cells. The expression of NKP30, NKG2D, granzyme B and perforin were partly restored by PGE2 inhibitor and IDO inhibitor and the production of TNF-α and IFN-γ were fully restored by them. PMID:23891282 IDO expressing fibroblasts promote the expansion of antigen specific regulatory T cells References_end </body> </html> </notes> <label text="IDO1"/> <bbox w="80.0" h="40.0" x="530.0" y="3620.0"/> </glyph> <glyph class="macromolecule" id="s181_sa167" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: galectin 1 HUGO:LGALS1 hgnc_id:HGNC:6561 HGNC:6561 ENTREZ:3956 UNIPROT:P09382 MODULE:FIBROBLAST_ACTIVATION_MARKERS Identifiers_end References_begin: PMID:21385934 Gal-1 expression is positively associated with α-SMA in the stroma of OSCC specimens. Gal-1 knockdown decreases activated CAF characteristics, resulting in a decrease in α-SMA expression and extracellular matrix protein production. Notably, blocking Gal-1 expression significantly inhibits CAF-conditioned medium-induced tumor cell migration and invasion, possibly by reducing the production of monocyte chemotactic protein-1 (MCP-1/CCL2). MCP-1 induces the migration of OSCC cells by binding to the receptor CCR2; adding an MCP-1 antibody to CAF-conditioned medium that inhibits the interaction between MCP-1 and CCR2 abolishes migration. Finally, we found that Gal-1 knockdown in CAFs significantly reduces CAF-augmented tumor growth and metastasis in vivo. collagen I, fibroblast activation protein (FAP), α-SMA, and fibronectin (FN) mRNA expression is reduced in sh-Gal-1 CAFs compared with sh-Luc CAFs. References_end </body> </html> </notes> <label text="LGALS1"/> <bbox w="80.0" h="40.0" x="2320.0" y="4190.0"/> </glyph> <glyph class="nucleic acid feature" id="s183_sa168" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL2 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:27216177 PMID:24531940 Cancer-associated fibroblasts (CAFs) have been described to play critical roles in initiation, progression and metastasis of various cancers. However, the involvement of CAFs in oral cancer (OC) has not been well addressed. In this study, we demonstrate that CAFs, when cocultured with OC cells (OCCs), produce high levels of chemokine (C-C motif) ligand 2 (CCL2) and, subsequently, enhance endogenous reactive oxygen species production in cells. Oxidative stress stimulates expression of cell cycle progression proteins in OCCs, leading to promotion of OCC proliferation, migration, invasion and, OC tumor growth. On the other hand, oxidative stress triggered the activation of nuclear factor-kappaB (NF-κB) and STAT3 in CAFs, resulting in accelerating CCL2 expression. References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="70.0" h="25.0" x="1095.0" y="3441.5"/> </glyph> <glyph class="nucleic acid feature" id="s184_sa169" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL2 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. STAT3 inducec CLL2 expression downstream of this signaling. References_end </body> </html> </notes> <label text="CCL2"/> <bbox w="90.0" h="25.0" x="1085.0" y="3517.0"/> <glyph class="unit of information" id="_efd0b7df-911c-4c10-ab2f-3a717500418e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1120.0" y="3512.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s185_sa170" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> collagen type I alpha 1 chain HUGO:COL1A1 hgnc_id:HGNC:2197 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen type I alpha 2 chain HUGO:COL1A2 hgnc_id:HGNC:2198 HGNC:2198 ENTREZ:1278 UNIPROT:P08123 collagen type II alpha 1 chain HUGO:COL2A1 hgnc_id:HGNC:2200 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 collagen type III alpha 1 chain HUGO:COL3A1 hgnc_id:HGNC:2201 HGNC:2201 ENTREZ:1281 UNIPROT:P02461 collagen type IV alpha 1 chain HUGO:COL4A1 hgnc_id:HGNC:2202 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 collagen type IV alpha 2 chain HUGO:COL4A2 hgnc_id:HGNC:2203 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 collagen type IV alpha 3 chain HUGO:COL4A3 hgnc_id:HGNC:2204 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 collagen type IV alpha 4 chain HUGO:COL4A4 hgnc_id:HGNC:2206 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 collagen type IV alpha 5 chain HUGO:COL4A5 hgnc_id:HGNC:2207 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 collagen type IV alpha 6 chain HUGO:COL4A6 hgnc_id:HGNC:2208 HGNC:2208 ENTREZ:1288 UNIPROT:Q14031 collagen type V alpha 1 chain HUGO:COL5A1 hgnc_id:HGNC:2209 HGNC:2209 ENTREZ:1289 UNIPROT:P20908 collagen type V alpha 2 chain HUGO:COL5A2 hgnc_id:HGNC:2210 HGNC:2210 ENTREZ:1290 UNIPROT:P05997 collagen type V alpha 3 chain HUGO:COL5A3 hgnc_id:HGNC:14864 HGNC:14864 ENTREZ:50509 UNIPROT:P25940 collagen type VI alpha 1 chain HUGO:COL6A1 hgnc_id:HGNC:2211 HGNC:2211 ENTREZ:1291 UNIPROT:P12109 collagen type VI alpha 2 chain HUGO:COL6A2 hgnc_id:HGNC:2212 HGNC:2212 ENTREZ:1292 UNIPROT:P12110 collagen type VI alpha 3 chain HUGO:COL6A3 hgnc_id:HGNC:2213 HGNC:2213 ENTREZ:1293 UNIPROT:P12111 collagen type VI alpha 4 pseudogene 1 HUGO:COL6A4P1 hgnc_id:HGNC:33484 HGNC:33484 ENTREZ:344875 collagen type VI alpha 4 pseudogene 2 HUGO:COL6A4P2 hgnc_id:HGNC:38501 HGNC:38501 ENTREZ:646300 collagen type VI alpha 5 chain HUGO:COL6A5 hgnc_id:HGNC:26674 HGNC:26674 ENTREZ:256076 UNIPROT:A8TX70 collagen type VI alpha 6 chain HUGO:COL6A6 hgnc_id:HGNC:27023 HGNC:27023 ENTREZ:131873 UNIPROT:A6NMZ7 collagen type VII alpha 1 chain HUGO:COL7A1 hgnc_id:HGNC:2214 HGNC:2214 ENTREZ:1294 UNIPROT:Q02388 collagen type VIII alpha 1 chain HUGO:COL8A1 hgnc_id:HGNC:2215 HGNC:2215 ENTREZ:1295 UNIPROT:P27658 collagen type VIII alpha 2 chain HUGO:COL8A2 hgnc_id:HGNC:2216 HGNC:2216 ENTREZ:1296 UNIPROT:P25067 collagen type IX alpha 1 chain HUGO:COL9A1 hgnc_id:HGNC:2217 HGNC:2217 ENTREZ:1297 UNIPROT:P20849 collagen type IX alpha 2 chain HUGO:COL9A2 hgnc_id:HGNC:2218 HGNC:2218 ENTREZ:1298 UNIPROT:Q14055 collagen type IX alpha 3 chain HUGO:COL9A3 hgnc_id:HGNC:2219 HGNC:2219 ENTREZ:1299 UNIPROT:Q14050 collagen type X alpha 1 chain HUGO:COL10A1 hgnc_id:HGNC:2185 HGNC:2185 ENTREZ:1300 UNIPROT:Q03692 collagen type XI alpha 1 chain HUGO:COL11A1 hgnc_id:HGNC:2186 HGNC:2186 ENTREZ:1301 UNIPROT:P12107 collagen type XI alpha 2 chain HUGO:COL11A2 hgnc_id:HGNC:2187 HGNC:2187 ENTREZ:1302 UNIPROT:P13942 collagen type XII alpha 1 chain HUGO:COL12A1 hgnc_id:HGNC:2188 HGNC:2188 ENTREZ:1303 UNIPROT:Q99715 collagen type XIII alpha 1 chain HUGO:COL13A1 hgnc_id:HGNC:2190 HGNC:2190 ENTREZ:1305 UNIPROT:Q5TAT6 collagen type XIV alpha 1 chain HUGO:COL14A1 hgnc_id:HGNC:2191 HGNC:2191 ENTREZ:7373 UNIPROT:Q05707 collagen type XV alpha 1 chain HUGO:COL15A1 hgnc_id:HGNC:2192 HGNC:2192 ENTREZ:1306 UNIPROT:P39059 collagen type XVI alpha 1 chain HUGO:COL16A1 hgnc_id:HGNC:2193 HGNC:2193 ENTREZ:1307 UNIPROT:Q07092 collagen type XVII alpha 1 chain HUGO:COL17A1 hgnc_id:HGNC:2194 HGNC:2194 ENTREZ:1308 UNIPROT:Q9UMD9 collagen type XVIII alpha 1 chain HUGO:COL18A1 hgnc_id:HGNC:2195 HGNC:2195 ENTREZ:80781 UNIPROT:P39060 collagen type XIX alpha 1 chain HUGO:COL19A1 hgnc_id:HGNC:2196 HGNC:2196 ENTREZ:1310 UNIPROT:Q14993 collagen type XX alpha 1 chain HUGO:COL20A1 hgnc_id:HGNC:14670 HGNC:14670 ENTREZ:57642 UNIPROT:Q9P218 collagen type XXI alpha 1 chain HUGO:COL21A1 hgnc_id:HGNC:17025 HGNC:17025 ENTREZ:81578 UNIPROT:Q96P44 collagen type XXII alpha 1 chain HUGO:COL22A1 hgnc_id:HGNC:22989 HGNC:22989 ENTREZ:169044 UNIPROT:Q8NFW1 collagen type XXIII alpha 1 chain HUGO:COL23A1 hgnc_id:HGNC:22990 HGNC:22990 ENTREZ:91522 UNIPROT:Q86Y22 collagen type XXIV alpha 1 chain HUGO:COL24A1 hgnc_id:HGNC:20821 HGNC:20821 ENTREZ:255631 UNIPROT:Q17RW2 collagen type XXV alpha 1 chain HUGO:COL25A1 hgnc_id:HGNC:18603 HGNC:18603 ENTREZ:84570 UNIPROT:Q9BXS0 collagen type XXVI alpha 1 chain HUGO:COL26A1 hgnc_id:HGNC:18038 HGNC:18038 ENTREZ:136227 UNIPROT:Q96A83 collagen type XXVII alpha 1 chain HUGO:COL27A1 hgnc_id:HGNC:22986 HGNC:22986 ENTREZ:85301 UNIPROT:Q8IZC6 collagen type XXVIII alpha 1 chain HUGO:COL28A1 hgnc_id:HGNC:22442 HGNC:22442 ENTREZ:340267 UNIPROT:Q2UY09 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IFNG CASCADE:IGF1R CASCADE:HH PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:16741519 TGFB induces collagen COL1A2 expression via 2/3 SMADs PMID:11134049 IFN-gamma abrogates TGF-beta-stimulated COL1A2 transcription in fibroblasts by inhibiting Smad activities. IFN-gamma appears to induce competition between activated Stat1alpha and Smad3 for interaction with limiting amounts of cellular p300/CBP. Overexpression of p300 restored COL1A2 stimulation by TGF-beta in the presence of IFN-gamma, and potentiated IFN-gamma-dependent positive transcriptional responses. PMID:24103846 IGFR pathway is imporatnd for fibroblast activation. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. PMID:24782617 IGF-1-induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. References_end </body> </html> </notes> <label text="Collagens*"/> <bbox w="70.0" h="25.0" x="5626.0" y="4227.5"/> </glyph> <glyph class="nucleic acid feature" id="s186_sa171" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> collagen type I alpha 1 chain HUGO:COL1A1 hgnc_id:HGNC:2197 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen type I alpha 2 chain HUGO:COL1A2 hgnc_id:HGNC:2198 HGNC:2198 ENTREZ:1278 UNIPROT:P08123 collagen type II alpha 1 chain HUGO:COL2A1 hgnc_id:HGNC:2200 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 collagen type III alpha 1 chain HUGO:COL3A1 hgnc_id:HGNC:2201 HGNC:2201 ENTREZ:1281 UNIPROT:P02461 collagen type IV alpha 1 chain HUGO:COL4A1 hgnc_id:HGNC:2202 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 collagen type IV alpha 2 chain HUGO:COL4A2 hgnc_id:HGNC:2203 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 collagen type IV alpha 3 chain HUGO:COL4A3 hgnc_id:HGNC:2204 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 collagen type IV alpha 4 chain HUGO:COL4A4 hgnc_id:HGNC:2206 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 collagen type IV alpha 5 chain HUGO:COL4A5 hgnc_id:HGNC:2207 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 collagen type IV alpha 6 chain HUGO:COL4A6 hgnc_id:HGNC:2208 HGNC:2208 ENTREZ:1288 UNIPROT:Q14031 collagen type V alpha 1 chain HUGO:COL5A1 hgnc_id:HGNC:2209 HGNC:2209 ENTREZ:1289 UNIPROT:P20908 collagen type V alpha 2 chain HUGO:COL5A2 hgnc_id:HGNC:2210 HGNC:2210 ENTREZ:1290 UNIPROT:P05997 collagen type V alpha 3 chain HUGO:COL5A3 hgnc_id:HGNC:14864 HGNC:14864 ENTREZ:50509 UNIPROT:P25940 collagen type VI alpha 1 chain HUGO:COL6A1 hgnc_id:HGNC:2211 HGNC:2211 ENTREZ:1291 UNIPROT:P12109 collagen type VI alpha 2 chain HUGO:COL6A2 hgnc_id:HGNC:2212 HGNC:2212 ENTREZ:1292 UNIPROT:P12110 collagen type VI alpha 3 chain HUGO:COL6A3 hgnc_id:HGNC:2213 HGNC:2213 ENTREZ:1293 UNIPROT:P12111 collagen type VI alpha 4 pseudogene 1 HUGO:COL6A4P1 hgnc_id:HGNC:33484 HGNC:33484 ENTREZ:344875 collagen type VI alpha 4 pseudogene 2 HUGO:COL6A4P2 hgnc_id:HGNC:38501 HGNC:38501 ENTREZ:646300 collagen type VI alpha 5 chain HUGO:COL6A5 hgnc_id:HGNC:26674 HGNC:26674 ENTREZ:256076 UNIPROT:A8TX70 collagen type VI alpha 6 chain HUGO:COL6A6 hgnc_id:HGNC:27023 HGNC:27023 ENTREZ:131873 UNIPROT:A6NMZ7 collagen type VII alpha 1 chain HUGO:COL7A1 hgnc_id:HGNC:2214 HGNC:2214 ENTREZ:1294 UNIPROT:Q02388 collagen type VIII alpha 1 chain HUGO:COL8A1 hgnc_id:HGNC:2215 HGNC:2215 ENTREZ:1295 UNIPROT:P27658 collagen type VIII alpha 2 chain HUGO:COL8A2 hgnc_id:HGNC:2216 HGNC:2216 ENTREZ:1296 UNIPROT:P25067 collagen type IX alpha 1 chain HUGO:COL9A1 hgnc_id:HGNC:2217 HGNC:2217 ENTREZ:1297 UNIPROT:P20849 collagen type IX alpha 2 chain HUGO:COL9A2 hgnc_id:HGNC:2218 HGNC:2218 ENTREZ:1298 UNIPROT:Q14055 collagen type IX alpha 3 chain HUGO:COL9A3 hgnc_id:HGNC:2219 HGNC:2219 ENTREZ:1299 UNIPROT:Q14050 collagen type X alpha 1 chain HUGO:COL10A1 hgnc_id:HGNC:2185 HGNC:2185 ENTREZ:1300 UNIPROT:Q03692 collagen type XI alpha 1 chain HUGO:COL11A1 hgnc_id:HGNC:2186 HGNC:2186 ENTREZ:1301 UNIPROT:P12107 collagen type XI alpha 2 chain HUGO:COL11A2 hgnc_id:HGNC:2187 HGNC:2187 ENTREZ:1302 UNIPROT:P13942 collagen type XII alpha 1 chain HUGO:COL12A1 hgnc_id:HGNC:2188 HGNC:2188 ENTREZ:1303 UNIPROT:Q99715 collagen type XIII alpha 1 chain HUGO:COL13A1 hgnc_id:HGNC:2190 HGNC:2190 ENTREZ:1305 UNIPROT:Q5TAT6 collagen type XIV alpha 1 chain HUGO:COL14A1 hgnc_id:HGNC:2191 HGNC:2191 ENTREZ:7373 UNIPROT:Q05707 collagen type XV alpha 1 chain HUGO:COL15A1 hgnc_id:HGNC:2192 HGNC:2192 ENTREZ:1306 UNIPROT:P39059 collagen type XVI alpha 1 chain HUGO:COL16A1 hgnc_id:HGNC:2193 HGNC:2193 ENTREZ:1307 UNIPROT:Q07092 collagen type XVII alpha 1 chain HUGO:COL17A1 hgnc_id:HGNC:2194 HGNC:2194 ENTREZ:1308 UNIPROT:Q9UMD9 collagen type XVIII alpha 1 chain HUGO:COL18A1 hgnc_id:HGNC:2195 HGNC:2195 ENTREZ:80781 UNIPROT:P39060 collagen type XIX alpha 1 chain HUGO:COL19A1 hgnc_id:HGNC:2196 HGNC:2196 ENTREZ:1310 UNIPROT:Q14993 collagen type XX alpha 1 chain HUGO:COL20A1 hgnc_id:HGNC:14670 HGNC:14670 ENTREZ:57642 UNIPROT:Q9P218 collagen type XXI alpha 1 chain HUGO:COL21A1 hgnc_id:HGNC:17025 HGNC:17025 ENTREZ:81578 UNIPROT:Q96P44 collagen type XXII alpha 1 chain HUGO:COL22A1 hgnc_id:HGNC:22989 HGNC:22989 ENTREZ:169044 UNIPROT:Q8NFW1 collagen type XXIII alpha 1 chain HUGO:COL23A1 hgnc_id:HGNC:22990 HGNC:22990 ENTREZ:91522 UNIPROT:Q86Y22 collagen type XXIV alpha 1 chain HUGO:COL24A1 hgnc_id:HGNC:20821 HGNC:20821 ENTREZ:255631 UNIPROT:Q17RW2 collagen type XXV alpha 1 chain HUGO:COL25A1 hgnc_id:HGNC:18603 HGNC:18603 ENTREZ:84570 UNIPROT:Q9BXS0 collagen type XXVI alpha 1 chain HUGO:COL26A1 hgnc_id:HGNC:18038 HGNC:18038 ENTREZ:136227 UNIPROT:Q96A83 collagen type XXVII alpha 1 chain HUGO:COL27A1 hgnc_id:HGNC:22986 HGNC:22986 ENTREZ:85301 UNIPROT:Q8IZC6 collagen type XXVIII alpha 1 chain HUGO:COL28A1 hgnc_id:HGNC:22442 HGNC:22442 ENTREZ:340267 UNIPROT:Q2UY09 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IFNG CASCADE:IGF1R CASCADE:HH PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 References_end </body> </html> </notes> <label text="Collagens*"/> <bbox w="90.0" h="25.0" x="5615.0" y="4317.5"/> <glyph class="unit of information" id="_a0446efa-86c7-48b6-900a-fb99f9b2b416"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5650.0" y="4312.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s188_sa173" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL1 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 PMID:23567181 inhibition of NF-κB signaling, driving expression of CXCL1 and CXCL2 in skin CAFs resulted in decreased macrophage infiltration into transplanted skin tumors, and reduced tumor growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumors PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs probably downstream of IL1B via NFkB References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="70.0" h="25.0" x="975.0" y="3441.5"/> </glyph> <glyph class="nucleic acid feature" id="s189_sa174" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL1 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 PMID:23567181 inhibition of NF-κB signaling, driving expression of CXCL1 and CXCL2 in skin CAFs resulted in decreased macrophage infiltration into transplanted skin tumors, and reduced tumor growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumors References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="90.0" h="25.0" x="965.0" y="3517.0"/> <glyph class="unit of information" id="_a9eb8da7-d049-4ee4-a6d3-74b2d1bf5e5e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1000.0" y="3512.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s190_sa175" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 1 HUGO:CXCL1 hgnc_id:HGNC:4602 HGNC:4602 ENTREZ:2919 UNIPROT:P09341 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 PMID:23567181 inhibition of NF-κB signaling, driving expression of CXCL1 and CXCL2 in skin CAFs resulted in decreased macrophage infiltration into transplanted skin tumors, and reduced tumor growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumors References_end </body> </html> </notes> <label text="CXCL1"/> <bbox w="80.0" h="40.0" x="970.0" y="3584.0"/> </glyph> <glyph class="macromolecule" id="s191_sa176" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-C motif chemokine ligand 3 HUGO:CCL3 hgnc_id:HGNC:10627 HGNC:10627 ENTREZ:6348 UNIPROT:P10147 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="80.0" h="40.0" x="880.0" y="3851.5"/> </glyph> <glyph class="nucleic acid feature" id="s192_sa177" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL5 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="90.0" h="25.0" x="1435.0" y="3993.5"/> <glyph class="unit of information" id="_8bd96647-4da6-459e-91be-ee43bccddee9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1470.0" y="3988.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s193_sa178" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL5 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="70.0" h="25.0" x="1445.0" y="3933.5"/> </glyph> <glyph class="nucleic acid feature" id="s194_sa179" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL3 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="70.0" h="25.0" x="885.0" y="3693.5"/> </glyph> <glyph class="nucleic acid feature" id="s195_sa180" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL3 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="CCL3"/> <bbox w="90.0" h="25.0" x="875.0" y="3773.5"/> <glyph class="unit of information" id="_4cf0321c-93d8-4b9e-a1a5-b754d6307df2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="910.0" y="3768.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s196_sa181" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 2 HUGO:CXCL2 hgnc_id:HGNC:4603 HGNC:4603 ENTREZ:2920 UNIPROT:P19875 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 PMID:23567181 inhibition of NF-κB signaling, driving expression of CXCL1 and CXCL2 in skin CAFs resulted in decreased macrophage infiltration into transplanted skin tumors, and reduced tumor growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumors References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="80.0" h="40.0" x="850.0" y="3584.0"/> </glyph> <glyph class="nucleic acid feature" id="s197_sa182" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL2 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 PMID:23567181 inhibition of NF-κB signaling, driving expression of CXCL1 and CXCL2 in skin CAFs resulted in decreased macrophage infiltration into transplanted skin tumors, and reduced tumor growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumors References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="90.0" h="25.0" x="845.0" y="3517.0"/> <glyph class="unit of information" id="_f38c4cbb-ed24-45ac-9b8d-6750376a9c96"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="880.0" y="3512.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s198_sa183" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL2 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 PMID:23567181 inhibition of NF-κB signaling, driving expression of CXCL1 and CXCL2 in skin CAFs resulted in decreased macrophage infiltration into transplanted skin tumors, and reduced tumor growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumors References_end </body> </html> </notes> <label text="CXCL2"/> <bbox w="70.0" h="25.0" x="855.0" y="3441.5"/> </glyph> <glyph class="macromolecule" id="s201_sa186" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: secreted phosphoprotein 1 HUGO:SPP1 hgnc_id:HGNC:11255 HGNC:11255 ENTREZ:6696 UNIPROT:P10451 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF PMID:19118022 fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts. PMID:20138012 SPP1 (OPN) , COX2, CXCL1, CXCL2, CYR61, IL1B, IL6 genes are upregulated in CAFs PMID:25099519 Tumor α9β1 integrin, contributes to tumor growth, lymphatic metastasis, recruitment of cancer-associated fibroblasts (CAFs), and host-derived OPN production. We also found that CAFs contributed to tumor growth, lymphatic metastasis, and host-derived OPN levels. Consistent with those findings, tumor volume was well-correlated with numbers of CAFs and levels of host-derived OPN. Furthermore, it was shown that the inoculation of D3H2LN cells into mammary fat pads with mouse embryonic fibroblasts (MEFs), obtained from wild type, but not OPN knock-out mice, resulted in enhancement of tumor growth, thus indicating that CAF-derived OPN enhanced tumor growth. References_end </body> </html> </notes> <label text="SPP1"/> <bbox w="80.0" h="40.0" x="4090.0" y="3580.0"/> </glyph> <glyph class="macromolecule" id="s202_sa187" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: cysteine rich angiogenic inducer 61 HUGO:CYR61 hgnc_id:HGNC:2654 HGNC:2654 ENTREZ:3491 UNIPROT:O00622 Identifiers_end Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:20138012 SPP1 (OPN) , COX2, CXCL1, CXCL2, CYR61, IL1B, IL6 genes are upregulated in CAFs References_end </body> </html> </notes> <label text="CYR61"/> <bbox w="80.0" h="40.0" x="2300.0" y="4700.0"/> </glyph> <glyph class="macromolecule" id="s203_sa188" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: hyaluronan synthase 2 HUGO:HAS2 hgnc_id:HGNC:4819 HGNC:4819 ENTREZ:3037 UNIPROT:Q92819 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:20823158 CAFs have been identified as a source of hyaluronan, and genetic ablation of the hyaluronan synthase gene (Has2) in fibroblasts strongly diminishes the entry of macrophages into the tumour microenvironment. References_end </body> </html> </notes> <label text="HAS2"/> <bbox w="80.0" h="40.0" x="5640.0" y="4700.0"/> </glyph> <glyph class="phenotype" id="s71_sa70"> <label text="FIBROBLAST_MARKERS"/> <bbox w="210.0" h="60.0" x="2335.0" y="5220.0"/> </glyph> <glyph class="phenotype" id="s404_sa197"> <label text="MATRIX_EFFECTS"/> <bbox w="350.0" h="57.5" x="5885.0" y="5361.25"/> </glyph> <glyph class="macromolecule" id="s1331_sa245" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 4 HUGO:SMAD4 hgnc_id:HGNC:6770 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts PMID:12702545 Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="3810.0" y="1740.0"/> </glyph> <glyph class="macromolecule" id="s1359_sa248" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 2 HUGO:SMAD2 hgnc_id:HGNC:6768 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts. For the TGF-β pathway, the Smad proteins, Smad2 and Smad3, are ligand-responsive PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="3690.0" y="1685.0"/> <glyph class="state variable" id="_9a153da9-88d4-43a5-820a-cbae9ba39501"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3685.0" y="1699.9681"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1376_sa249" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:16713975 SMAD2, SMAD3 and SMAD4 participate in suppression of TBX21 (T-BET) promoter activity downstream of TGFB. costimulation of NK cells with IL-12 and IL-18 downregulated SMAD2 transcript. References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="90.0" h="25.0" x="3915.0" y="1557.5"/> <glyph class="unit of information" id="_910e5206-d921-43c7-bbf7-ddc77042fe8a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3950.0" y="1552.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s1312_sa252" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 3 HUGO:SMAD3 hgnc_id:HGNC:6769 HGNC:6769 ENTREZ:4088 UNIPROT:P84022 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:12702545, PMID:8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="3920.0" y="1635.0"/> <glyph class="state variable" id="_a4290193-c337-48df-8eda-b672d927b8c4"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3915.0" y="1650.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1310_sa254" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:TGFB PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="90.0" h="25.0" x="3645.0" y="4607.5"/> <glyph class="unit of information" id="_1428688b-2c67-4f34-a71c-6c3587a1405c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3680.0" y="4602.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1373_sa256" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: PMID:16713975 IL12,IL15 and IL18 significantly suppresse TGF-BRII mRNA expression. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="90.0" h="25.0" x="3645.0" y="1447.5"/> <glyph class="unit of information" id="_f892acdb-312c-4781-ae1c-014f957f1f58"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3680.0" y="1442.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1372_sa257" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: PMID:16713975 IL12,IL15 and IL18 significantly suppresse TGF-BRII mRNA expression and inhibit downstream signaling. References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="70.0" h="25.0" x="3655.0" y="1507.5"/> </glyph> <glyph class="complex" id="s1360_csa11" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SMAD2:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 TGFB upregulates FSP1 (S100A4) expression via Smad2 and smad3 Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. References_end </body> </html> </notes> <label text="s1360"/> <bbox w="100.0" h="120.0" x="3760.0" y="1855.0"/> <glyph class="macromolecule" id="s1361_sa260"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 4 HUGO:SMAD4 hgnc_id:HGNC:6770 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts PMID:12702545 Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="3770.0" y="1915.0"/> </glyph> <glyph class="macromolecule" id="s1362_sa261"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 2 HUGO:SMAD2 hgnc_id:HGNC:6768 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts. For the TGF-β pathway, the Smad proteins, Smad2 and Smad3, are ligand-responsive PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="3770.0" y="1865.0"/> <glyph class="state variable" id="_12cec814-911f-403c-910f-8268c2bd19bb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3762.5" y="1879.9681"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1320_csa13" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TGFB*:TGFBR1:TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB 15265520, 11792802, 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation References_end </body> </html> </notes> <label text="s1320"/> <bbox w="120.0" h="170.0" x="3880.0" y="1005.0"/> <glyph class="macromolecule" id="s1322_sa264"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor beta receptor 1 HUGO:TGFBR1 hgnc_id:HGNC:11772 HGNC:11772 ENTREZ:7046 UNIPROT:P36897 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110, PMID:15265520 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end </body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="3900.0" y="1065.0"/> <glyph class="unit of information" id="_8ec9f8db-a026-4f81-b8a0-11e72931b890"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3917.5" y="1060.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1321_sa265"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor beta receptor 2 HUGO:TGFBR2 hgnc_id:HGNC:11773 HGNC:11773 ENTREZ:7048 UNIPROT:P37173 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110,PMID:15265520 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:24336330 TGFBR2 in CAFs References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="3900.0" y="1115.0"/> <glyph class="state variable" id="_5491b7d3-4736-479d-9122-23b3cb5c93c2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3895.0" y="1135.0"/> </glyph> <glyph class="unit of information" id="_3a76ece4-c4e1-473e-a6e1-21a364c98847"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3917.5" y="1110.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s407_sa267"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta 1 HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137 transforming growth factor beta 2 HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812 transforming growth factor beta 3 HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF PMID:21098712 Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:23784029, PMID:16572188, PMID:8515656 TGF-β1 treatment successfully transformed primary resting fibroblasts into CAFs PMID:19038247 TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3. Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1–3 and ERK inhibition reduces TGFβ-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGFβ [9]. Similarly, p38 MAPK has been shown to be central to TGFβ mediated-collagen and fibronectin expression in SSc fibroblasts [10]. PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:18423981 Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. PMID:23034983 Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects PMID:21041659 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts PMID:17768418 TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). ??? both TGF-β1 and TGF-β2 are up-regulated in CAFs PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, PMID:17979848 TGF-β promotes the generation and function of Treg cells TGF-β is able to convert CD4+CD25− non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3900.0" y="1020.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s408_sa268" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 7 HUGO:SMAD7 hgnc_id:HGNC:6773 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: CASCADE:TGFB _INHIBITION_ANTITUMOR PMID:15265520,PMID:14722617 SMAD7 has been shown to interact with the E3 ubiquitin ligases Smurf 1 and Smurf 2, recruiting them to TβR complexes and inducing the degradation of activated TβRI [20] and [21]. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="SMAD7"/> <bbox w="80.0" h="40.0" x="3130.0" y="2560.0"/> </glyph> <glyph class="source and sink" id="s409_sa269" compartmentRef="c5_ca5"> <label text="sa259_degraded"/> <bbox w="30.0" h="30.0" x="3724.0" y="1235.0"/> </glyph> <glyph class="macromolecule" id="s1326_sa246" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 3 HUGO:SMAD3 hgnc_id:HGNC:6769 HGNC:6769 ENTREZ:4088 UNIPROT:P84022 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:12702545, PMID:8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="3920.0" y="1705.0"/> <glyph class="state variable" id="_27bd2bbb-addf-4033-a3a4-ba5251aa7662"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3912.5" y="1720.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s410_sa270" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TIMP1 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL6 CASCADE:LIF CASCADE:IL1 PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:8515078; PMID:8559663 OMS, IL-6, LIF, and IL-1 alpha elevated the TIMP-1 expression at the RNA level in fibroblasts probably via STAT3 PMID:16834928 TIMP1 expression in fibroblasts is STAT3 dependent References_end </body> </html> </notes> <label text="TIMP1"/> <bbox w="70.0" h="25.0" x="5510.0" y="4228.75"/> </glyph> <glyph class="nucleic acid feature" id="s411_sa271" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TIMP1 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL6 CASCADE:LIF CASCADE:IL1 PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 References_end </body> </html> </notes> <label text="TIMP1"/> <bbox w="90.0" h="25.0" x="5500.0" y="4308.75"/> <glyph class="unit of information" id="_f19439b2-b3f3-404c-a43f-d383baffe24f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5535.0" y="4303.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s412_sa272" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TIMP metallopeptidase inhibitor 1 HUGO:TIMP1 hgnc_id:HGNC:11820 HGNC:11820 ENTREZ:7076 UNIPROT:P01033 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL6 CASCADE:LIF CASCADE:IL1 PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 References_end </body> </html> </notes> <label text="TIMP1"/> <bbox w="80.0" h="40.0" x="5505.0" y="4381.25"/> </glyph> <glyph class="macromolecule" id="s415_sa275" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: epidermal growth factor receptor HUGO:EGFR hgnc_id:HGNC:3236 HGNC:3236 ENTREZ:1956 UNIPROT:P00533 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25987127; PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist References_end </body> </html> </notes> <label text="EGFR"/> <bbox w="80.0" h="50.0" x="5180.0" y="1095.0"/> <glyph class="unit of information" id="_65a4b6d9-82fc-4492-92aa-e027efc66236"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5197.5" y="1090.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s416_sa276" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: erb-b2 receptor tyrosine kinase 2 HUGO:ERBB2 hgnc_id:HGNC:3430 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 erb-b2 receptor tyrosine kinase 3 HUGO:ERBB3 hgnc_id:HGNC:3431 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 erb-b2 receptor tyrosine kinase 4 HUGO:ERBB4 hgnc_id:HGNC:3432 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:10404636 EGFR interacts with most members of the c-erbB subfamily of RPTK. References_end </body> </html> </notes> <label text="ERBB*"/> <bbox w="80.0" h="50.0" x="5120.0" y="1025.0"/> <glyph class="unit of information" id="_8429a943-445d-4a77-9d95-d07488a535f9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5137.5" y="1020.0"/> </glyph> </glyph> <glyph class="complex" id="s417_csa14" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PDGF*:PDGFR* Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling References_end </body> </html> </notes> <label text="s417"/> <bbox w="100.0" h="130.0" x="4380.0" y="1125.0"/> <glyph class="macromolecule" id="s413_sa273"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS HUGO:PDGFRA HUGO:PDGFRB Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:LIF CASCADE:TGFB PMID:19118022 Fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts probably via PDGFR-α. PMID:24857661 we noted an increased expression of PDGFRα after LIF stimulation in hPDF PMID:15229650 PDGFR alpha signaling is required for the recruitment of VEGF-producing stromal fibroblasts for tumor angiogenesis and growth PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling References_end </body> </html> </notes> <label text="PDGFR*"/> <bbox w="80.0" h="50.0" x="4390.0" y="1185.0"/> <glyph class="unit of information" id="_1bdf8f59-8416-4ff1-83bb-6a59925f1f22"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4407.5" y="1180.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s424_sa281"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: platelet derived growth factor subunit A HUGO:PDGFA hgnc_id:HGNC:8799 HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet derived growth factor subunit B HUGO:PDGFB hgnc_id:HGNC:8800 HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC hgnc_id:HGNC:8801 HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:23123598 paracrine PDGF stimulation of CAFs induces production of the prototypical pro-angiogenic inducer fibroblast growth factor (FGF)-2 in both cervical carcinomas and melanoma [11] and [85]. Interestingly, CAFs activated by PDGF-CC in melanomas also secrete the extracellular matrix protein osteopontin, the action of which is known to synergistically stimulate angiogenesis together with FGF-2 and promote autocrine VEGF-A signaling in endothelial cells PMID:15207817; PMID:19118022 PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Tumor fibroblasts a recruted by PDGF PMID:18232728 Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. PMID:19111878 PDGF-C is upregulated in TAFs derived from refractory tumors and that PDGF-C, together with VEGF-A, mediates the angiogenesis induced by such TAFs in vivo. This study also demonstrates that inhibition of PDGF-C may reduce tumor angiogenesis and growth in vivo. PMID:26921338 TGFB induces expression of PDGFB and PDGFR in CAFs and indirectly suppresses PEDF expression via PDGFB signaling References_end </body> </html> </notes> <label text="PDGF*"/> <bbox w="80.0" h="40.0" x="4390.0" y="1140.0"/> </glyph> </glyph> <glyph class="complex" id="s419_csa16" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:EGFR:ERBB* Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end </body> </html> </notes> <label text="s419"/> <bbox w="100.0" h="142.5" x="4940.0" y="1098.0"/> <glyph class="macromolecule" id="s421_sa278"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: epidermal growth factor receptor HUGO:EGFR hgnc_id:HGNC:3236 HGNC:3236 ENTREZ:1956 UNIPROT:P00533 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25987127; PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist References_end </body> </html> </notes> <label text="EGFR"/> <bbox w="80.0" h="50.0" x="4950.0" y="1115.5"/> <glyph class="unit of information" id="_e0132628-e0ed-4cff-b86d-66c45e7f7545"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4967.5" y="1110.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s422_sa279"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: erb-b2 receptor tyrosine kinase 2 HUGO:ERBB2 hgnc_id:HGNC:3430 HGNC:3430 ENTREZ:2064 UNIPROT:P04626 erb-b2 receptor tyrosine kinase 3 HUGO:ERBB3 hgnc_id:HGNC:3431 HGNC:3431 ENTREZ:2065 UNIPROT:P21860 erb-b2 receptor tyrosine kinase 4 HUGO:ERBB4 hgnc_id:HGNC:3432 HGNC:3432 ENTREZ:2066 UNIPROT:Q15303 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:10404636 EGFR interacts with most members of the c-erbB subfamily of RPTK. References_end </body> </html> </notes> <label text="ERBB*"/> <bbox w="80.0" h="50.0" x="4950.0" y="1165.5"/> <glyph class="unit of information" id="_82da6f4f-f027-44fd-9194-f51fe9682c14"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4967.5" y="1160.5"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s423_sa280" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS HUGO:PDGFRA HUGO:PDGFRB Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:LIF CASCADE:TGFB PMID:19118022 Fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts probably via PDGFR-α. PMID:24857661 we noted an increased expression of PDGFRα after LIF stimulation in hPDF PMID:15229650 PDGFR alpha signaling is required for the recruitment of VEGF-producing stromal fibroblasts for tumor angiogenesis and growth PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling References_end </body> </html> </notes> <label text="PDGFR*"/> <clone/> <bbox w="80.0" h="50.0" x="4510.0" y="1125.0"/> <glyph class="unit of information" id="_e657ff85-6749-4087-a846-046a7659617e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4527.5" y="1120.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s423_sa1170" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS HUGO:PDGFRA HUGO:PDGFRB Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:LIF CASCADE:TGFB PMID:19118022 Fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts probably via PDGFR-α. PMID:24857661 we noted an increased expression of PDGFRα after LIF stimulation in hPDF PMID:15229650 PDGFR alpha signaling is required for the recruitment of VEGF-producing stromal fibroblasts for tumor angiogenesis and growth PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling References_end </body> </html> </notes> <label text="PDGFR*"/> <clone/> <bbox w="80.0" h="50.0" x="2020.0" y="4625.0"/> <glyph class="unit of information" id="_ed690c8f-98f9-45ca-a7ca-e856a1821f74"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2037.5" y="4620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1305_sa284"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: macrophage migration inhibitory factor HUGO:MIF hgnc_id:HGNC:7097 HGNC:7097 ENTREZ:4282 UNIPROT:P14174 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:MIF PMID:12782713 CD74 mediates MIF stimulation of ERK-1/2 (p44/p42) phosphorylation and proliferation of CCL210 human lung fibroblasts. PMID:20861157 MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="4090.0" y="500.0"/> </glyph> <glyph class="macromolecule" id="s3580_sa285" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: CD74 molecule HUGO:CD74 hgnc_id:HGNC:1697 HGNC:1697 ENTREZ:972 UNIPROT:P04233 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:MIF PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation. References_end </body> </html> </notes> <label text="CD74"/> <bbox w="80.0" h="40.0" x="4100.0" y="1110.0"/> </glyph> <glyph class="complex" id="s3581_csa17" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CD74:MIF Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:MIF PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 mediates MIF stimulation of ERK-1/2 (p44/p42) phosphorylation and proliferation of CCL210 human lung fibroblasts.. References_end </body> </html> </notes> <label text="s3581"/> <bbox w="110.0" h="140.0" x="4225.0" y="1150.0"/> <glyph class="macromolecule" id="s3583_sa286"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: macrophage migration inhibitory factor HUGO:MIF hgnc_id:HGNC:7097 HGNC:7097 ENTREZ:4282 UNIPROT:P14174 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:MIF PMID:12782713 CD74 mediates MIF stimulation of ERK-1/2 (p44/p42) phosphorylation and proliferation of CCL210 human lung fibroblasts. PMID:20861157 MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. References_end </body> </html> </notes> <label text="MIF"/> <bbox w="80.0" h="40.0" x="4240.0" y="1160.0"/> </glyph> <glyph class="macromolecule" id="s3582_sa287"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: CD74 molecule HUGO:CD74 hgnc_id:HGNC:1697 HGNC:1697 ENTREZ:972 UNIPROT:P04233 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:MIF PMID:12782713 MIF signal transduction initiated by binding to CD74. CD74 Mediates MIF Induction of ERK-1/2 Phosphorylation, PGE2 Production, and Proliferation. References_end </body> </html> </notes> <label text="CD74"/> <bbox w="80.0" h="40.0" x="4240.0" y="1210.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2453_sa295" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NFKB inhibitor alpha HUGO:NFKBIA hgnc_id:HGNC:7797 HGNC:7797 ENTREZ:4792 UNIPROT:P25963 NFKB inhibitor beta HUGO:NFKBIB hgnc_id:HGNC:7798 HGNC:7798 ENTREZ:4793 UNIPROT:Q15653 NFKB inhibitor epsilon HUGO:NFKBIE hgnc_id:HGNC:7799 HGNC:7799 ENTREZ:4794 UNIPROT:O00221 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="1670.0" y="2540.0"/> <glyph class="state variable" id="_78d3f3de-c327-4019-a78a-e7d1fd05a506"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1665.0" y="2555.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2452_sa297" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELB proto-oncogene, NF-kB subunit HUGO:RELB hgnc_id:HGNC:9956 HGNC:9956 ENTREZ:5971 UNIPROT:Q01201 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:18697742 RelB is constitutively expressed in mouse lung fibroblasts. PMID:10523657 RelB is an important transcription suppressor in fibroblasts which limits the expression of proinflammatory mediators and may exert its function by modulating the stability Fibroblasts from relb(-/-) mice overexpress interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in response to lipopolysaccharide (LPS) stimulation. These cells have an augmented and prolonged LPS-inducible IKK activity and an accelerated degradation which results in a diminished level of IkappaBalpha protein, despite an upregulated IkappaBalpha mRNA expression. References_end </body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="40.0" x="2105.0" y="2530.0"/> </glyph> <glyph class="macromolecule" id="s81_sa300" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NFKB inhibitor alpha HUGO:NFKBIA hgnc_id:HGNC:7797 HGNC:7797 ENTREZ:4792 UNIPROT:P25963 NFKB inhibitor beta HUGO:NFKBIB hgnc_id:HGNC:7798 HGNC:7798 ENTREZ:4793 UNIPROT:Q15653 NFKB inhibitor epsilon HUGO:NFKBIE hgnc_id:HGNC:7799 HGNC:7799 ENTREZ:4794 UNIPROT:O00221 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="1680.0" y="3200.0"/> <glyph class="state variable" id="_9228dc83-08f8-45ba-8606-a5dc1ecf60e7"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="1672.5" y="3215.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3465_sa304" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELA proto-oncogene, NF-kB subunit HUGO:RELA hgnc_id:HGNC:9955 HGNC:9955 ENTREZ:5970 UNIPROT:Q04206 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 CASCADE:TNF MODULE:CORE PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice References_end Maps_Modules_end </body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="2340.0" y="2530.0"/> </glyph> <glyph class="complex" id="s647_csa19" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IKBKG:IKK_alpha_*:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID‭:15145317, PMID:15573129 The activated IKK complex, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="2080.0" y="2038.0"/> <glyph class="macromolecule" id="s89_sa309"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: inhibitor of nuclear factor kappa B kinase subunit gamma HUGO:IKBKG hgnc_id:HGNC:5961 HGNC:5961 ENTREZ:8517 UNIPROT:Q9Y6K9 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="2088.0" y="2045.0"/> <glyph class="state variable" id="_049e6264-7762-49eb-894b-4368be43ea7e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2163.0" y="2060.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3611_sa310"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: inhibitor of nuclear factor kappa B kinase subunit beta HUGO:IKBKB hgnc_id:HGNC:5960 HGNC:5960 ENTREZ:3551 UNIPROT:O14920 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="2090.0" y="2090.0"/> <glyph class="state variable" id="_cfebc163-0abe-4308-ac47-471d4110bdd8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2085.0" y="2105.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3610_sa311"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: conserved helix-loop-helix ubiquitous kinase HUGO:CHUK hgnc_id:HGNC:1974 HGNC:1974 ENTREZ:1147 UNIPROT:O15111 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKKα*"/> <bbox w="80.0" h="40.0" x="2091.0" y="2135.0"/> <glyph class="state variable" id="_1a89f11b-50db-43c2-b787-518fd2f33762"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2086.0" y="2150.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3590_csa21" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IkB*:NFKB1_p50*:RELB Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s29"/> <bbox w="105.0" h="155.0" x="1937.0" y="2762.0"/> <glyph class="macromolecule" id="s2292_sa315"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELB proto-oncogene, NF-kB subunit HUGO:RELB hgnc_id:HGNC:9956 HGNC:9956 ENTREZ:5971 UNIPROT:Q01201 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:18697742 RelB is constitutively expressed in mouse lung fibroblasts. PMID:10523657 RelB is an important transcription suppressor in fibroblasts which limits the expression of proinflammatory mediators and may exert its function by modulating the stability Fibroblasts from relb(-/-) mice overexpress interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in response to lipopolysaccharide (LPS) stimulation. These cells have an augmented and prolonged LPS-inducible IKK activity and an accelerated degradation which results in a diminished level of IkappaBalpha protein, despite an upregulated IkappaBalpha mRNA expression. References_end </body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="40.0" x="1947.0" y="2817.0"/> </glyph> <glyph class="macromolecule" id="s3507_sa316"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="1952.0" y="2857.0"/> <glyph class="unit of information" id="_9e9e694a-ae8d-4d39-ba6d-9fd76f50da81"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1967.0" y="2852.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3490_sa317"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NFKB inhibitor alpha HUGO:NFKBIA hgnc_id:HGNC:7797 HGNC:7797 ENTREZ:4792 UNIPROT:P25963 NFKB inhibitor beta HUGO:NFKBIB hgnc_id:HGNC:7798 HGNC:7798 ENTREZ:4793 UNIPROT:Q15653 NFKB inhibitor epsilon HUGO:NFKBIE hgnc_id:HGNC:7799 HGNC:7799 ENTREZ:4794 UNIPROT:O00221 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="1952.0" y="2777.0"/> <glyph class="state variable" id="_9669d7a5-b58e-4971-8123-ab24ecf65b26"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1947.0" y="2792.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3591_csa23" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IkB*:NFKB1_p50*:RELB Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s32"/> <bbox w="107.5" h="160.0" x="2046.0" y="2950.0"/> <glyph class="macromolecule" id="s3599_sa321"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="2061.0" y="3050.0"/> <glyph class="unit of information" id="_efe85dbd-25d1-4e8f-81f5-540448795c1d"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2076.0" y="3045.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s41_sa322"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELB proto-oncogene, NF-kB subunit HUGO:RELB hgnc_id:HGNC:9956 HGNC:9956 ENTREZ:5971 UNIPROT:Q01201 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:18697742 RelB is constitutively expressed in mouse lung fibroblasts. PMID:10523657 RelB is an important transcription suppressor in fibroblasts which limits the expression of proinflammatory mediators and may exert its function by modulating the stability Fibroblasts from relb(-/-) mice overexpress interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in response to lipopolysaccharide (LPS) stimulation. These cells have an augmented and prolonged LPS-inducible IKK activity and an accelerated degradation which results in a diminished level of IkappaBalpha protein, despite an upregulated IkappaBalpha mRNA expression. References_end </body> </html> </notes> <label text="RELB"/> <bbox w="90.0" h="40.0" x="2056.0" y="3010.0"/> </glyph> <glyph class="macromolecule" id="s3495_sa323"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NFKB inhibitor alpha HUGO:NFKBIA hgnc_id:HGNC:7797 HGNC:7797 ENTREZ:4792 UNIPROT:P25963 NFKB inhibitor beta HUGO:NFKBIB hgnc_id:HGNC:7798 HGNC:7798 ENTREZ:4793 UNIPROT:Q15653 NFKB inhibitor epsilon HUGO:NFKBIE hgnc_id:HGNC:7799 HGNC:7799 ENTREZ:4794 UNIPROT:O00221 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="2061.0" y="2960.0"/> <glyph class="state variable" id="_66a3de58-d1bd-46eb-963b-654782bc6ade"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2053.5" y="2975.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3499_csa25" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:RELB Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s2440"/> <bbox w="110.0" h="130.0" x="2135.0" y="3295.0"/> <glyph class="macromolecule" id="s2441_sa327"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELB proto-oncogene, NF-kB subunit HUGO:RELB hgnc_id:HGNC:9956 HGNC:9956 ENTREZ:5971 UNIPROT:Q01201 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:18697742 RelB is constitutively expressed in mouse lung fibroblasts. PMID:10523657 RelB is an important transcription suppressor in fibroblasts which limits the expression of proinflammatory mediators and may exert its function by modulating the stability Fibroblasts from relb(-/-) mice overexpress interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha in response to lipopolysaccharide (LPS) stimulation. These cells have an augmented and prolonged LPS-inducible IKK activity and an accelerated degradation which results in a diminished level of IkappaBalpha protein, despite an upregulated IkappaBalpha mRNA expression. References_end </body> </html> </notes> <label text="RELB"/> <bbox w="68.75" h="46.0" x="2150.625" y="3352.0"/> </glyph> <glyph class="macromolecule" id="s2442_sa328"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="81.25" h="46.0" x="2143.75" y="3305.0"/> <glyph class="unit of information" id="_0b7a310d-2eba-41d3-a31b-6cce7e3801b7"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2159.375" y="3300.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3593_csa27" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:NFKB1_p50*:RELA Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice PMID:23831470 we performed immunostaining for the NF-κB subunit p65 (RelA). When active, the NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes [31]. Indeed, we found that in addition to its accumulation in the tumor cells, NF-κB was upregulated in CAFs in the stroma of breast and ovarian tumorsReferences_end References_end </body> </html> </notes> <label text="RELA:p50"/> <bbox w="140.0" h="174.5" x="2300.0" y="3252.0"/> <glyph class="macromolecule" id="s235_sa331"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NFKB1 MODULE:MACROPHAGE PMID:19171876, PMID:17145890 NFkB p50/p50 homodimers (which lack the transactivation domain) compete with canonical p65/p50 heterodimers for the binding sites on the inflammatory gene promoters, thereby blocking p65/p50 promoter binding and gene transcription. p50 NF-kappaB overexpression accounts for the inability of tumor assasiated macrophages to mount an effective M1 antitumor response capable of inhibiting tumor growth. ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="118.5" h="66.5" x="2310.75" y="3333.25"/> <glyph class="unit of information" id="_10de1ffd-a3e4-4618-8c32-c4c423bd0455"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2345.0" y="3328.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s3608_sa332"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELA proto-oncogene, NF-kB subunit HUGO:RELA hgnc_id:HGNC:9955 HGNC:9955 ENTREZ:5970 UNIPROT:Q04206 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 CASCADE:TNF MODULE:CORE PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice References_end Maps_Modules_end </body> </html> </notes> <label text="RELA"/> <bbox w="120.5" h="58.5" x="2310.0" y="3268.0"/> </glyph> </glyph> <glyph class="complex" id="s3492_csa28" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IkB*:NFKB1_p50*:RELA Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice References_end </body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="2202.0" y="2762.0"/> <glyph class="macromolecule" id="s3603_sa333"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELA proto-oncogene, NF-kB subunit HUGO:RELA hgnc_id:HGNC:9955 HGNC:9955 ENTREZ:5970 UNIPROT:Q04206 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 CASCADE:TNF MODULE:CORE PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice References_end Maps_Modules_end </body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="2219.5" y="2827.25"/> </glyph> <glyph class="macromolecule" id="s3604_sa334"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="2217.0" y="2869.0"/> <glyph class="unit of information" id="_c4e9807d-71b7-4879-aea5-499a46db9910"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2232.0" y="2864.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3605_sa335"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NFKB inhibitor alpha HUGO:NFKBIA hgnc_id:HGNC:7797 HGNC:7797 ENTREZ:4792 UNIPROT:P25963 NFKB inhibitor beta HUGO:NFKBIB hgnc_id:HGNC:7798 HGNC:7798 ENTREZ:4793 UNIPROT:Q15653 NFKB inhibitor epsilon HUGO:NFKBIE hgnc_id:HGNC:7799 HGNC:7799 ENTREZ:4794 UNIPROT:O00221 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="2219.5" y="2779.5"/> <glyph class="state variable" id="_470adaa0-1c82-480b-961d-1ef16738d5eb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2214.5" y="2794.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s3510_csa29" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IkB*:NFKB1_p50*:RELA Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice References_end </body> </html> </notes> <label text="RELA:p50/NFKBIA"/> <bbox w="115.0" h="175.0" x="2362.0" y="2952.0"/> <glyph class="macromolecule" id="s3512_sa336"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RELA proto-oncogene, NF-kB subunit HUGO:RELA hgnc_id:HGNC:9955 HGNC:9955 ENTREZ:5970 UNIPROT:Q04206 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 CASCADE:TNF MODULE:CORE PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control mice References_end Maps_Modules_end </body> </html> </notes> <label text="RELA"/> <bbox w="80.0" h="40.0" x="2374.5" y="3011.0"/> </glyph> <glyph class="macromolecule" id="s3606_sa337"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="80.0" h="40.0" x="2377.0" y="3059.0"/> <glyph class="unit of information" id="_b3258abb-53c0-4ca6-83a2-07a316321f98"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="2392.0" y="3054.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3511_sa338"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NFKB inhibitor alpha HUGO:NFKBIA hgnc_id:HGNC:7797 HGNC:7797 ENTREZ:4792 UNIPROT:P25963 NFKB inhibitor beta HUGO:NFKBIB hgnc_id:HGNC:7798 HGNC:7798 ENTREZ:4793 UNIPROT:Q15653 NFKB inhibitor epsilon HUGO:NFKBIE hgnc_id:HGNC:7799 HGNC:7799 ENTREZ:4794 UNIPROT:O00221 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23086447, PMID:25305492, PMID:23422957 In canonical NFkB pathway RelB/p50, RelA/p50 and c-Rel/p50 heterodimers are sequestered by IκB-α, IκB-β, and IκB-ε References_end </body> </html> </notes> <label text="IkB*"/> <bbox w="80.0" h="40.0" x="2376.0" y="2969.0"/> <glyph class="state variable" id="_ff9b0d3a-0c4d-4c50-b117-7ea0b75be266"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2368.5" y="2984.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s3473_sa339" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:NFKB1 MODULE:CAF MODULE:CORE Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 Maps_Modules_end References_begin: PMID:20138012 NF-κB heterodimer (RelA-p50) translocates to the nucleus, where it activates the transcription of its target genes ( Karin and Ben-Neriah, 2000 and Pereira and Oakley, 2008). Nuclear p65 staining was detected in the stroma of HPV skin sections but not in the skin of nontransgenic control miceReferences_end References_end </body> </html> </notes> <label text="NFKB1_p50*"/> <bbox w="140.0" h="90.0" x="1600.0" y="2685.0"/> <glyph class="unit of information" id="_c9f9b8eb-07ed-4ccb-aee8-0dd872b64cb2"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1645.0" y="2680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3151_sa341"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL1B Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 Tumor-enhancing activity of skin CAFs is NF-κB dependent and activatable by IL-1β PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="trIL1B"/> <bbox w="80.0" h="40.0" x="1890.0" y="810.0"/> <glyph class="unit of information" id="_8bbea255-2a41-4bda-96f8-406cdb6e66c7"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1905.0" y="805.0"/> </glyph> </glyph> <glyph class="complex" id="s1099_csa30" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL1R1:IL1RAP Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:19161412 IL-1 signaling is initiated by the recruitment of MyD88 to the IL-1RI/IL-1RAcP complex. The recruitment of MyD88 leads to the recruitment of IRAK1 and IRAK4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. References_end </body> </html> </notes> <label text="s1099"/> <bbox w="110.0" h="140.0" x="1815.0" y="1160.0"/> <glyph class="macromolecule" id="s1102_sa342"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor type 1 HUGO:IL1R1 hgnc_id:HGNC:5993 HGNC:5993 ENTREZ:3554 UNIPROT:P14778 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1R1"/> <bbox w="80.0" h="50.0" x="1825.0" y="1225.0"/> <glyph class="unit of information" id="_eef26d27-290e-4db1-9dde-81d52ac7c39f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1842.5" y="1220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1103_sa343"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor accessory protein HUGO:IL1RAP hgnc_id:HGNC:5995 HGNC:5995 ENTREZ:3556 UNIPROT:Q9NPH3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1RAP"/> <bbox w="80.0" h="50.0" x="1825.0" y="1175.0"/> <glyph class="unit of information" id="_c407d776-79a3-48b4-a62e-20c2e602b36e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1842.5" y="1170.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s669_sa347" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor associated kinase 1 HUGO:IRAK1 hgnc_id:HGNC:6112 HGNC:6112 ENTREZ:3654 UNIPROT:P51617 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12620219, PMID:19161412 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6. References_end </body> </html> </notes> <label text="IRAK1"/> <bbox w="80.0" h="40.0" x="2010.0" y="1490.0"/> <glyph class="state variable" id="_4550bdd3-f920-470a-8703-ccc51ae396a4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2002.5" y="1505.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s641_sa348" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor associated kinase 1 HUGO:IRAK1 hgnc_id:HGNC:6112 HGNC:6112 ENTREZ:3654 UNIPROT:P51617 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12620219, PMID:19161412 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6. References_end </body> </html> </notes> <label text="IRAK1"/> <bbox w="80.0" h="40.0" x="2130.0" y="1490.0"/> <glyph class="state variable" id="_32a80a84-f3ed-4d4e-bf2b-d2ae9f744eaf"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2125.0" y="1505.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4153_sa354" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGF-beta activated kinase 1 and MAP3K7 binding protein 3 HUGO:TAB3 hgnc_id:HGNC:30681 HGNC:30681 ENTREZ:257397 UNIPROT:Q8N5C8 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19161412, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. K63-pUb-Traf6 can then recruit transforming growth factor β-activated protein kinase (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (41). This somehow activates TAK1, which then couples to the inhibitor of NF-κB (IκB) kinase (IKK) complex, which contains the scaffold protein NF-κB essential modulator (NEMO) and IKK2, the kinase responsible for phosphorylation of IκB. References_end </body> </html> </notes> <label text="TAB3"/> <bbox w="80.0" h="40.0" x="1670.0" y="2210.0"/> </glyph> <glyph class="macromolecule" id="s653_sa355" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGF-beta activated kinase 1/MAP3K7 binding protein 2 HUGO:TAB2 hgnc_id:HGNC:17075 HGNC:17075 ENTREZ:23118 UNIPROT:Q9NYJ8 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TAB2"/> <bbox w="80.0" h="40.0" x="1670.0" y="2150.0"/> </glyph> <glyph class="macromolecule" id="s652_sa356" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase kinase kinase 7 HUGO:MAP3K7 hgnc_id:HGNC:6859 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE CASCADE:IL1 Maps_Modules_end References_begin: PMID:19161412, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. K63-pUb-Traf6 can then recruit transforming growth factor β-activated protein kinase (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (41). This somehow activates TAK1, which then couples to the inhibitor of NF-κB (IκB) kinase (IKK) complex, which contains the scaffold protein NF-κB essential modulator (NEMO) and IKK2, the kinase responsible for phosphorylation of IκB. References_end </body> </html> </notes> <label text="MAP3K7"/> <bbox w="80.0" h="40.0" x="1670.0" y="2090.0"/> </glyph> <glyph class="complex" id="s651_csa32" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MAP3K7:TAB2:TAB3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1. PMID:23681101, PMID:11477091 There are three main signaling pathways could be activated downstream of TRR4/MyD88/TAK1 signaling : p38 (via MKK3 or MKK6), JNK (via MKK4 or MKK7) and NfkB ) IN DC all these signaling pathways are activated downstream of TLR4 and TLR2 signaling ) PMID:21232017, PMID:21133840 PMID:17301840, PMID:18641653, PMID:24958845, PMID:16603398, PMID:14633987 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modieed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. References_end </body> </html> </notes> <label text="s651"/> <bbox w="110.0" h="165.0" x="1885.0" y="2207.0"/> <glyph class="macromolecule" id="s3538_sa357"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase kinase kinase 7 HUGO:MAP3K7 hgnc_id:HGNC:6859 HGNC:6859 ENTREZ:6885 UNIPROT:O43318 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE CASCADE:IL1 Maps_Modules_end References_begin: PMID:19161412, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. K63-pUb-Traf6 can then recruit transforming growth factor β-activated protein kinase (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (41). This somehow activates TAK1, which then couples to the inhibitor of NF-κB (IκB) kinase (IKK) complex, which contains the scaffold protein NF-κB essential modulator (NEMO) and IKK2, the kinase responsible for phosphorylation of IκB. References_end </body> </html> </notes> <label text="MAP3K7"/> <bbox w="80.0" h="40.0" x="1895.0" y="2222.0"/> </glyph> <glyph class="macromolecule" id="s645_sa358"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGF-beta activated kinase 1/MAP3K7 binding protein 2 HUGO:TAB2 hgnc_id:HGNC:17075 HGNC:17075 ENTREZ:23118 UNIPROT:Q9NYJ8 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TAB2"/> <bbox w="80.0" h="40.0" x="1895.0" y="2272.0"/> </glyph> <glyph class="macromolecule" id="s4154_sa359"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGF-beta activated kinase 1 and MAP3K7 binding protein 3 HUGO:TAB3 hgnc_id:HGNC:30681 HGNC:30681 ENTREZ:257397 UNIPROT:Q8N5C8 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19161412, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. K63-pUb-Traf6 can then recruit transforming growth factor β-activated protein kinase (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (41). This somehow activates TAK1, which then couples to the inhibitor of NF-κB (IκB) kinase (IKK) complex, which contains the scaffold protein NF-κB essential modulator (NEMO) and IKK2, the kinase responsible for phosphorylation of IκB. References_end </body> </html> </notes> <label text="TAB3"/> <bbox w="80.0" h="40.0" x="1895.0" y="2312.0"/> </glyph> </glyph> <glyph class="complex" id="s3895_csa35" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL6R:gp130* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: 1439146 IL6 sirnaling acts through IL6 receptor and receptor-associated signal transducer, gp130. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="123.25" h="133.625" x="368.0" y="2223.0"/> <glyph class="macromolecule" id="s3897_sa369"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 receptor HUGO:IL6R hgnc_id:HGNC:6019 HGNC:6019 ENTREZ:3570 UNIPROT:P08887 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="391.25" y="2238.0"/> <glyph class="unit of information" id="_c461fbe4-50a0-4ddd-bdbd-3d19345a69ed"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="408.75" y="2233.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3969_sa373"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="389.625" y="2284.8125"/> <glyph class="state variable" id="_90ad5e90-9db4-4fd7-abc7-837b4f0cae2b"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="452.125" y="2282.3535"/> </glyph> <glyph class="unit of information" id="_25b55923-ec7b-40bb-a6b0-26676f8bc903"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="407.125" y="2279.8125"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4160_sa386" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: prostaglandin E receptor 2 HUGO:PTGER2 hgnc_id:HGNC:9594 HGNC:9594 ENTREZ:5732 UNIPROT:P43116 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. PMID:21209948 PGE2 can induce IL-6 expression in fibroblasts through EP2 References_end </body> </html> </notes> <label text="PTGER2"/> <bbox w="80.0" h="50.0" x="1000.0" y="1695.0"/> <glyph class="unit of information" id="_b1670d52-e429-4348-9328-160d8cd9e323"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1017.5" y="1690.0"/> </glyph> </glyph> <glyph class="complex" id="s4162_csa40" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PGE2:PTGER2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4162"/> <bbox w="100.0" h="120.0" x="1100.0" y="1830.0"/> <glyph class="macromolecule" id="s4163_sa388"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: prostaglandin E receptor 2 HUGO:PTGER2 hgnc_id:HGNC:9594 HGNC:9594 ENTREZ:5732 UNIPROT:P43116 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. PMID:21209948 PGE2 can induce IL-6 expression in fibroblasts through EP2 References_end </body> </html> </notes> <label text="PTGER2"/> <bbox w="80.0" h="50.0" x="1110.0" y="1875.0"/> <glyph class="unit of information" id="_8423cee7-9833-4948-84d6-b6e6a7560c37"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1127.5" y="1870.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s4164_sa389"> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="1115.0" y="1847.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s760_sa390"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor necrosis factor HUGO:TNF hgnc_id:HGNC:11892 HGNC:11892 ENTREZ:7124 UNIPROT:P01375 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION CASCADE:TNF Maps_Modules_end References_begin: PMID:23769623 TNF is one of key CAF activating agents PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts Tnfr1 is essential in mediating proliferative signals Tnfr1 Exclusively Activates Transcription Factor NF-κB in Mouse Fibroblasts Ap-1 was independently activated through both Tnf receptors, probably via prolonged activation of the c-Jun kinase Tnfr1 and Tnfr2 Control Erk1 and Erk2 Kinase Activity Tnfr1 and Tnfr2 Control activation of RPS6KA1 Raf-1, Mek-1, and Mekk responded with enhanced kinase activity to Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts, supporting again that both Tnf receptors individually are signaling-competent. The activation factors were about 1.5-4 for Raf-1, Mekk, and Mek-1 in wt, tnfr1o, and tnfr2o fibroblasts (Table II). Interestingly, Raf-B, an isoform of c-Raf-1 reported to be mainly localized to the brain (64, 65, 66), also responded to Tnf treatment of the fibroblasts. PMID:11112697 TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:20184663 PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="1250.0" y="1100.0"/> </glyph> <glyph class="macromolecule" id="s778_sa391" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor superfamily member 1A HUGO:TNFRSF1A hgnc_id:HGNC:11916 HGNC:11916 ENTREZ:7132 UNIPROT:P19438 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs TRADD was also required for TRIF-dependent Toll-like receptor signaling in mouse embryonic fibroblasts but not macrophages PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="1240.0" y="1425.0"/> <glyph class="unit of information" id="_9a8d086a-a4f4-4c3d-a432-d4dd9b5445d0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1257.5" y="1420.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3073_sa392" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNFRSF1A associated via death domain HUGO:TRADD hgnc_id:HGNC:12030 HGNC:12030 ENTREZ:8717 UNIPROT:Q15628 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="1240.0" y="1497.0"/> </glyph> <glyph class="macromolecule" id="s3082_sa393" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: receptor interacting serine/threonine kinase 1 HUGO:RIPK1 hgnc_id:HGNC:10019 HGNC:10019 ENTREZ:8737 UNIPROT:Q13546 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:TNF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="1240.0" y="1548.0"/> <glyph class="state variable" id="_0ad56b0c-45bd-42d0-9429-f21bc149e79c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1315.0" y="1563.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s781_sa394" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 2 HUGO:TRAF2 hgnc_id:HGNC:12032 HGNC:12032 ENTREZ:7186 UNIPROT:Q12933 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="1532.0" y="1280.0"/> <glyph class="state variable" id="_9fd8f0f4-9d19-4f37-af5b-824f2021ff1b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1607.0" y="1293.6672"/> </glyph> </glyph> <glyph class="complex" id="s3111_csa41" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:FADD:RIPK1:TNF:TNFR1*:TRADD:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs TRADD was also required for TRIF-dependent Toll-like receptor signaling in mouse embryonic fibroblasts but not macrophages References_end </body> </html> </notes> <label text="TNFR1"/> <bbox w="210.0" h="180.0" x="1385.0" y="1400.0"/> <glyph class="macromolecule" id="s814_sa396"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: receptor interacting serine/threonine kinase 1 HUGO:RIPK1 hgnc_id:HGNC:10019 HGNC:10019 ENTREZ:8737 UNIPROT:Q13546 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:TNF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="1390.0" y="1470.0"/> <glyph class="state variable" id="_696bfef8-4997-48ee-9d5c-5ff61883cc3a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1465.0" y="1485.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s3122_sa397"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNFRSF1A associated via death domain HUGO:TRADD hgnc_id:HGNC:12030 HGNC:12030 ENTREZ:8717 UNIPROT:Q15628 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="1510.0" y="1510.0"/> </glyph> <glyph class="macromolecule" id="s812_sa398"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 2 HUGO:TRAF2 hgnc_id:HGNC:12032 HGNC:12032 ENTREZ:7186 UNIPROT:Q12933 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="1400.0" y="1520.0"/> <glyph class="state variable" id="_6f7828f3-9fa1-4420-a68f-8285f240cfad"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1475.0" y="1533.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s811_sa399"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor necrosis factor HUGO:TNF hgnc_id:HGNC:11892 HGNC:11892 ENTREZ:7124 UNIPROT:P01375 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION CASCADE:TNF Maps_Modules_end References_begin: PMID:23769623 TNF is one of key CAF activating agents PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts Tnfr1 is essential in mediating proliferative signals Tnfr1 Exclusively Activates Transcription Factor NF-κB in Mouse Fibroblasts Ap-1 was independently activated through both Tnf receptors, probably via prolonged activation of the c-Jun kinase Tnfr1 and Tnfr2 Control Erk1 and Erk2 Kinase Activity Tnfr1 and Tnfr2 Control activation of RPS6KA1 Raf-1, Mek-1, and Mekk responded with enhanced kinase activity to Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts, supporting again that both Tnf receptors individually are signaling-competent. The activation factors were about 1.5-4 for Raf-1, Mekk, and Mek-1 in wt, tnfr1o, and tnfr2o fibroblasts (Table II). Interestingly, Raf-B, an isoform of c-Raf-1 reported to be mainly localized to the brain (64, 65, 66), also responded to Tnf treatment of the fibroblasts. PMID:11112697 TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:20184663 PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="1495.0" y="1410.0"/> </glyph> <glyph class="macromolecule" id="s3124_sa400"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor superfamily member 1A HUGO:TNFRSF1A hgnc_id:HGNC:11916 HGNC:11916 ENTREZ:7132 UNIPROT:P19438 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs TRADD was also required for TRIF-dependent Toll-like receptor signaling in mouse embryonic fibroblasts but not macrophages PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="1495.0" y="1455.0"/> <glyph class="unit of information" id="_4b58b5b6-20cc-40db-b29d-b36094c0f7a6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1512.5" y="1450.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s809_sa401"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Fas associated via death domain HUGO:FADD hgnc_id:HGNC:3573 HGNC:3573 ENTREZ:8772 UNIPROT:Q13158 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="FADD"/> <bbox w="80.0" h="40.0" x="1390.0" y="1410.0"/> </glyph> </glyph> <glyph class="complex" id="s3112_csa42" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:FADD:RIPK1:TNF:TNFR1*:TRADD:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21133840, PMID:24378531 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modiﬁed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce classical NFkB activation via IKBa degradation. Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. References_end </body> </html> </notes> <label text="TNFR1"/> <bbox w="210.0" h="180.0" x="1395.0" y="1720.0"/> <glyph class="macromolecule" id="s832_sa402"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: receptor interacting serine/threonine kinase 1 HUGO:RIPK1 hgnc_id:HGNC:10019 HGNC:10019 ENTREZ:8737 UNIPROT:Q13546 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:TNF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs References_end </body> </html> </notes> <label text="RIPK1"/> <bbox w="80.0" h="40.0" x="1400.0" y="1780.0"/> <glyph class="state variable" id="_dd005b0f-8953-4739-9965-5b66ab53eec1"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="1470.0" y="1795.4336"/> </glyph> </glyph> <glyph class="macromolecule" id="s831_sa403"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNFRSF1A associated via death domain HUGO:TRADD hgnc_id:HGNC:12030 HGNC:12030 ENTREZ:8717 UNIPROT:Q15628 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TRADD is an adaptor molecule important for transducing signals from TNFR1. After binding of TNF, TRADD is recruited to TNFR1 and interacts with the cytoplasmic death domain region of TNFR1 through homotypic interactions. The TNFR1-TRADD complex serves as scaffolding for the recruitment of other signaling molecules that mediate the downstream actions of TNF. References_end </body> </html> </notes> <label text="TRADD"/> <bbox w="80.0" h="40.0" x="1510.0" y="1830.0"/> </glyph> <glyph class="macromolecule" id="s833_sa404"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 2 HUGO:TRAF2 hgnc_id:HGNC:12032 HGNC:12032 ENTREZ:7186 UNIPROT:Q12933 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="1400.0" y="1830.0"/> <glyph class="state variable" id="_4957fe00-a033-44ac-aff8-73230482e483"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="1470.0" y="1843.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s830_sa405"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor necrosis factor HUGO:TNF hgnc_id:HGNC:11892 HGNC:11892 ENTREZ:7124 UNIPROT:P01375 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION CASCADE:TNF Maps_Modules_end References_begin: PMID:23769623 TNF is one of key CAF activating agents PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts Tnfr1 is essential in mediating proliferative signals Tnfr1 Exclusively Activates Transcription Factor NF-κB in Mouse Fibroblasts Ap-1 was independently activated through both Tnf receptors, probably via prolonged activation of the c-Jun kinase Tnfr1 and Tnfr2 Control Erk1 and Erk2 Kinase Activity Tnfr1 and Tnfr2 Control activation of RPS6KA1 Raf-1, Mek-1, and Mekk responded with enhanced kinase activity to Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts, supporting again that both Tnf receptors individually are signaling-competent. The activation factors were about 1.5-4 for Raf-1, Mekk, and Mek-1 in wt, tnfr1o, and tnfr2o fibroblasts (Table II). Interestingly, Raf-B, an isoform of c-Raf-1 reported to be mainly localized to the brain (64, 65, 66), also responded to Tnf treatment of the fibroblasts. PMID:11112697 TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:20184663 PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="1510.0" y="1730.0"/> </glyph> <glyph class="macromolecule" id="s829_sa406"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor superfamily member 1A HUGO:TNFRSF1A hgnc_id:HGNC:11916 HGNC:11916 ENTREZ:7132 UNIPROT:P19438 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TRADD is essential for TNFR1 signaling in MEFs TRADD was also required for TRIF-dependent Toll-like receptor signaling in mouse embryonic fibroblasts but not macrophages PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts References_end </body> </html> </notes> <label text="TNFR1*"/> <bbox w="80.0" h="50.0" x="1510.0" y="1775.0"/> <glyph class="unit of information" id="_efc1fd68-6535-4168-b19f-12cfe58d0379"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1527.5" y="1770.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s828_sa407"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Fas associated via death domain HUGO:FADD hgnc_id:HGNC:3573 HGNC:3573 ENTREZ:8772 UNIPROT:Q13158 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="FADD"/> <bbox w="80.0" h="40.0" x="1410.0" y="1730.0"/> </glyph> </glyph> <glyph class="complex" id="s791_csa43" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:TNF:TNFR2*:TRAF1:TRAF2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts Tnfr1 is essential in mediating proliferative signals Tnfr1 Exclusively Activates Transcription Factor NF-κB in Mouse Fibroblasts Ap-1 was independently activated through both Tnf receptors, probably via prolonged activation of the c-Jun kinase Tnfr1 and Tnfr2 Control Erk1 and Erk2 Kinase Activity Tnfr1 and Tnfr2 Control activation of RPS6KA1 Raf-1, Mek-1, and Mekk responded with enhanced kinase activity to Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts, supporting again that both Tnf receptors individually are signaling-competent. The activation factors were about 1.5-4 for Raf-1, Mekk, and Mek-1 in wt, tnfr1o, and tnfr2o fibroblasts (Table II). Interestingly, Raf-B, an isoform of c-Raf-1 reported to be mainly localized to the brain (64, 65, 66), also responded to Tnf treatment of the fibroblasts. References_end </body> </html> </notes> <label text="TNFR2"/> <bbox w="190.0" h="120.0" x="1675.0" y="1440.0"/> <glyph class="macromolecule" id="s795_sa408"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor necrosis factor HUGO:TNF hgnc_id:HGNC:11892 HGNC:11892 ENTREZ:7124 UNIPROT:P01375 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION CASCADE:TNF Maps_Modules_end References_begin: PMID:23769623 TNF is one of key CAF activating agents PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts Tnfr1 is essential in mediating proliferative signals Tnfr1 Exclusively Activates Transcription Factor NF-κB in Mouse Fibroblasts Ap-1 was independently activated through both Tnf receptors, probably via prolonged activation of the c-Jun kinase Tnfr1 and Tnfr2 Control Erk1 and Erk2 Kinase Activity Tnfr1 and Tnfr2 Control activation of RPS6KA1 Raf-1, Mek-1, and Mekk responded with enhanced kinase activity to Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts, supporting again that both Tnf receptors individually are signaling-competent. The activation factors were about 1.5-4 for Raf-1, Mekk, and Mek-1 in wt, tnfr1o, and tnfr2o fibroblasts (Table II). Interestingly, Raf-B, an isoform of c-Raf-1 reported to be mainly localized to the brain (64, 65, 66), also responded to Tnf treatment of the fibroblasts. PMID:11112697 TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:20184663 PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="1770.0" y="1450.0"/> </glyph> <glyph class="macromolecule" id="s3126_sa409"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 2 HUGO:TRAF2 hgnc_id:HGNC:12032 HGNC:12032 ENTREZ:7186 UNIPROT:Q12933 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:18641653 TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1. TNFR2 interacts with TRAF2 and TRAF1. PMID:24378531 TNF via TNFR2 induces TRAF2 degradation. References_end </body> </html> </notes> <label text="TRAF2"/> <bbox w="80.0" h="40.0" x="1680.0" y="1500.0"/> <glyph class="state variable" id="_3e77a369-9071-417e-94d3-52f004ad91a9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="1755.0" y="1513.6672"/> </glyph> </glyph> <glyph class="macromolecule" id="s3127_sa410"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 1 HUGO:TRAF1 hgnc_id:HGNC:12031 HGNC:12031 ENTREZ:7185 UNIPROT:Q13077 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end </body> </html> </notes> <label text="TRAF1"/> <bbox w="80.0" h="40.0" x="1680.0" y="1450.0"/> </glyph> <glyph class="macromolecule" id="s792_sa411"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor superfamily member 1B HUGO:TNFRSF1B hgnc_id:HGNC:11917 HGNC:11917 ENTREZ:7133 UNIPROT:P20333 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:TNF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts References_end </body> </html> </notes> <label text="TNFR2*"/> <bbox w="80.0" h="50.0" x="1775.0" y="1495.0"/> <glyph class="unit of information" id="_c1398c41-d650-428e-b53f-cc4ba82a049f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1792.5" y="1490.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4167_sa422" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: lactate dehydrogenase A HUGO:LDHA hgnc_id:HGNC:6535 HGNC:6535 ENTREZ:3939 UNIPROT:P00338 Identifiers_end Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:22101652; PMID:19923890 PKM2 and lactate dehydrogenase are highly expressed in the stroma of breast cancer lacking caveolin-1 expression References_end </body> </html> </notes> <label text="LDH5*"/> <bbox w="80.0" h="40.0" x="2630.0" y="4700.0"/> </glyph> <glyph class="simple chemical" id="s4168_sa423" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: HUGO:PKM Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:22101652; PMID:19923890 The M1 or M2 splice isoforms of pyruvate kinase (PK), a mandatory regulatory glycolytic enzyme, shift glucose metabolism towards aerobic glycolysis (PKM2) or oxidative phosphorylation (PKM1) PKM2 and lactate dehydrogenase are highly expressed in the stroma of breast cancer lacking caveolin-1 expression References_end </body> </html> </notes> <label text="piruvat"/> <bbox w="70.0" h="25.0" x="2715.0" y="4637.5"/> </glyph> <glyph class="macromolecule" id="s4169_sa424"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase HUGO:PLAU hgnc_id:HGNC:9052 HGNC:9052 ENTREZ:5328 UNIPROT:P00749 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU MODULE/CAF PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. uPA (PLAU) signaling has a negative influence on myofibroblast differentiation; References_end </body> </html> </notes> <label text="PLAU"/> <bbox w="80.0" h="40.0" x="600.0" y="1630.0"/> <glyph class="unit of information" id="_e8d8748f-c293-43ff-be67-7fdb9be4dfaa"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="615.0" y="1625.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4170_sa425" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase receptor HUGO:PLAUR hgnc_id:HGNC:9053 HGNC:9053 ENTREZ:5329 UNIPROT:Q03405 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="PLAUR"/> <bbox w="80.0" h="50.0" x="900.0" y="2225.0"/> <glyph class="unit of information" id="_e7e65d47-c37e-45f9-b7e3-a8505019b383"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="917.5" y="2220.0"/> </glyph> </glyph> <glyph class="complex" id="s4171_csa46" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:JAK1:PLAU:PLAUR:gp130* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. PMID:22595692 The structure of receptors of IL6 like cytokines References_end </body> </html> </notes> <label text="s4171"/> <bbox w="200.0" h="110.0" x="700.0" y="2025.0"/> <glyph class="macromolecule" id="s4172_sa426"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase receptor HUGO:PLAUR hgnc_id:HGNC:9053 HGNC:9053 ENTREZ:5329 UNIPROT:Q03405 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="PLAUR"/> <bbox w="80.0" h="50.0" x="710.0" y="2070.0"/> <glyph class="unit of information" id="_0675e413-82a4-4197-91c7-d4c26e1c24fd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="727.5" y="2065.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4173_sa427"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase HUGO:PLAU hgnc_id:HGNC:9052 HGNC:9052 ENTREZ:5328 UNIPROT:P00749 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU MODULE/CAF PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. uPA (PLAU) signaling has a negative influence on myofibroblast differentiation; References_end </body> </html> </notes> <label text="PLAU"/> <bbox w="80.0" h="40.0" x="710.0" y="2030.0"/> <glyph class="unit of information" id="_c643b413-656c-440c-9bfd-7e5ff7e44dd4"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="725.0" y="2025.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4174_sa428"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="800.0" y="2075.0"/> <glyph class="state variable" id="_6307bbc4-ad49-425e-8de4-e364548449d5"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="862.5" y="2072.541"/> </glyph> <glyph class="unit of information" id="_d2f6cc2e-d8fe-4ede-914f-35e6380ce6c5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="817.5" y="2070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4438_sa720"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 1 HUGO:JAK1 hgnc_id:HGNC:6190 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end References_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IL6 CASCADE:PLAU CASCADE:LIF CASCADE:IFNG PMID:21840487 CAF-dependent matrix remodelling is essential for collective carcinoma cell invasion JAK kinase inhibitor P6 tested blocked remodelling (Hooper et al., 2010). P6 inhibits multiple members of the JAK family (Pedranzini et al., 2006), so we used JAK isoform-specific inhibitors to probe which JAKs are involved; neither JAK2 nor JAK3-specific inhibitors recapitulated the effect of the pan-JAK inhibitor (P6) on matrix remodelling (Figure 1A), suggesting that JAKI is the family member involved. Jak 1 regulates Actomyosin Contractility in CAFs downstream of GP130-IL6ST IL6 and oncostatin M (OSM) and via STAT3 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="800.0" y="2030.0"/> <glyph class="state variable" id="_d8ccb1c3-2f37-45ee-a220-548af83d094f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="792.5" y="2045.0"/> </glyph> </glyph> </glyph> <glyph class="simple chemical" id="s2439_sa433" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION Maps_Modules_end References_begin: PMID:15817676 PIP2 is mainly synthesized by the phosphorylation of phosphatidylinositol4-phosphate (PI4P) at the D-5 position of the inositol ring by phosphatidylinositol4phosphate 5-kinase type I (PI5KI) References_end </body> </html> </notes> <label text="PtdIns(4)-P"/> <bbox w="70.0" h="25.0" x="3700.0" y="2207.5"/> </glyph> <glyph class="simple chemical" id="s2448_sa434" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION Maps_Modules_end References_begin: PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. References_end </body> </html> </notes> <label text="PIP2*"/> <bbox w="70.0" h="25.0" x="3700.0" y="2367.5"/> </glyph> <glyph class="simple chemical" id="s745_sa435" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:11696562 Integrin-linked kinase (ILK) is a binding partner of the integrin 1 and 3 subunits and is involved in the signal transduction from integrin receptors The activity is stimulated in a phosphatidylinositol (PI) 3-kinase–dependent manner and likely involves binding of the phosphoinositide phospholipid product of PI 3-kinase, PI 3,4,5-triphosphate, to the PH-like domain of ILK ILK has been shown recently to directly phosphorylate proteins such as PKB (PKB/Akt) on ser 473. PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast References_end </body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="3700.0" y="2557.5"/> </glyph> <glyph class="macromolecule" id="s1114_sa436" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: pyruvate dehydrogenase kinase 1 HUGO:PDK1 hgnc_id:HGNC:8809 HGNC:8809 ENTREZ:5163 UNIPROT:Q15118 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). PMID:11747822 Akt but not SGK promotes cell motility downstream of the PI3-K-PDK1 pathway. References_end </body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="3865.0" y="2675.0"/> </glyph> <glyph class="macromolecule" id="s1113_sa438" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: AKT serine/threonine kinase 1 HUGO:AKT1 hgnc_id:HGNC:391 HGNC:391 ENTREZ:207 UNIPROT:P31749 AKT serine/threonine kinase 2 HUGO:AKT2 hgnc_id:HGNC:392 HGNC:392 ENTREZ:208 UNIPROT:P31751 AKT serine/threonine kinase 3 HUGO:AKT3 hgnc_id:HGNC:393 HGNC:393 ENTREZ:10000 UNIPROT:Q9Y243 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:PDGF PMID:11696562 Integrin-linked kinase (ILK) is a binding partner of the integrin 1 and 3 subunits and is involved in the signal transduction from integrin receptors The activity is stimulated in a phosphatidylinositol (PI) 3-kinase–dependent manner and likely involves binding of the phosphoinositide phospholipid product of PI 3-kinase, PI 3,4,5-triphosphate, to the PH-like domain of ILK ILK has been shown recently to directly phosphorylate proteins such as PKB (PKB/Akt) on ser 473. PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast PMID:25732845 Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling PMID:11747822 Akt but not SGK promotes cell motility downstream of the PI3-K-PDK1 pathway. References_end </body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="4260.0" y="2850.0"/> <glyph class="state variable" id="_401a843b-c623-4e55-9088-a05a428f3e61"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4255.0" y="2865.0"/> </glyph> </glyph> <glyph class="complex" id="s1115_csa48" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PDPK1:PIP3* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF References_end </body> </html> </notes> <label text="s1115"/> <bbox w="100.0" h="120.0" x="4000.0" y="2620.0"/> <glyph class="macromolecule" id="s1116_sa441"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: pyruvate dehydrogenase kinase 1 HUGO:PDK1 hgnc_id:HGNC:8809 HGNC:8809 ENTREZ:5163 UNIPROT:Q15118 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF PMID:11687500 Binding to second messenger lipids allows PDK1 and AKT (PKB) to interact with each other, resulting in the phosphorylation and consequent activation of AKT (PKB). PMID:11747822 Akt but not SGK promotes cell motility downstream of the PI3-K-PDK1 pathway. References_end </body> </html> </notes> <label text="PDPK1"/> <bbox w="80.0" h="40.0" x="4010.0" y="2630.0"/> </glyph> <glyph class="simple chemical" id="s3588_sa442"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> MODULE:NK PMID:12040186 The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. PMID:9438848 PI3K product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav proteins PMID:12393695 SHIP1 inhinits NK cells activation via bloking of PI3K pathway. It hydrolyzes the 5′-phosphate of PI3,4,5P3l eading to its conversion to PI3,4P2. PMID:20363967, PMID:16204085 Src homology 2-containing inositol 5'-phosphatase 1 negatively regulates IFN-gamma production by natural killer cells stimulated with antibody-coated tumor cells and interleukin-12, probably via inhibition of PI3K pathway and downstream ERK signaling. </body> </html> </notes> <label text="PIP3*"/> <bbox w="70.0" h="25.0" x="4015.0" y="2687.5"/> </glyph> </glyph> <glyph class="complex" id="s1700_csa82" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CDC42:GTP Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:CAV PMID:18037882 Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells PMID:11747822 Rac and Cdc42 are capable of inducing phosphorylation of Akt and that PDGF induces phosphorylation of Akt at least in part through Rac in fibroblasts. Expression of Rac V12 or Cdc42 V12 stimulated cell motility Figure 2 and Figure 3[14]. Coexpression of dominant-negative Akt suppressed cell motility stimulated by active Rac and Cdc42 to the basal levels (Figure 2d), suggesting that Akt is an essential downstream effector of Rac and Cdc42 in stimulating cell motility. PMID:10753747 Pten regulates PI3K pathway via its phosphatase activity on phosphatidylinositol (PI) 3,4,5-trisphosphate (PI(3,4,5)P3), a product of PI 3-kinase. Pten-deficient fibroblasts migrate faster than wild type. there are marked increases of the GTP-bound forms of Rac1 and Cdc42 in logarithmically growing Pten−/− cells compared to wild-type cells, although the total protein levels are not affected by the Pten status. similar to Akt, Rac1 and Cdc42 activation in Pten−/− cells is downstream of PI 3-kinase. References_end </body> </html> </notes> <label text="s1700"/> <bbox w="100.0" h="120.0" x="6170.0" y="3034.0"/> <glyph class="macromolecule" id="s1694_sa687"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: cell division cycle 42 HUGO:CDC42 hgnc_id:HGNC:1736 HGNC:1736 ENTREZ:998 UNIPROT:P60953 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:CAV PMID:17517963 caveolin-deficient MEFs showed a notable decrease in basal Rho activity and a significant increase in Rac and Cdc42 activity PMID:21178402 Rac1 and Cdc42 activate ARP2/3 complex; Rac1 and Cdc42 activate Wiskott-Aldrich Syndrome family of proteins including WASP, N-WASP and WAVE1/2. Cdc42 is also involved in Golgi apparatus and MTOC reorientation in wound-edge fibroblasts. PMID:27248291 Cdc42 regulates Cdc42EP3 function in cancer-associated ﬁbroblasts Inhibiting Cdc42 function by transient expression of the dominant negative Cdc42-N17 protein resulted in a loss of ﬁlamentous Cdc42EP3 structures and reduced F-actin stress ﬁbers and ﬁlamentous SEPT2 PMID:15882626 Cdc42 and MRCK Activate Nuclear Movement to Reorient the MTOC (The microtubule-organizing center )in fibroblasts References_end </body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="6180.0" y="3054.0"/> </glyph> <glyph class="simple chemical" id="s1701_sa688"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="6185.0" y="3101.5"/> </glyph> </glyph> <glyph class="complex" id="s1703_csa83" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CDC42:GDP Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:CAV References_end </body> </html> </notes> <label text="s1703"/> <bbox w="100.0" h="120.0" x="6390.0" y="3034.0"/> <glyph class="simple chemical" id="s1704_sa689"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="6408.75" y="3100.875"/> </glyph> <glyph class="macromolecule" id="s1702_sa690"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: cell division cycle 42 HUGO:CDC42 hgnc_id:HGNC:1736 HGNC:1736 ENTREZ:998 UNIPROT:P60953 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:CAV PMID:17517963 caveolin-deficient MEFs showed a notable decrease in basal Rho activity and a significant increase in Rac and Cdc42 activity PMID:21178402 Rac1 and Cdc42 activate ARP2/3 complex; Rac1 and Cdc42 activate Wiskott-Aldrich Syndrome family of proteins including WASP, N-WASP and WAVE1/2. Cdc42 is also involved in Golgi apparatus and MTOC reorientation in wound-edge fibroblasts. PMID:27248291 Cdc42 regulates Cdc42EP3 function in cancer-associated ﬁbroblasts Inhibiting Cdc42 function by transient expression of the dominant negative Cdc42-N17 protein resulted in a loss of ﬁlamentous Cdc42EP3 structures and reduced F-actin stress ﬁbers and ﬁlamentous SEPT2 PMID:15882626 Cdc42 and MRCK Activate Nuclear Movement to Reorient the MTOC (The microtubule-organizing center )in fibroblasts References_end </body> </html> </notes> <label text="CDC42"/> <bbox w="80.0" h="40.0" x="6401.0" y="3044.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4177_sa460" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase 11 HUGO:MAPK11 hgnc_id:HGNC:6873 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 mitogen-activated protein kinase 12 HUGO:MAPK12 hgnc_id:HGNC:6874 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 mitogen-activated protein kinase 13 HUGO:MAPK13 hgnc_id:HGNC:6875 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 mitogen-activated protein kinase 14 HUGO:MAPK14 hgnc_id:HGNC:6876 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 CASCADE:TNF CASCADE:TGFB CASCADE:PDGFB PMID:15653932 TNF signaling activates ERK,JNK and p38 kinases in fibroblasts and induses TGFB expression via ERK PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,p38) PMID:26921338 PDGFB inhibits PEDF expression via p38 and JNK References_end </body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="5320.0" y="3186.0"/> <glyph class="state variable" id="_e5a31acb-8aee-43e4-9701-cfa4effa75d8"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5315.0" y="3200.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s742_sa461" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 TLR2 activates (induses phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: mitogen-activated protein kinase 8 HUGO:MAPK8 hgnc_id:HGNC:6881 HGNC:6881 ENTREZ:5599 UNIPROT:P45983 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 mitogen-activated protein kinase 9 HUGO:MAPK9 hgnc_id:HGNC:6886 HGNC:6886 ENTREZ:5601 UNIPROT:P45984 mitogen-activated protein kinase 10 HUGO:MAPK10 hgnc_id:HGNC:6872 HGNC:6872 ENTREZ:5602 UNIPROT:P53779 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: REACTOME:59293 KEGG:5599 ATLASONC:JNK1ID196 WIKI:MAPK8 mitogen-activated protein kinase 9 REACTOME:59295 KEGG:5601 ATLASONC:JNK2ID426 WIKI:MAPK9 mitogen-activated protein kinase 10 REACTOME:59297 KEGG:5602 ATLASONC:JNK3ID427 WIKI:MAPK10 CADCADE:TNF CASCADE:IL1 CASCADE:PDGFB PMID:15653932 TNF signaling activates ERK,JNK and p38 kinases in fibroblasts and induses TGFB expression via ERK PMID:26921338 PDGFB inhibits PEDF expression via p38 and JNK References_end </body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="5080.0" y="3191.0"/> <glyph class="state variable" id="_1c5dd79e-ed0a-4c3c-acd1-689be05b6075"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5075.0" y="3206.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4178_sa463" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase 11 HUGO:MAPK11 hgnc_id:HGNC:6873 HGNC:6873 ENTREZ:5600 UNIPROT:Q15759 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 mitogen-activated protein kinase 12 HUGO:MAPK12 hgnc_id:HGNC:6874 HGNC:6874 ENTREZ:6300 UNIPROT:P53778 mitogen-activated protein kinase 13 HUGO:MAPK13 hgnc_id:HGNC:6875 HGNC:6875 ENTREZ:5603 UNIPROT:O15264 mitogen-activated protein kinase 14 HUGO:MAPK14 hgnc_id:HGNC:6876 HGNC:6876 ENTREZ:1432 UNIPROT:Q16539 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: REACTOME:59299 KEGG:5600 ATLASONC:GC_MAPK11 WIKI:MAPK11 REACTOME:69723 KEGG:6300 ATLASONC:MAPK12ID41290ch22q13 WIKI:MAPK12 REACTOME:59303 KEGG:5603 ATLASONC:MAPK13ID41291ch6p21 WIKI:MAPK13 REACTOME:405912 KEGG:1432 ATLASONC:MAPK14ID41292ch6p21 WIKI:MAPK14 CASCADE:TNF CASCADE:TGFB CASCADE:PDGFB PMID:15653932 TNF signaling activates ERK,JNK and p38 kinases in fibroblasts and induses TGFB expression via ERK PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,p38) PMID:26921338 PDGFB inhibits PEDF expression via p38 and JNK References_end </body> </html> </notes> <label text="p38*"/> <bbox w="80.0" h="40.0" x="5320.0" y="3315.0"/> <glyph class="state variable" id="_2b7946c5-868e-4987-bea6-a171765962f0"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5312.5" y="3329.9683"/> </glyph> </glyph> <glyph class="macromolecule" id="s4182_sa767" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: phosphatase and tensin homolog HUGO:PTEN hgnc_id:HGNC:9588 HGNC:9588 ENTREZ:5728 UNIPROT:P60484 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:24254977 PMID:19847259 Fibroblast-speciﬁc deletion of Pten in this manner resulted in increased primary tumour growth the authors linked Pten loss in ﬁbroblasts to increased Ras–Akt signalling, as well as increased activity of the Ets-2 transcription factor and associated increases in expression of MMP9, an Ets-2 target genes. PMID:10753747 Pten regulates PI3K pathway via its phosphatase activity on phosphatidylinositol (PI) 3,4,5-trisphosphate (PI(3,4,5)P3), a product of PI 3-kinase. Pten-deficient fibroblasts migrate faster than wild type. there are marked increases of the GTP-bound forms of Rac1 and Cdc42 in logarithmically growing Pten−/− cells compared to wild-type cells, although the total protein levels are not affected by the Pten status. similar to Akt, Rac1 and Cdc42 activation in Pten−/− cells is downstream of PI 3-kinase. PMID:11747822 phosphorylation of Akt is elevated in the PTEN-deficient mouse embryonic fibroblasts (PTEN−/− MEFs) compared to the level in PTEN+/− MEFs (Figure 4b) and that the cell motility of the PTEN-deficient MEFs is higher than that of PTEN+/− MEFs PMID:25364523 We cultured cardiac fibroblasts of mice were in hypoxia or normoxia conditions for 12, 24 and 48 hours. At all the time points, caveolin-1 and PTEN expression were gradually reduced, whereas, α-SMA was gradually increased. PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="PTEN"/> <bbox w="80.0" h="40.0" x="3490.0" y="2450.0"/> </glyph> <glyph class="macromolecule" id="s4183_sa466" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RB transcriptional corepressor 1 HUGO:RB1 hgnc_id:HGNC:9884 HGNC:9884 ENTREZ:5925 UNIPROT:P06400 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:24254977 Mouse models have validated the tumour-promoting effects of deleting Rb, Pten or p53 in fibroblasts that converts them from normal fibroblasts to carcinoma associated fibroblasts (CAFs). PMID:18458534 Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation References_end </body> </html> </notes> <label text="RB1"/> <bbox w="80.0" h="40.0" x="2980.0" y="2720.0"/> </glyph> <glyph class="macromolecule" id="s4184_sa467" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor protein p53 HUGO:TP53 hgnc_id:HGNC:11998 HGNC:11998 ENTREZ:7157 UNIPROT:P04637 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26302407 Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation Levels of CSL, p53 and CDKN1A expression were all significantly decreased in lesion-adjacent stroma versus distant unaffected skin PMID:24254977 Mouse models have validated the tumour-promoting effects of deleting Rb, Pten or p53 in fibroblasts that converts them from normal fibroblasts to carcinoma associated fibroblasts (CAFs). PMID:19836055 P53 expression in tumor-stromal fibroblasts is closely associated with the nodal metastasis and outcome of patients with invasive ductal carcinoma who received neoadjuvant therapy References_end </body> </html> </notes> <label text="TP53"/> <bbox w="80.0" h="40.0" x="2520.0" y="2760.0"/> </glyph> <glyph class="macromolecule" id="s4198_sa468"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:WNT7 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:26777421 Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Wnt7a does not signal through the classical Wnt pathways to trigger CAF conversion but potentiates TGFβ receptor signalling. References_end </body> </html> </notes> <label text="WNT7"/> <bbox w="80.0" h="40.0" x="3170.0" y="510.0"/> </glyph> <glyph class="macromolecule" id="s1118_sa437" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: AKT serine/threonine kinase 1 HUGO:AKT1 hgnc_id:HGNC:391 HGNC:391 ENTREZ:207 UNIPROT:P31749 AKT serine/threonine kinase 2 HUGO:AKT2 hgnc_id:HGNC:392 HGNC:392 ENTREZ:208 UNIPROT:P31751 AKT serine/threonine kinase 3 HUGO:AKT3 hgnc_id:HGNC:393 HGNC:393 ENTREZ:10000 UNIPROT:Q9Y243 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:PDGF PMID:11696562 Integrin-linked kinase (ILK) is a binding partner of the integrin 1 and 3 subunits and is involved in the signal transduction from integrin receptors The activity is stimulated in a phosphatidylinositol (PI) 3-kinase–dependent manner and likely involves binding of the phosphoinositide phospholipid product of PI 3-kinase, PI 3,4,5-triphosphate, to the PH-like domain of ILK ILK has been shown recently to directly phosphorylate proteins such as PKB (PKB/Akt) on ser 473. PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast PMID:25732845 Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling PMID:11747822 Akt but not SGK promotes cell motility downstream of the PI3-K-PDK1 pathway. References_end </body> </html> </notes> <label text="AKT*"/> <bbox w="80.0" h="40.0" x="4010.0" y="2850.0"/> <glyph class="state variable" id="_e03cd258-a55f-4c7b-9626-d01e7de14d1f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4002.5" y="2865.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4201_sa471" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCDC88A Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:25732845 PMID:16139227 Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression, probably via regulation of fibroblast migration. Phosphorylation of Girdin by Akt Is Required for Cell Migration. Girdin Is Required for the Formation of Actin Stress Fibers and Cell Migration References_end </body> </html> </notes> <label text="CCDC88A"/> <bbox w="80.0" h="40.0" x="4275.0" y="3025.0"/> <glyph class="state variable" id="_a0112de6-9e7a-43e2-98f4-91c877f747f9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4270.0" y="3040.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4202_sa472" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCDC88A Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:25732845 PMID:16139227 Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression, probably via regulation of fibroblast migration. Phosphorylation of Girdin by Akt Is Required for Cell Migration. Girdin Is Required for the Formation of Actin Stress Fibers and Cell Migration References_end </body> </html> </notes> <label text="CCDC88A"/> <bbox w="80.0" h="40.0" x="4460.0" y="3020.0"/> <glyph class="state variable" id="_cf7f30c8-34d2-4cd4-ab59-274dfa1748ba"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4452.5" y="3035.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4204_sa474" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12702545 Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="90.0" h="25.0" x="3805.0" y="1662.5"/> <glyph class="unit of information" id="_8429de93-fe72-4e7f-8c7f-0034807a48bd"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3840.0" y="1657.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4205_sa475" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:S100A4 Maps_Modules_begin: MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 TGFB upregulates FSP1 (S100A4) expression via Smad2 and smad3 PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1, BMP4, IL6, CXCL7, IL6R,IL6ST,CXCL5 References_end </body> </html> </notes> <label text="S100A4"/> <bbox w="70.0" h="25.0" x="1815.0" y="3947.5"/> </glyph> <glyph class="nucleic acid feature" id="s4206_sa476" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:S100A4 Maps_Modules_begin: MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 TGFB upregulates FSP1 (S100A4) expression via Smad2 and smad3 PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1, BMP4, IL6, CXCL7, IL6R,IL6ST,CXCL5 References_end </body> </html> </notes> <label text="S100A4"/> <bbox w="90.0" h="25.0" x="1805.0" y="4027.5"/> <glyph class="unit of information" id="_3ae67cb8-d0a7-419c-9066-849c240c5903"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1840.0" y="4022.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4207_sa477" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD7 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="SMAD7"/> <bbox w="90.0" h="25.0" x="3424.0" y="1107.5"/> <glyph class="unit of information" id="_edc92587-de6b-444c-91bc-42b8c5145375"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3459.0" y="1102.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4208_sa478" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD7 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="SMAD7"/> <bbox w="70.0" h="25.0" x="3434.0" y="1047.5"/> </glyph> <glyph class="nucleic acid feature" id="s4209_sa479" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR21 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="MIR21"/> <bbox w="90.0" h="25.0" x="3325.0" y="1107.5"/> <glyph class="unit of information" id="_17abe119-ec6b-47c8-b9f2-aedebb0d7022"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3355.0" y="1102.5"/> </glyph> </glyph> <glyph class="complex" id="s4210_csa53" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR21:SMAD7 Identifiers_end References_begin: PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="s4210"/> <bbox w="100.0" h="120.0" x="3350.0" y="1170.0"/> <glyph class="nucleic acid feature" id="s4211_sa480"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMAD7 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="SMAD7"/> <bbox w="90.0" h="25.0" x="3355.0" y="1227.5"/> <glyph class="unit of information" id="_4e7fb3c5-927e-4369-b7f8-946fdff74c29"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3390.0" y="1222.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4212_sa481"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR21 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="MIR21"/> <bbox w="90.0" h="25.0" x="3355.0" y="1187.5"/> <glyph class="unit of information" id="_c553cb24-6e27-4683-8dda-756551fde76b"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3385.0" y="1182.5"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4213_sa482" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR21 Maps_Modules_begin: MODULE:CAF MODULE:CORE MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="MIR21"/> <bbox w="70.0" h="25.0" x="3235.0" y="1107.5"/> </glyph> <glyph class="macromolecule" id="s4215_sa244" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 2 HUGO:SMAD2 hgnc_id:HGNC:6768 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts. For the TGF-β pathway, the Smad proteins, Smad2 and Smad3, are ligand-responsive PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="3690.0" y="1765.0"/> <glyph class="state variable" id="_a8a4e4ed-a755-4a19-9176-25deb9cae1de"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3682.5" y="1779.9681"/> </glyph> </glyph> <glyph class="complex" id="s4216_csa54" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SMAD2:SMAD7 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: PMID:23784029 Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. References_end </body> </html> </notes> <label text="s4216"/> <bbox w="100.0" h="120.0" x="3430.0" y="1340.0"/> <glyph class="macromolecule" id="s4218_sa484"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 7 HUGO:SMAD7 hgnc_id:HGNC:6773 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: CASCADE:TGFB _INHIBITION_ANTITUMOR PMID:15265520,PMID:14722617 SMAD7 has been shown to interact with the E3 ubiquitin ligases Smurf 1 and Smurf 2, recruiting them to TβR complexes and inducing the degradation of activated TβRI [20] and [21]. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="SMAD7"/> <bbox w="80.0" h="40.0" x="3440.0" y="1400.0"/> </glyph> <glyph class="macromolecule" id="s4221_sa487"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 2 HUGO:SMAD2 hgnc_id:HGNC:6768 HGNC:6768 ENTREZ:4087 UNIPROT:Q15796 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts. For the TGF-β pathway, the Smad proteins, Smad2 and Smad3, are ligand-responsive PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD2"/> <bbox w="80.0" h="40.0" x="3440.0" y="1350.0"/> <glyph class="state variable" id="_4309b47d-fd9c-49b7-8ff7-85cb84b7a7d3"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3435.0" y="1364.9681"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4217_csa55" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SMAD3:SMAD7 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: PMID:23784029 Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. References_end </body> </html> </notes> <label text="s4217"/> <bbox w="100.0" h="120.0" x="3550.0" y="1330.0"/> <glyph class="macromolecule" id="s4219_sa485"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 7 HUGO:SMAD7 hgnc_id:HGNC:6773 HGNC:6773 ENTREZ:4092 UNIPROT:O15105 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: CASCADE:TGFB _INHIBITION_ANTITUMOR PMID:15265520,PMID:14722617 SMAD7 has been shown to interact with the E3 ubiquitin ligases Smurf 1 and Smurf 2, recruiting them to TβR complexes and inducing the degradation of activated TβRI [20] and [21]. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts PMID:23784029 mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. References_end </body> </html> </notes> <label text="SMAD7"/> <bbox w="80.0" h="40.0" x="3560.0" y="1390.0"/> </glyph> <glyph class="macromolecule" id="s4220_sa486"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 3 HUGO:SMAD3 hgnc_id:HGNC:6769 HGNC:6769 ENTREZ:4088 UNIPROT:P84022 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:12702545, PMID:8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="3560.0" y="1340.0"/> <glyph class="state variable" id="_7130ce98-ac99-4755-afab-0573e6c4f071"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3555.0" y="1355.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s1332_csa12" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:SMAD3:SMAD4 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB 11013125 ; 11376132 CTGF expression is induced by TGF- beta in fibroblasts via SMAD3 and SMAD4 pathway 11792802, 12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocatio 12702545, 8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. 23784029 Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. 21098712; 22652804; 25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,jnk,p38) References_end </body> </html> </notes> <label text="s1332"/> <bbox w="100.0" h="120.0" x="4050.0" y="1810.0"/> <glyph class="macromolecule" id="s1333_sa263"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 4 HUGO:SMAD4 hgnc_id:HGNC:6770 HGNC:6770 ENTREZ:4089 UNIPROT:Q13485 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling in fibroblasts PMID:12702545 Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment References_end </body> </html> </notes> <label text="SMAD4"/> <bbox w="80.0" h="40.0" x="4060.0" y="1870.0"/> </glyph> <glyph class="macromolecule" id="s1334_sa262"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD family member 3 HUGO:SMAD3 hgnc_id:HGNC:6769 HGNC:6769 ENTREZ:4088 UNIPROT:P84022 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:11792802, PMID:12809600 The canonical TGFB signalling pathway involves phosphorylation of the carboxy-terminal serine residue of the internal modulator SMAD proteins, SMAD2 or SMAD3, by the activated receptors. This phosphorylation induces oligomerization of SMAD2 or SMAD3 with SMAD4, which is necessary for nuclear translocation. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:12702545, PMID:8515656 Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Protein level of SMAD3 and SMAD4 is upregulated after TGFB treatment PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation References_end </body> </html> </notes> <label text="SMAD3"/> <bbox w="80.0" h="40.0" x="4060.0" y="1820.0"/> <glyph class="state variable" id="_c3761d34-61ec-41ba-966f-9934ea8cc535"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4052.5" y="1835.0"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4222_sa488" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TNC Maps_Modules_begin: MODULE:CAF MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1, BMP4, IL6, CXCL7, IL6R,IL6ST,CXCL5 References_end </body> </html> </notes> <label text="TNC"/> <bbox w="90.0" h="25.0" x="1765.0" y="4257.5"/> <glyph class="unit of information" id="_b928acf8-15be-425a-a0d8-db9ec3f95567"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1800.0" y="4252.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4223_sa489" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TNC Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983; PMID:18423981 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1, BMP4, IL6, CXCL7, IL6R,IL6ST,CXCL5 PMID:15001984 Tenascin-C upregulation by transforming growth factor-β in human dermal fibroblasts involves Smad3, Sp1, and Ets1 References_end </body> </html> </notes> <label text="TNC"/> <bbox w="70.0" h="25.0" x="1775.0" y="4187.5"/> </glyph> <glyph class="nucleic acid feature" id="s4224_sa490" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL12 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HGF PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:20535745 junD−/− fibroblasts exhibit features of carcinoma-associated myofibroblasts. The expression of the chemokine CXCL12 was increased in junD−/− fibroblasts. HIF-1α protein accumulates in junD−/− fibroblasts and mice (Gerald et al, 2004; Laurent et al, 2008), the up-regulation of CXCL12 in junD−/− fibroblasts could be mediated, at least partly, through HIF. Specific inhibition of HIF-1α by siRNA strongly reduced HIF-1α mRNA levels (Fig S3A) and decreased the expression of its target gene, CXCL12 References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="70.0" h="25.0" x="1025.0" y="3693.5"/> </glyph> <glyph class="nucleic acid feature" id="s4225_sa491" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL12 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HGF PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="90.0" h="25.0" x="1015.0" y="3773.5"/> <glyph class="unit of information" id="_5c0d9a31-5c7a-4185-acfe-5d09636b150b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1050.0" y="3768.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4226_sa492" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:BMP4 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="BMP4"/> <bbox w="70.0" h="25.0" x="4165.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4227_sa493" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:BMP4 Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="BMP4"/> <bbox w="90.0" h="25.0" x="4155.0" y="4342.5"/> <glyph class="unit of information" id="_1133b62e-adde-4037-aebd-f12faa91269f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4190.0" y="4337.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4228_sa494" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: bone morphogenetic protein 4 HUGO:BMP4 hgnc_id:HGNC:1071 HGNC:1071 ENTREZ:652 UNIPROT:P12644 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="BMP4"/> <bbox w="80.0" h="40.0" x="4160.0" y="4431.0"/> </glyph> <glyph class="nucleic acid feature" id="s4229_sa498" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6R Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="70.0" h="25.0" x="315.0" y="2847.5"/> </glyph> <glyph class="nucleic acid feature" id="s4230_sa499" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6ST Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="70.0" h="25.0" x="445.0" y="2847.5"/> </glyph> <glyph class="nucleic acid feature" id="s4231_sa500" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6R Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="90.0" h="25.0" x="305.0" y="2777.5"/> <glyph class="unit of information" id="_558254ab-0067-4fcb-af68-eb2de5a11ba7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="340.0" y="2772.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4232_sa501" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6ST Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="gp130"/> <bbox w="90.0" h="25.0" x="435.0" y="2777.5"/> <glyph class="unit of information" id="_e10f0d5d-f52d-4ccc-b33d-68d200f998ae"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="470.0" y="2772.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4233_sa502" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 5 HUGO:CXCL5 hgnc_id:HGNC:10642 HGNC:10642 ENTREZ:6374 UNIPROT:P42830 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CXCL5"/> <bbox w="80.0" h="40.0" x="1370.0" y="3584.0"/> </glyph> <glyph class="nucleic acid feature" id="s4234_sa503" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PPBP Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CXCL7"/> <bbox w="70.0" h="25.0" x="1235.0" y="3441.5"/> </glyph> <glyph class="nucleic acid feature" id="s4235_sa504" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PPBP Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CXCL7"/> <bbox w="90.0" h="25.0" x="1225.0" y="3517.0"/> <glyph class="unit of information" id="_ad67a4d0-d7c1-4518-bc7a-75fee87cfb3d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1260.0" y="3512.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4236_sa505" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL5 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CXCL5"/> <bbox w="70.0" h="25.0" x="1375.0" y="3441.5"/> </glyph> <glyph class="nucleic acid feature" id="s4237_sa506" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL5 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 References_end </body> </html> </notes> <label text="CXCL5"/> <bbox w="90.0" h="25.0" x="1365.0" y="3517.0"/> <glyph class="unit of information" id="_34d04499-785e-46ca-b387-1c651bc771b1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1400.0" y="3512.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4239_sa509" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 receptor HUGO:IL6R hgnc_id:HGNC:6019 HGNC:6019 ENTREZ:3570 UNIPROT:P08887 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="310.0" y="2685.0"/> <glyph class="unit of information" id="_372450a5-6ff5-4453-91d6-c8330af38beb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="327.5" y="2680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4238_sa508" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="440.0" y="2685.0"/> <glyph class="state variable" id="_1c310faf-f50d-4d28-adc7-c5119ebcbe9b"> <state value="" variable="Y759"/> <bbox w="30.0" h="10.0" x="505.0" y="2682.541"/> </glyph> <glyph class="unit of information" id="_da96987b-4f54-430b-a721-e5e87e288ee1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="457.5" y="2680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4240_sa511" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: FK506 binding protein 1A HUGO:FKBP1A hgnc_id:HGNC:3711 HGNC:3711 ENTREZ:2280 UNIPROT:P62942 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:14766396 , PMID:11226255 FKBP12 functions as a "guardian" for the type I receptors to prevent them from leaky signaling under sub-optimal ligand concentrations, thereby providing a molecular "gradient reader" for TGF-beta family morphogens. Unphosphorylated TβRI forms complexes with the FK506-binding protein (FKBP12). Binding of the latter to the GS region of TβRI caps the TβRII phosphorylation sites, thus further stabilizing TβRI in its inactive conformation References_end </body> </html> </notes> <label text="FKBP1A"/> <bbox w="80.0" h="40.0" x="3570.0" y="1060.0"/> </glyph> <glyph class="macromolecule" id="s4242_sa513" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1 hgnc_id:HGNC:16807 HGNC:16807 ENTREZ:57154 UNIPROT:Q9HCE7 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 SMAD7 has been shown to interact with the E3 ubiquitin ligases Smurf 1 and Smurf 2, recruiting them to TβR complexes and inducing the degradation of activated TβRI PMID:14722617 Overexpression of Smurf1 and Smurf2 further significantly reduced the levels of TβRI protein in normal fibroblasts treated with TGF-β1 References_end </body> </html> </notes> <label text="SMURF1"/> <bbox w="80.0" h="40.0" x="3550.0" y="1140.0"/> </glyph> <glyph class="macromolecule" id="s4243_sa514" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SMAD specific E3 ubiquitin protein ligase 1 HUGO:SMURF1 hgnc_id:HGNC:16807 HGNC:16807 ENTREZ:57154 UNIPROT:Q9HCE7 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 SMAD7 has been shown to interact with the E3 ubiquitin ligases Smurf 1 and Smurf 2, recruiting them to TβR complexes and inducing the degradation of activated TβRI PMID:14722617 Overexpression of Smurf1 and Smurf2 further significantly reduced the levels of TβRI protein in normal fibroblasts treated with TGF-β1 References_end </body> </html> </notes> <label text="SMURF2"/> <bbox w="80.0" h="40.0" x="3540.0" y="1240.0"/> </glyph> <glyph class="macromolecule" id="s4244_sa515" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: CREB binding protein HUGO:CREBBP hgnc_id:HGNC:2348 HGNC:2348 ENTREZ:1387 UNIPROT:Q92793 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 The role for CREB binding protein (CBP) and p300 as essential coactivators for SMAD-driven gene expression has been well documented and competition for p300/CBP has been suggested to mediate some examples of signal-induced transcriptional repression. References_end </body> </html> </notes> <label text="CREBBP"/> <bbox w="80.0" h="40.0" x="5390.0" y="3520.0"/> </glyph> <glyph class="macromolecule" id="s4245_sa516" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: E1A binding protein p300 HUGO:EP300 hgnc_id:HGNC:3373 HGNC:3373 ENTREZ:2033 UNIPROT:Q09472 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 The role for CREB binding protein (CBP) and p300 as essential coactivators for SMAD-driven gene expression has been well documented and competition for p300/CBP has been suggested to mediate some examples of signal-induced transcriptional repression. PMID:10918613 For Smad-dependent stimulation of collagen (COL1A2 )synthesis, the interaction of activated Smad2/3 with p300 is essential (Ghosh et al., 2001, 2004a). Furthermore, the acetyltransferase activity of p300 is required for maximal stimulation as shown by the fact that fibroblasts transfected with HAT-deleted mutants of p300 showed markedly reduced TGF-β stimulation of COL1A2 promoter activity (Ghosh et al., 2000). References_end </body> </html> </notes> <label text="EP300"/> <bbox w="80.0" h="40.0" x="5030.0" y="3810.0"/> </glyph> <glyph class="macromolecule" id="s4241_sa512" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: zinc finger FYVE-type containing 9 HUGO:ZFYVE9 hgnc_id:HGNC:6775 HGNC:6775 ENTREZ:9372 UNIPROT:O95405 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:9865696 ZFYVE9 (SARA, Smad anchor for receptor activation), is a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor PMID:19620243 BUT!!! the transition of epithelial cells to a mesenchymal/fibroblastic phenotype might include a reduction in the expression of SARA. TGF-β1 treatment for 3 and 5 days resulted in a reduction in SARA corresponding to the timing of an increase in TGF-β1-induced smooth muscle α-actin (αSMA) expression. References_end </body> </html> </notes> <label text="ZFYVE9"/> <bbox w="80.0" h="40.0" x="3590.0" y="1725.0"/> </glyph> <glyph class="nucleic acid feature" id="s4247_sa518" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EP300 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:TGFB References_end </body> </html> </notes> <label text="EP300"/> <bbox w="90.0" h="25.0" x="5025.0" y="3737.5"/> <glyph class="unit of information" id="_6898053d-32bc-4799-9e48-a93721423c3f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5060.0" y="3732.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4246_sa517" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EP300 Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:17559085 in both skin and lung fibroblasts, TGF-β enhanced p300 mRNA, and protein expression. The human p300 gene has been recently cloned. The regulatory region is highly GC-rich, and contains six early growth response 1 (Egr-1) binding sites, along with serum response elements and Sp1 binding sites (Yu et al., 2004). Ectopic expression of Egr-1 in skin fibroblasts by itself stimulated basal p300 gene expression, and further enhanced the stimulation induced by TGF-β. Furthermore, reporter constructs driven by p300 promoter fragments harboring mutations in the Egr-1 binding sites failed to respond to TGF-β in transient transfection assays (Ghosh et al., unpublished data). These observations establish a critical role for Egr-1 in the regulation of p300 gene expression by TGF-β in normal fibroblasts. References_end </body> </html> </notes> <label text="EP300"/> <bbox w="70.0" h="25.0" x="5035.0" y="3667.5"/> </glyph> <glyph class="complex" id="s4250_csa56" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:EP300:STAT1 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IFNG PMID:17559085, PMID:11134049 IFN-γ induced a direct interaction between activated STAT1α and p300 in normal skin fibroblasts (Ghosh et al., 2001). Furthermore, ectopic expression of p300 overcame the inhibition by IFN-γ and rescued stimulation by TGF-β, suggesting that in response to IFN-γ, activated STAT1α and/or downstream factor(s) sequestered p300, preventing its recruitment to the transcriptional machinery and thereby inhibiting collagen gene transcription (Ghosh et al., 2001). Similarly, IFN-γ suppression of COL1A2 promoter activation by YB-1 also appears to involve p300 sequestration (Higashi et al., 2003). References_end </body> </html> </notes> <label text="s4250"/> <bbox w="100.0" h="120.0" x="5530.0" y="3640.0"/> <glyph class="macromolecule" id="s4251_sa522"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: signal transducer and activator of transcription 1 HUGO:STAT1 hgnc_id:HGNC:11362 HGNC:11362 ENTREZ:6772 UNIPROT:P42224 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR CASCADE:IFNG PMID:17559085, PMID:11134049 IFN-γ induced a direct interaction between activated STAT1α and p300 in normal skin fibroblasts (Ghosh et al., 2001). Furthermore, ectopic expression of p300 overcame the inhibition by IFN-γ and rescued stimulation by TGF-β, suggesting that in response to IFN-γ, activated STAT1α and/or downstream factor(s) sequestered p300, preventing its recruitment to the transcriptional machinery and thereby inhibiting collagen gene transcription (Ghosh et al., 2001). Similarly, IFN-γ suppression of COL1A2 promoter activation by YB-1 also appears to involve p300 sequestration (Higashi et al., 2003). References_end </body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="5540.0" y="3700.0"/> <glyph class="state variable" id="_daa744d1-ea60-48a9-b447-1fa35b5f013a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5535.0" y="3715.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4252_sa523"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: E1A binding protein p300 HUGO:EP300 hgnc_id:HGNC:3373 HGNC:3373 ENTREZ:2033 UNIPROT:Q09472 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 The role for CREB binding protein (CBP) and p300 as essential coactivators for SMAD-driven gene expression has been well documented and competition for p300/CBP has been suggested to mediate some examples of signal-induced transcriptional repression. PMID:10918613 For Smad-dependent stimulation of collagen (COL1A2 )synthesis, the interaction of activated Smad2/3 with p300 is essential (Ghosh et al., 2001, 2004a). Furthermore, the acetyltransferase activity of p300 is required for maximal stimulation as shown by the fact that fibroblasts transfected with HAT-deleted mutants of p300 showed markedly reduced TGF-β stimulation of COL1A2 promoter activity (Ghosh et al., 2000). References_end </body> </html> </notes> <label text="EP300"/> <bbox w="80.0" h="40.0" x="5540.0" y="3650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4249_sa753" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: signal transducer and activator of transcription 1 HUGO:STAT1 hgnc_id:HGNC:11362 HGNC:11362 ENTREZ:6772 UNIPROT:P42224 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR CASCADE:IFNG PMID:17559085, PMID:11134049 IFN-γ induced a direct interaction between activated STAT1α and p300 in normal skin fibroblasts (Ghosh et al., 2001). Furthermore, ectopic expression of p300 overcame the inhibition by IFN-γ and rescued stimulation by TGF-β, suggesting that in response to IFN-γ, activated STAT1α and/or downstream factor(s) sequestered p300, preventing its recruitment to the transcriptional machinery and thereby inhibiting collagen gene transcription (Ghosh et al., 2001). Similarly, IFN-γ suppression of COL1A2 promoter activation by YB-1 also appears to involve p300 sequestration (Higashi et al., 2003). References_end </body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="2850.0" y="1590.0"/> <glyph class="state variable" id="_db6a4cbf-522b-4f41-99cc-662de2e0e16e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2845.0" y="1605.0"/> </glyph> </glyph> <glyph class="complex" id="s4253_csa57" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CREBBP:EP300 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s4253"/> <bbox w="100.0" h="120.0" x="5360.0" y="3720.0"/> <glyph class="macromolecule" id="s4254_sa524"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: CREB binding protein HUGO:CREBBP hgnc_id:HGNC:2348 HGNC:2348 ENTREZ:1387 UNIPROT:Q92793 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 The role for CREB binding protein (CBP) and p300 as essential coactivators for SMAD-driven gene expression has been well documented and competition for p300/CBP has been suggested to mediate some examples of signal-induced transcriptional repression. References_end </body> </html> </notes> <label text="CREBBP"/> <bbox w="80.0" h="40.0" x="5370.0" y="3730.0"/> </glyph> <glyph class="macromolecule" id="s4255_sa525"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: E1A binding protein p300 HUGO:EP300 hgnc_id:HGNC:3373 HGNC:3373 ENTREZ:2033 UNIPROT:Q09472 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:TGFB PMID:15265520 The role for CREB binding protein (CBP) and p300 as essential coactivators for SMAD-driven gene expression has been well documented and competition for p300/CBP has been suggested to mediate some examples of signal-induced transcriptional repression. PMID:10918613 For Smad-dependent stimulation of collagen (COL1A2 )synthesis, the interaction of activated Smad2/3 with p300 is essential (Ghosh et al., 2001, 2004a). Furthermore, the acetyltransferase activity of p300 is required for maximal stimulation as shown by the fact that fibroblasts transfected with HAT-deleted mutants of p300 showed markedly reduced TGF-β stimulation of COL1A2 promoter activity (Ghosh et al., 2000). References_end </body> </html> </notes> <label text="EP300"/> <bbox w="80.0" h="40.0" x="5370.0" y="3780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4257_sa528" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase 3 HUGO:MAPK3 hgnc_id:HGNC:6877 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 mitogen-activated protein kinase 1 HUGO:MAPK1 hgnc_id:HGNC:6871 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 CASCADE:MIF CASCADE:TNF CASCADE:FGF CASCADE:EGFR CASCADE:TGFB GASCADE:IGF1R PMID:12782713 CD74 mediates MIF stimulation of ERK-1/2 (p44/p42) phosphorylation and proliferation of CCL210 human lung fibroblasts. PMID:15653932 TNF signaling activates ERK,JNK and p38 kinases in fibroblasts and induses TGFB expression via ERK PMID:22652804 TGF-β1 CM enhanced fibroblast proliferation and differentiation. FGF-2 is necessary for the fibroblast proliferation induced by TGF. . Fibroblast ERK signaling is required for TGF-β1 CM-induced cell differentiation and proliferation PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,p38) PMID:23010081 FGF2 and EGF signalings act via ERK1/2 in fibroblasts PMID:24782617 IGFR pathway is imporatnd for fibroblast activation. IGF-1-induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="4860.0" y="3186.0"/> <glyph class="state variable" id="_32a6a144-f639-4bb8-a0d0-b72b616afa75"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4855.0" y="3201.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4258_sa529" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase 3 HUGO:MAPK3 hgnc_id:HGNC:6877 HGNC:6877 ENTREZ:5595 UNIPROT:P27361 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 mitogen-activated protein kinase 1 HUGO:MAPK1 hgnc_id:HGNC:6871 HGNC:6871 ENTREZ:5594 UNIPROT:P28482 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: KEGG:5595 ATLASONC:MAPK3ID425ch16p11 WIKI:MAPK3 REACTOME:59283 KEGG:5594 ATLASONC:MAPK1ID41288ch22q11 WIKI:MAPK1 CASCADE:MIF CASCADE:TNF CASCADE:FGF CASCADE:EGFR CASCADE:TGFB GASCADE:IGF1R PMID:12782713 CD74 mediates MIF stimulation of ERK-1/2 (p44/p42) phosphorylation and proliferation of CCL210 human lung fibroblasts. PMID:15653932 TNF signaling activates ERK,JNK and p38 kinases in fibroblasts and induses TGFB expression via ERK PMID:22652804 TGF-β1 CM enhanced fibroblast proliferation and differentiation. FGF-2 is necessary for the fibroblast proliferation induced by TGF. . Fibroblast ERK signaling is required for TGF-β1 CM-induced cell differentiation and proliferation PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,p38) PMID:23010081 FGF2 and EGF signalings act via ERK1/2 in fibroblasts PMID:24782617 IGFR pathway is imporatnd for fibroblast activation. IGF-1-induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="ERK1/2*"/> <bbox w="80.0" h="40.0" x="4860.0" y="3315.0"/> <glyph class="state variable" id="_7d705dfd-fbee-49a7-b617-36c04d5ec2c4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4852.5" y="3330.0"/> </glyph> </glyph> <glyph class="phenotype" id="s4259_sa530" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16572188 Fibroblasts can acquire an activated phenotype, which is associated with an increased proliferative activity and enhanced secretion of ECM proteins such as type I collagen and tenascin C, and also fibronectin that contains the extra domain a (EDA-fibronectin) and SPARC (secreted protein acidic and rich in cysteine). PDGF induces the proliferation of fibroblasts, but does not induce the acquisition of an activated phenotype that is associated with excessive ECM deposition. FGF2 was originally identified as a 'basic fibroblast growth factor', which stimulates the proliferation of 3T3 fibroblasts but not the expression of -smooth-muscle actin. PMID:12782713 CD74 mediates MIF stimulation of ERK-1/2 (p44/p42) phosphorylation and proliferation of CCL210 human lung fibroblasts. PMID:22652804 TGF-β1 CM enhanced fibroblast proliferation and differentiation. FGF-2 is necessary for the fibroblast proliferation induced by TGF. . Fibroblast ERK signaling is required for TGF-β1 CM-induced cell differentiation and proliferation References_end </body> </html> </notes> <label text="Fibroblast_proliferation"/> <bbox w="220.0" h="75.0" x="4540.0" y="3932.5"/> </glyph> <glyph class="complex" id="s4260_csa31" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL1R1:IL1RAP:IRAK4:MYD88 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:19161412 IL-1 signaling is initiated by the recruitment of MyD88 to the IL-1RI/IL-1RAcP complex. The recruitment of MyD88 leads to the recruitment of IRAK1 and IRAK4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. References_end </body> </html> </notes> <label text="s1099"/> <bbox w="186.25" h="145.0" x="2003.0" y="1165.0"/> <glyph class="macromolecule" id="s4261_sa344"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor type 1 HUGO:IL1R1 hgnc_id:HGNC:5993 HGNC:5993 ENTREZ:3554 UNIPROT:P14778 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1R1"/> <bbox w="80.0" h="50.0" x="2009.25" y="1235.0"/> <glyph class="unit of information" id="_2263635c-174a-4c6a-a805-93b6a773efc2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2026.75" y="1230.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4262_sa345"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor accessory protein HUGO:IL1RAP hgnc_id:HGNC:5995 HGNC:5995 ENTREZ:3556 UNIPROT:Q9NPH3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:18977329 IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. References_end </body> </html> </notes> <label text="IL1RAP"/> <bbox w="80.0" h="50.0" x="2013.0" y="1180.0"/> <glyph class="unit of information" id="_a7b4786d-e578-464a-929d-bc791096eab5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2030.5" y="1175.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4158_sa351"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: interleukin 1 receptor associated kinase 4 HUGO:IRAK4 hgnc_id:HGNC:17967 HGNC:17967 ENTREZ:51135 UNIPROT:Q9NWZ3 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 PMID:12682231 IL18 signaling induces IRAK4 activation (phosphorylation) and activate JNK/AP1 pathway via IRAK4 References_end </body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="2099.25" y="1240.0"/> </glyph> <glyph class="macromolecule" id="s3162_sa352"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myeloid differentiation primary response 88 HUGO:MYD88 hgnc_id:HGNC:7562 HGNC:7562 ENTREZ:4615 UNIPROT:Q99836 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL1 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:23811849 HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and iactivates TLR4/MyD88 pathway in dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. PMID:17704786 DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="2099.25" y="1190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4264_sa532" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myeloid differentiation primary response 88 HUGO:MYD88 hgnc_id:HGNC:7562 HGNC:7562 ENTREZ:4615 UNIPROT:Q99836 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL1 Maps_Modules_end References_begin: PMID:14660645, PMID:16878026, PMID:23681101 The adaptor proteins MyD88 and TIRAP associate with TLR 2 and TLR 4 after receptor engagement. PMID:23811849 HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and iactivates TLR4/MyD88 pathway in dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. PMID:17704786 DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. References_end </body> </html> </notes> <label text="MYD88"/> <bbox w="80.0" h="40.0" x="1840.0" y="1330.0"/> </glyph> <glyph class="macromolecule" id="s4265_sa533" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 receptor associated kinase 4 HUGO:IRAK4 hgnc_id:HGNC:17967 HGNC:17967 ENTREZ:51135 UNIPROT:Q9NWZ3 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 PMID:12682231 IL18 signaling induces IRAK4 activation (phosphorylation) and activate JNK/AP1 pathway via IRAK4 References_end </body> </html> </notes> <label text="IRAK4"/> <bbox w="80.0" h="40.0" x="1930.0" y="1370.0"/> </glyph> <glyph class="macromolecule" id="s4266_sa534"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 alpha HUGO:IL1A hgnc_id:HGNC:5991 HGNC:5991 ENTREZ:3552 UNIPROT:P01583 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:19937793 Interleukin-1alpha was an inducer of CCL7 secretion by CAF. PMID:21847358 IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. IL1A upregulates expression of IL6, CCL20, CXCL8, COX2 in CAFs. IL-1α Expression Levels in prostate cancer Tissue Correlated to Poor Clinical Outcome PMID:8910423 IL1A signaling induces ERK1/2 activity and AP1 activation and controls activation of RPS6KA1. In tnfr1o/tnfr2o fibroblasts, hIL-1α, but not mTnfα, activated Raf-1, Raf-B, Mekk, and Mek-1. Also IL1A induces NFkB pathway References_end </body> </html> </notes> <label text="trIL1A"/> <bbox w="80.0" h="40.0" x="1570.0" y="900.0"/> <glyph class="unit of information" id="_dfbb435f-e4e2-4a93-bb12-80f9268fb240"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1585.0" y="895.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4267_sa535" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL1B Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="70.0" h="25.0" x="595.0" y="3168.5"/> </glyph> <glyph class="nucleic acid feature" id="s4268_sa536" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL1B Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="90.0" h="25.0" x="585.0" y="3247.5"/> <glyph class="unit of information" id="_147e3442-26a7-4d3e-9d44-6ec0a92adac6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="620.0" y="3242.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4269_sa537" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 1 beta HUGO:IL1B hgnc_id:HGNC:5992 HGNC:5992 ENTREZ:3553 UNIPROT:P01584 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:20138012 The role of IL-1β as a main upstream regulator of NF-κβ activation in CAFs was also demonstrated References_end </body> </html> </notes> <label text="IL1B"/> <bbox w="80.0" h="40.0" x="590.0" y="3321.5"/> </glyph> <glyph class="macromolecule" id="s3098_sa546" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 1 HUGO:TRAF1 hgnc_id:HGNC:12031 HGNC:12031 ENTREZ:7185 UNIPROT:Q13077 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end </body> </html> </notes> <label text="TRAF1"/> <bbox w="80.0" h="40.0" x="1650.0" y="1360.0"/> </glyph> <glyph class="macromolecule" id="s4282_sa547" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor superfamily member 1B HUGO:TNFRSF1B hgnc_id:HGNC:11917 HGNC:11917 ENTREZ:7133 UNIPROT:P20333 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:TNF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:21232017; PMID:18641653 TNF acts through two transmembrane receptors: TNF receptor 1 (TNFR1), also known as p55 or p60, and TNF receptor 2 (TNFR2), also known as p75 or p80. Macrophages are reported to express both receptors. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts References_end </body> </html> </notes> <label text="TNFR2*"/> <bbox w="80.0" h="50.0" x="1650.0" y="1275.0"/> <glyph class="unit of information" id="_6da2f099-0c99-4b1f-8d7e-a58752c53234"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1667.5" y="1270.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3085_sa548" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: HUGO:BIRC2 HUGO:BIRC3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. References_end </body> </html> </notes> <label text="cIAP*"/> <bbox w="80.0" h="40.0" x="1330.0" y="1630.0"/> </glyph> <glyph class="macromolecule" id="s3095_sa549" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: baculoviral IAP repeat containing 3 HUGO:BIRC3 hgnc_id:HGNC:591 HGNC:591 ENTREZ:330 UNIPROT:Q13489 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. References_end </body> </html> </notes> <label text="BIRC3"/> <bbox w="80.0" h="40.0" x="1310.0" y="1710.0"/> </glyph> <glyph class="macromolecule" id="s3084_sa550" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: baculoviral IAP repeat containing 2 HUGO:BIRC2 hgnc_id:HGNC:590 HGNC:590 ENTREZ:329 UNIPROT:Q13490 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:21232017, PMID:21133840, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. References_end </body> </html> </notes> <label text="BIRC2"/> <bbox w="80.0" h="40.0" x="1220.0" y="1710.0"/> </glyph> <glyph class="complex" id="s804_csa59" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:RBCK1:RNF31:SHARPIN Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 PMID:21232017, PMID:17301840 cIAP1 and cIAP2 modify RIP1, TRAF2 and themselves with K63-linked ubiquitin chains. This creates docking sites for the LUBAC complex, an E3 ligase capable of forming linear polyubiquitin chains. The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex, which by help of its IKK2 subunit also interacts with TRADD-bound TRAF2. In parallel, the TAK1-TAB 2 complex interacts with K63-ubiquitin modiﬁed RIP1 by use of the K63-ubiquitin binding TAB 2 subunit. TAK1 become activated and then phosphorylates and activates IKK2 which in turn now phosphorylates IjBa, marking it for K48-ubiquitination and proteasomal degradation. PMID:24958845 NFkB activation (IkBa degradation) downstream of TNF is LUBAC-dependent in MEFs References_end </body> </html> </notes> <label text="LUBAC"/> <bbox w="110.0" h="150.0" x="1505.0" y="2145.0"/> <glyph class="macromolecule" id="s4195_sa551"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ring finger protein 31 HUGO:RNF31 hgnc_id:HGNC:16031 HGNC:16031 ENTREZ:55072 UNIPROT:Q96EP0 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1. References_end </body> </html> </notes> <label text="RNF31"/> <bbox w="80.0" h="40.0" x="1525.0" y="2155.0"/> </glyph> <glyph class="macromolecule" id="s806_sa552"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SHANK associated RH domain interactor HUGO:SHARPIN hgnc_id:HGNC:25321 HGNC:25321 ENTREZ:81858 UNIPROT:Q9H0F6 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 References_end </body> </html> </notes> <label text="SHARPIN"/> <bbox w="80.0" h="40.0" x="1525.0" y="2195.0"/> </glyph> <glyph class="macromolecule" id="s4196_sa553"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RANBP2-type and C3HC4-type zinc finger containing 1 HUGO:RBCK1 hgnc_id:HGNC:15864 HGNC:15864 ENTREZ:10616 UNIPROT:Q9BYM8 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:TNF Maps_Modules_end References_begin: PMID:24699077 LUBAC, linear ubiquitin chain assembly complex comprises SHANK-associated RH-domain interactor (SHARPIN), heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL1/RBCK1) and the E3 HOIL-1–interacting protein (HOIP/RNF31) —is recruited to the TNFR1 complex via binding to the autoubiquitinated c-IAP1 and c-IAP2 proteins to mediate the assembly of linear polyubiquitin chains on NF-κB essential modifier (NEMO/IKBKG) and RIPK1 References_end </body> </html> </notes> <label text="RBCK1"/> <bbox w="80.0" h="40.0" x="1525.0" y="2235.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4283_sa554" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TSLP Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:IL1 PMID:21339327 TSLP is produced by cancer-associated fibroblasts (CAFs) after activation by tumor-derived TNF and IL-1β TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. PMID:22270071 Probably IL1 and TNF regulate TSLP expression via NFkB References_end </body> </html> </notes> <label text="TSLP"/> <bbox w="70.0" h="25.0" x="1305.0" y="3693.5"/> </glyph> <glyph class="nucleic acid feature" id="s4284_sa555" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TSLP Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF CASCADE:IL1 PMID:21339327 TSLP is produced by cancer-associated fibroblasts (CAFs) after activation by tumor-derived TNF and IL-1β TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. PMID:22270071 Probably IL1 and TNF regulate TSLP expression via NFkB References_end </body> </html> </notes> <label text="TSLP"/> <bbox w="90.0" h="25.0" x="1295.0" y="3773.5"/> <glyph class="unit of information" id="_d84c2408-08ec-4e08-8f39-749764e16ccc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1330.0" y="3768.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4285_sa556" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: thymic stromal lymphopoietin HUGO:TSLP hgnc_id:HGNC:30743 HGNC:30743 ENTREZ:85480 UNIPROT:Q969D9 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:TNF CASCADE:IL1 PMID:21339327 TSLP is produced by cancer-associated fibroblasts (CAFs) after activation by tumor-derived TNF and IL-1β TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. PMID:22270071 Probably IL1 and TNF regulate TSLP expression via NFkB References_end </body> </html> </notes> <label text="TSLP"/> <bbox w="80.0" h="40.0" x="1300.0" y="3851.5"/> </glyph> <glyph class="macromolecule" id="s4289_sa563" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: matrix metallopeptidase 14 HUGO:MMP14 hgnc_id:HGNC:7160 HGNC:7160 ENTREZ:4323 UNIPROT:P50281 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:INTEGRIN PMID:11112697 TNF-α upregulates MT1-MMP mRNA in organ-cultured human skin and dermal fibroblasts in a collagen environment NF-κB inhibitor, SN50, blocks TNF-α and collagen mediated MT1-MMP expression and pro-MMP-2 activation. PMID:18037882 MT1-MMP (MMP14) is required to mediate matrix proteolysis during collective invasion References_end </body> </html> </notes> <label text="MMP14"/> <bbox w="80.0" h="40.0" x="5100.0" y="4590.0"/> </glyph> <glyph class="nucleic acid feature" id="s4290_sa564" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP14 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF CASCADE:INTEGRIN PMID:11112697 TNF-α upregulates MT1-MMP (MMP14) mRNA in organ-cultured human skin and dermal fibroblasts in a collagen environment NF-κB inhibitor, SN50, blocks TNF-α and collagen mediated MT1-MMP expression and pro-MMP-2 activation. PMID:17420280 Analysis of matrix metalloproteinase in vitro and in vivo revealed disturbed MMP13 and MMP14 synthesis in alpha11(-/-) cells. References_end </body> </html> </notes> <label text="MMP14"/> <bbox w="70.0" h="25.0" x="5105.0" y="4427.5"/> </glyph> <glyph class="nucleic acid feature" id="s4291_sa565" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP14 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:INTEGRIN PMID:11112697 TNF-α upregulates MT1-MMP mRNA in organ-cultured human skin and dermal fibroblasts in a collagen environment NF-κB inhibitor, SN50, blocks TNF-α and collagen mediated MT1-MMP expression and pro-MMP-2 activation. References_end </body> </html> </notes> <label text="MMP14"/> <bbox w="90.0" h="25.0" x="5095.0" y="4507.5"/> <glyph class="unit of information" id="_9a4aad73-10cd-465a-8fde-418bfe074a93"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5130.0" y="4502.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4294_sa568"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: collagen type I alpha 1 chain HUGO:COL1A1 hgnc_id:HGNC:2197 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen type I alpha 2 chain HUGO:COL1A2 hgnc_id:HGNC:2198 HGNC:2198 ENTREZ:1278 UNIPROT:P08123 collagen type II alpha 1 chain HUGO:COL2A1 hgnc_id:HGNC:2200 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 collagen type III alpha 1 chain HUGO:COL3A1 hgnc_id:HGNC:2201 HGNC:2201 ENTREZ:1281 UNIPROT:P02461 collagen type IV alpha 1 chain HUGO:COL4A1 hgnc_id:HGNC:2202 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 collagen type IV alpha 2 chain HUGO:COL4A2 hgnc_id:HGNC:2203 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 collagen type IV alpha 3 chain HUGO:COL4A3 hgnc_id:HGNC:2204 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 collagen type IV alpha 4 chain HUGO:COL4A4 hgnc_id:HGNC:2206 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 collagen type IV alpha 5 chain HUGO:COL4A5 hgnc_id:HGNC:2207 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 collagen type IV alpha 6 chain HUGO:COL4A6 hgnc_id:HGNC:2208 HGNC:2208 ENTREZ:1288 UNIPROT:Q14031 collagen type V alpha 1 chain HUGO:COL5A1 hgnc_id:HGNC:2209 HGNC:2209 ENTREZ:1289 UNIPROT:P20908 collagen type V alpha 2 chain HUGO:COL5A2 hgnc_id:HGNC:2210 HGNC:2210 ENTREZ:1290 UNIPROT:P05997 collagen type V alpha 3 chain HUGO:COL5A3 hgnc_id:HGNC:14864 HGNC:14864 ENTREZ:50509 UNIPROT:P25940 collagen type VI alpha 1 chain HUGO:COL6A1 hgnc_id:HGNC:2211 HGNC:2211 ENTREZ:1291 UNIPROT:P12109 collagen type VI alpha 2 chain HUGO:COL6A2 hgnc_id:HGNC:2212 HGNC:2212 ENTREZ:1292 UNIPROT:P12110 collagen type VI alpha 3 chain HUGO:COL6A3 hgnc_id:HGNC:2213 HGNC:2213 ENTREZ:1293 UNIPROT:P12111 collagen type VI alpha 4 pseudogene 1 HUGO:COL6A4P1 hgnc_id:HGNC:33484 HGNC:33484 ENTREZ:344875 collagen type VI alpha 4 pseudogene 2 HUGO:COL6A4P2 hgnc_id:HGNC:38501 HGNC:38501 ENTREZ:646300 collagen type VI alpha 5 chain HUGO:COL6A5 hgnc_id:HGNC:26674 HGNC:26674 ENTREZ:256076 UNIPROT:A8TX70 collagen type VI alpha 6 chain HUGO:COL6A6 hgnc_id:HGNC:27023 HGNC:27023 ENTREZ:131873 UNIPROT:A6NMZ7 collagen type VII alpha 1 chain HUGO:COL7A1 hgnc_id:HGNC:2214 HGNC:2214 ENTREZ:1294 UNIPROT:Q02388 collagen type VIII alpha 1 chain HUGO:COL8A1 hgnc_id:HGNC:2215 HGNC:2215 ENTREZ:1295 UNIPROT:P27658 collagen type VIII alpha 2 chain HUGO:COL8A2 hgnc_id:HGNC:2216 HGNC:2216 ENTREZ:1296 UNIPROT:P25067 collagen type IX alpha 1 chain HUGO:COL9A1 hgnc_id:HGNC:2217 HGNC:2217 ENTREZ:1297 UNIPROT:P20849 collagen type IX alpha 2 chain HUGO:COL9A2 hgnc_id:HGNC:2218 HGNC:2218 ENTREZ:1298 UNIPROT:Q14055 collagen type IX alpha 3 chain HUGO:COL9A3 hgnc_id:HGNC:2219 HGNC:2219 ENTREZ:1299 UNIPROT:Q14050 collagen type X alpha 1 chain HUGO:COL10A1 hgnc_id:HGNC:2185 HGNC:2185 ENTREZ:1300 UNIPROT:Q03692 collagen type XI alpha 1 chain HUGO:COL11A1 hgnc_id:HGNC:2186 HGNC:2186 ENTREZ:1301 UNIPROT:P12107 collagen type XI alpha 2 chain HUGO:COL11A2 hgnc_id:HGNC:2187 HGNC:2187 ENTREZ:1302 UNIPROT:P13942 collagen type XII alpha 1 chain HUGO:COL12A1 hgnc_id:HGNC:2188 HGNC:2188 ENTREZ:1303 UNIPROT:Q99715 collagen type XIII alpha 1 chain HUGO:COL13A1 hgnc_id:HGNC:2190 HGNC:2190 ENTREZ:1305 UNIPROT:Q5TAT6 collagen type XIV alpha 1 chain HUGO:COL14A1 hgnc_id:HGNC:2191 HGNC:2191 ENTREZ:7373 UNIPROT:Q05707 collagen type XV alpha 1 chain HUGO:COL15A1 hgnc_id:HGNC:2192 HGNC:2192 ENTREZ:1306 UNIPROT:P39059 collagen type XVI alpha 1 chain HUGO:COL16A1 hgnc_id:HGNC:2193 HGNC:2193 ENTREZ:1307 UNIPROT:Q07092 collagen type XVII alpha 1 chain HUGO:COL17A1 hgnc_id:HGNC:2194 HGNC:2194 ENTREZ:1308 UNIPROT:Q9UMD9 collagen type XVIII alpha 1 chain HUGO:COL18A1 hgnc_id:HGNC:2195 HGNC:2195 ENTREZ:80781 UNIPROT:P39060 collagen type XIX alpha 1 chain HUGO:COL19A1 hgnc_id:HGNC:2196 HGNC:2196 ENTREZ:1310 UNIPROT:Q14993 collagen type XX alpha 1 chain HUGO:COL20A1 hgnc_id:HGNC:14670 HGNC:14670 ENTREZ:57642 UNIPROT:Q9P218 collagen type XXI alpha 1 chain HUGO:COL21A1 hgnc_id:HGNC:17025 HGNC:17025 ENTREZ:81578 UNIPROT:Q96P44 collagen type XXII alpha 1 chain HUGO:COL22A1 hgnc_id:HGNC:22989 HGNC:22989 ENTREZ:169044 UNIPROT:Q8NFW1 collagen type XXIII alpha 1 chain HUGO:COL23A1 hgnc_id:HGNC:22990 HGNC:22990 ENTREZ:91522 UNIPROT:Q86Y22 collagen type XXIV alpha 1 chain HUGO:COL24A1 hgnc_id:HGNC:20821 HGNC:20821 ENTREZ:255631 UNIPROT:Q17RW2 collagen type XXV alpha 1 chain HUGO:COL25A1 hgnc_id:HGNC:18603 HGNC:18603 ENTREZ:84570 UNIPROT:Q9BXS0 collagen type XXVI alpha 1 chain HUGO:COL26A1 hgnc_id:HGNC:18038 HGNC:18038 ENTREZ:136227 UNIPROT:Q96A83 collagen type XXVII alpha 1 chain HUGO:COL27A1 hgnc_id:HGNC:22986 HGNC:22986 ENTREZ:85301 UNIPROT:Q8IZC6 collagen type XXVIII alpha 1 chain HUGO:COL28A1 hgnc_id:HGNC:22442 HGNC:22442 ENTREZ:340267 UNIPROT:Q2UY09 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IFNG CASCADE:INTERGIN CASCADE:IGF1R CASCADE:HH PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. ???? collagen type I, which is known to be secreted by activated fibroblasts, can promote infiltration of immune cells. However it also inhibits the ability of macrophages to kill cancer cells by affecting their polarization into an immunosuppressive phenotype. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells PMID:19397781 collagens are ligands for a1b1, a2b1 and a11b1 integrins in CAFs PMID:24856586 Myofibroblast Depletion Reduced Type I Collagen Content and Altered Extracellular Matrix Organization in PDAC. These results are consistent with the ability of αSMA+ myofibroblasts to produce type I collagen and induce fibrosis in PDAC. References_end </body> </html> </notes> <label text="Collagens*"/> <bbox w="80.0" h="40.0" x="7380.0" y="1410.0"/> </glyph> <glyph class="nucleic acid feature" id="s4300_sa576" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ILK Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:11696562 Integrin-linked kinase (ILK) is a binding partner of the integrin 1 and 3 subunits and is involved in the signal transduction from integrin receptors The activity is stimulated in a phosphatidylinositol (PI) 3-kinase–dependent manner and likely involves binding of the phosphoinositide phospholipid product of PI 3-kinase, PI 3,4,5-triphosphate, to the PH-like domain of ILK ILK has been shown recently to directly phosphorylate proteins such as PKB (PKB/Akt) on ser 473. PMID:15905178 Knock-down of ILK by small, interfering RNA (siRNA) attenuated Akt phosphorylation in response to ligation of beta1 integrin by collagen or activating antibody and enhanced fibroblast apoptosis in response to collagen contraction. PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast References_end </body> </html> </notes> <label text="ILK"/> <bbox w="70.0" h="25.0" x="6285.0" y="2117.5"/> </glyph> <glyph class="nucleic acid feature" id="s4301_sa577" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ILK Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:27111285 TGFB upregulates ILK protein level in fibroblasts References_end </body> </html> </notes> <label text="ILK"/> <bbox w="90.0" h="25.0" x="6275.0" y="2207.5"/> <glyph class="unit of information" id="_0e705dd0-27ec-4275-a6dc-13419fe20011"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6310.0" y="2202.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4302_sa259" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta receptor 1 HUGO:TGFBR1 hgnc_id:HGNC:11772 HGNC:11772 ENTREZ:7046 UNIPROT:P36897 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110, PMID:15265520 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. References_end </body> </html> </notes> <label text="TGFBR1"/> <bbox w="80.0" h="50.0" x="3699.0" y="1155.0"/> <glyph class="unit of information" id="_26efe229-eb66-42d3-a1af-0e13cf5b412d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3716.5" y="1150.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4303_sa258" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta receptor 2 HUGO:TGFBR2 hgnc_id:HGNC:11773 HGNC:11773 ENTREZ:7048 UNIPROT:P37173 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110,PMID:15265520 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:24336330 TGFBR2 in CAFs References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="3769.0" y="1285.0"/> <glyph class="state variable" id="_76755434-aea0-40e4-8e38-db5507282599"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3764.0" y="1305.0"/> </glyph> <glyph class="unit of information" id="_4bd4efa5-63c4-4273-b1d4-46f08ac32713"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3786.5" y="1280.0"/> </glyph> </glyph> <glyph class="source and sink" id="s4304_sa579" compartmentRef="c5_ca5"> <label text="sa578_degraded"/> <bbox w="30.0" h="30.0" x="3905.0" y="1445.0"/> </glyph> <glyph class="macromolecule" id="s4305_sa578" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta receptor 2 HUGO:TGFBR2 hgnc_id:HGNC:11773 HGNC:11773 ENTREZ:7048 UNIPROT:P37173 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110,PMID:15265520 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:24336330 TGFBR2 in CAFs References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="3769.0" y="1385.0"/> <glyph class="state variable" id="_47e9b49d-24c9-4cde-a475-1bb9122c29a0"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="3759.0" y="1405.0"/> </glyph> <glyph class="unit of information" id="_e61ec62f-700b-4c83-9b42-5d979e9bc12f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="3786.5" y="1380.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4315_sa586" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: secreted phosphoprotein 1 HUGO:SPP1 hgnc_id:HGNC:11255 HGNC:11255 ENTREZ:6696 UNIPROT:P10451 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:18353785, PMID:23338822 SP1 regulates fibronectin expression downstream of TGFB signaling PMID:23338822 collagen mRNA expression were also reduced by 48% in the transfection SP1 decoy ODN group. Suppression of cell proliferation by Sp1 decoy ODNs PMID:10964912 SP1 probably upregulates integrin b5 expression in fibroblasts downstream of TGFB (condurmed for osteoblastic cells only) PMID:15001984 Smad3 complex interact with SP1 and ETS1 and induces activity of TN-C promoter. PMID:11007770 Synergistic Cooperation between Sp1 and Smad3/Smad4 Mediates Transforming Growth Factor β1 Stimulation of α2(I)-Collagen (COL1A2) Transcription in fibroblasts PMID:21252118 OPN promotes tumor progression via the transformation of MSC into CAF. References_end </body> </html> </notes> <label text="SP1"/> <bbox w="80.0" h="40.0" x="4130.0" y="3770.0"/> </glyph> <glyph class="macromolecule" id="s4316_sa587" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 5 HUGO:ITGB5 hgnc_id:HGNC:6160 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. uPA (PLAU) signaling has a negative influence on myofibroblast differentiation; References_end </body> </html> </notes> <label text="ITGB5"/> <bbox w="80.0" h="50.0" x="7950.0" y="2655.0"/> <glyph class="state variable" id="_01ac62d1-3e0a-42ea-ab06-b3c5fc19182f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7945.0" y="2674.9602"/> </glyph> <glyph class="unit of information" id="_fa8b6d9b-f404-4022-8f05-4cc8f8cd869e"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7967.5" y="2650.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4317_sa588" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <bbox w="80.0" h="50.0" x="7810.0" y="2435.0"/> <glyph class="unit of information" id="_53f9578b-9919-4954-9759-aac7aa568239"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7827.5" y="2430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4318_sa589" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 3 HUGO:ITGB3 hgnc_id:HGNC:6156 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 TGFβ1-induced β3 Integrin Expression Is Dependent on αvβ3 Activation References_end </body> </html> </notes> <label text="ITGB3"/> <bbox w="80.0" h="50.0" x="7700.0" y="2315.0"/> <glyph class="unit of information" id="_d25a2971-a4f0-4147-b513-516863f5530d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7717.5" y="2310.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4319_sa590" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGB5 Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785; PMID:10964912,PMID:22470492 TGFB upregulates ITGB5 expression via SMAD Pathway References_end </body> </html> </notes> <label text="ITGB5"/> <bbox w="90.0" h="25.0" x="7235.0" y="2857.5"/> <glyph class="unit of information" id="_ad82a980-850c-4410-8701-a5de05b2d9a7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7270.0" y="2852.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4320_sa591" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGB5 Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785; PMID:10964912,PMID:22470492 TGFB upregulates ITGB5 expression via SMAD Pathway References_end </body> </html> </notes> <label text="ITGB5"/> <bbox w="70.0" h="25.0" x="7245.0" y="2927.5"/> </glyph> <glyph class="macromolecule" id="s4324_sa600" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein tyrosine kinase 2 HUGO:PTK2 hgnc_id:HGNC:9611 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:12531888 Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. TGF-β1 induces tyrosine phosphorylation of focal adhesion kinase PTK2(FAK) including that of its autophosphorylation site, Tyr-397, an effect that is dependent on cell adhesion and is delayed relative to early Smad signaling. Pharmacologic inhibition of FAK or expression of kinase-deficient FAK, mutated by substituting Tyr-397 with Phe, inhibit TGF-β1-induced α-smooth muscle actin expression, stress fiber formation, and cellular hypertrophy. PMID:27216177; PMID:20027185 PlAUR induces FAK activation downstream of FAP, probably via activation of integrin signaling, because Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process. References_end </body> </html> </notes> <label text="PTK2"/> <bbox w="80.0" h="40.0" x="6440.0" y="2250.0"/> <glyph class="state variable" id="_30906336-831b-4f68-8213-5c438163f8cd"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6435.0" y="2249.3052"/> </glyph> <glyph class="state variable" id="_5d3b38c3-9487-4082-b82a-cfca661e3d26"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6435.0" y="2265.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4325_sa597" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein tyrosine kinase 2 HUGO:PTK2 hgnc_id:HGNC:9611 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:12531888 Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. TGF-β1 induces tyrosine phosphorylation of focal adhesion kinase PTK2(FAK) including that of its autophosphorylation site, Tyr-397, an effect that is dependent on cell adhesion and is delayed relative to early Smad signaling. Pharmacologic inhibition of FAK or expression of kinase-deficient FAK, mutated by substituting Tyr-397 with Phe, inhibit TGF-β1-induced α-smooth muscle actin expression, stress fiber formation, and cellular hypertrophy. PMID:27216177; PMID:20027185 PlAUR induces FAK activation downstream of FAP, probably via activation of integrin signaling, because Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process. References_end </body> </html> </notes> <label text="PTK2"/> <bbox w="80.0" h="40.0" x="6440.0" y="2340.0"/> <glyph class="state variable" id="_6e76f700-e1fd-4ead-9c83-25dce6c1e45a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6435.0" y="2339.3052"/> </glyph> <glyph class="state variable" id="_c9b9f01f-9c5c-4fa1-a837-a22e982ff2e5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6432.5" y="2355.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4326_sa598" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SRC proto-oncogene, non-receptor tyrosine kinase HUGO:SRC hgnc_id:HGNC:11283 HGNC:11283 ENTREZ:6714 UNIPROT:P12931 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:CAV PMID:11476890 Src kinases participate in PTK2 (FAK) phosphorylation downstream of integrin signaling Src−/− fibroblasts are slightly defective and fibroblasts deficient for the src, fyn and yes genes exhibit a dramatic defect in the cell adhesion-dependent tyrosine phosphorylation of FAK. hese observations suggest that cell adhesion-dependent tyrosine phosphorylation of FAK occurs in two phases. The first, autophosphorylation phase, occurs in the absence of Src and results in the tyrosine phosphorylation of FAK residue 397. The second phase occurs following recruitment of Src into complex with FAK and results in phosphorylation of FAK at other tyrosine residues leading to the full activation of FAK and transmission of downstream signals. PMID:16919435 Integrin-stimulated FAK phosphorylation at Y397 creates a high-affinity binding site for the Src-homology 2 (SH2) domain of SFKs. The binding of Src to FAK can lead to the conformational activation of SFKs and the formation of a transient FAK–Src signaling complex in fibroblasts and epithelial cells PMID:25572304 FAK undergoes autophosphorylation that leads to its association with Src, resulting in activation of both kinases. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. PMID:17517963 Src is involved in activation of Rac (Servitja et al., 2003; Kawakatsu et al., 2005) and Cdc42 (Miyamoto et al., 2003; Tu et al., 2003; Fukuyama et al., 2005) and can inhibit Rho through activation of p190RhoGAP caveolin-1 stimulates normal Rho GTP loading through inactivation of the Src–p190RhoGAP pathway. References_end </body> </html> </notes> <label text="SRC"/> <bbox w="80.0" h="40.0" x="6620.0" y="2460.0"/> <glyph class="state variable" id="_ebe3919e-3e8e-4369-a49f-5bd07bb6995b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6615.0" y="2475.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4327_sa596" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein tyrosine kinase 2 HUGO:PTK2 hgnc_id:HGNC:9611 HGNC:9611 ENTREZ:5747 UNIPROT:Q05397 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:12531888 Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. TGF-β1 induces tyrosine phosphorylation of focal adhesion kinase PTK2(FAK) including that of its autophosphorylation site, Tyr-397, an effect that is dependent on cell adhesion and is delayed relative to early Smad signaling. Pharmacologic inhibition of FAK or expression of kinase-deficient FAK, mutated by substituting Tyr-397 with Phe, inhibit TGF-β1-induced α-smooth muscle actin expression, stress fiber formation, and cellular hypertrophy. PMID:27216177; PMID:20027185 PlAUR induces FAK activation downstream of FAP, probably via activation of integrin signaling, because Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process. References_end </body> </html> </notes> <label text="PTK2"/> <bbox w="80.0" h="40.0" x="6440.0" y="2430.0"/> <glyph class="state variable" id="_9a5c8301-6028-4199-aa64-2526d2d6ff3d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6432.5" y="2429.3052"/> </glyph> <glyph class="state variable" id="_c5353639-e57b-41d5-b4c1-a2e54f98edea"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6432.5" y="2445.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4328_sa605" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 6 HUGO:ITGB6 hgnc_id:HGNC:6161 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:23673986 Expression of fibronectin receptro αvβ6 in CAFs is a negative factor for patient survival. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ6 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="ITGB6"/> <bbox w="80.0" h="50.0" x="7920.0" y="2545.0"/> <glyph class="unit of information" id="_8e449a99-103b-4d72-81a8-76407902dd5c"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7937.5" y="2540.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4332_sa608" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 3 HUGO:ITGA3 hgnc_id:HGNC:6139 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:21666923 Integrin α3 blockade enhances microtopographical down-regulation of α-smooth muscle actin: role of microtopography in ECM regulation. PMID:18037882 Integrin a3 and a5 are important in leading fibroblasts in SCC. siRNA against integrin 3 or integrin 5 in stromal fibroblasts would prevent the invasion of SCC cells and Figure 4C shows that siRNA-mediated depletion of either integrin 3 or integrin 5 in stromal fibroblasts, but not in SCC cells, reduced the collective invasion of SCC cells. References_end </body> </html> </notes> <label text="ITGA3"/> <bbox w="80.0" h="50.0" x="7420.0" y="1995.0"/> <glyph class="unit of information" id="_85134f35-6f5f-435c-a9ab-0458a2330325"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7437.5" y="1990.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4333_sa609" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 5 HUGO:ITGB5 hgnc_id:HGNC:6160 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. uPA (PLAU) signaling has a negative influence on myofibroblast differentiation; References_end </body> </html> </notes> <label text="ITGB5"/> <bbox w="80.0" h="50.0" x="7950.0" y="2755.0"/> <glyph class="state variable" id="_992dbca3-b989-4cba-9d69-c29905aabcb3"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="7940.0" y="2774.9602"/> </glyph> <glyph class="unit of information" id="_a4928402-d804-4885-878d-fc04b666b858"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7967.5" y="2750.0"/> </glyph> </glyph> <glyph class="source and sink" id="s4334_sa610" compartmentRef="c5_ca5"> <label text="sa609_degraded"/> <bbox w="30.0" h="30.0" x="7975.0" y="2835.0"/> </glyph> <glyph class="macromolecule" id="s4335_sa611" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <bbox w="80.0" h="40.0" x="6920.0" y="1720.0"/> <glyph class="unit of information" id="_ca19e2ef-9109-4cf8-b841-13b3e04c88ea"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6937.5" y="1715.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4336_sa612" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGB1 Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU PMID:22470492 1.33 fold increase in the levels of cell-surface integrin β1 after uPA-silencing this corresponded with an average 1.25 fold increase in β1 gene expression . References_end </body> </html> </notes> <label text="ITGB1"/> <bbox w="70.0" h="25.0" x="6905.0" y="1967.5"/> </glyph> <glyph class="nucleic acid feature" id="s4337_sa613" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGB1 Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU PMID:22470492 1.33 fold increase in the levels of cell-surface integrin β1 after uPA-silencing this corresponded with an average 1.25 fold increase in β1 gene expression . References_end </body> </html> </notes> <label text="ITGB1"/> <bbox w="90.0" h="25.0" x="6895.0" y="1897.5"/> <glyph class="unit of information" id="_c99d1ce7-13e7-4a6f-be72-b45c78938fb1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6930.0" y="1892.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4338_sa614" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 2 HUGO:ITGA2 hgnc_id:HGNC:6137 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor References_end </body> </html> </notes> <label text="ITGA2"/> <bbox w="80.0" h="40.0" x="6650.0" y="1570.0"/> <glyph class="unit of information" id="_28aa6914-fc3a-4fe5-9c0a-385864a1122f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6667.5" y="1565.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4348_sa620" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 11 HUGO:ITGA11 hgnc_id:HGNC:6136 HGNC:6136 ENTREZ:22801 UNIPROT:Q9UKX5 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:TGFB PMID:20129924 Integrin alpha11beta1 is a collagen receptor on fibroblasts alpha11beta1 can act as a mechanosensor to promote the myofibroblast phenotype PMID:25076207 fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. References_end </body> </html> </notes> <label text="ITGA11"/> <bbox w="80.0" h="50.0" x="7250.0" y="1865.0"/> <glyph class="unit of information" id="_6649d902-ee95-4f37-9836-1debe0dae1b0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7267.5" y="1860.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4349_sa621" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGA11 Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:INTEGRIN PMID:19913614 The human alpha11 integrin promoter drives fibroblast-restricted expression in vivo and is regulated by TGF-beta1 in a Smad- and Sp1-dependent manner. References_end </body> </html> </notes> <label text="ITGA11"/> <bbox w="90.0" h="25.0" x="7205.0" y="2027.5"/> <glyph class="unit of information" id="_725f1437-29a9-4e88-93e4-a57911459008"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="7240.0" y="2022.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4350_sa622" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ITGA11 Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:INTEGRIN PMID:20129924; PMID:19913614 The human alpha11 integrin promoter drives fibroblast-restricted expression in vivo and is regulated by TGF-beta1 in a Smad- and Sp1-dependent manner. Transfection and expression of the inhibitory Smad7 in the cells attenuated the TGF-beta1-dependent alpha11 induction both at the RNA and the protein level. Mutation and deletion analyses identified a Smad-binding element, SBE2 (nt -182/-176), as an important Smad3-binding site in this part of the promoter. Further analyses suggested that the Sp1-binding site SBS1 (nt -140/-134) takes part in the responsiveness to TGF-beta1 in a Smad2-dependent manner. References_end </body> </html> </notes> <label text="ITGA11"/> <bbox w="70.0" h="25.0" x="7215.0" y="2147.5"/> </glyph> <glyph class="nucleic acid feature" id="s4351_sa625" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP13 Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17420280 Analysis of matrix metalloproteinase in vitro and in vivo revealed disturbed MMP13 and MMP14 synthesis in alpha11(-/-) cells. References_end </body> </html> </notes> <label text="MMP13"/> <bbox w="70.0" h="25.0" x="5205.0" y="4427.5"/> </glyph> <glyph class="nucleic acid feature" id="s4352_sa626" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP13 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17420280 Analysis of matrix metalloproteinase in vitro and in vivo revealed disturbed MMP13 and MMP14 synthesis in alpha11(-/-) cells. References_end </body> </html> </notes> <label text="MMP13"/> <bbox w="90.0" h="25.0" x="5195.0" y="4507.5"/> <glyph class="unit of information" id="_7cbfb35c-c026-473b-a999-9fb44c93fb68"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5230.0" y="4502.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4353_sa627" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: matrix metallopeptidase 13 HUGO:MMP13 hgnc_id:HGNC:7159 HGNC:7159 ENTREZ:4322 UNIPROT:P45452 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17420280 Analysis of matrix metalloproteinase in vitro and in vivo revealed disturbed MMP13 and MMP14 synthesis in alpha11(-/-) cells. References_end </body> </html> </notes> <label text="MMP13"/> <bbox w="80.0" h="40.0" x="5200.0" y="4590.0"/> </glyph> <glyph class="macromolecule" id="s4354_sa628" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 5 HUGO:ITGA5 hgnc_id:HGNC:6141 HGNC:6141 ENTREZ:3678 UNIPROT:P08648 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18037882 Integrin a3 and a5 are important in leading fibroblasts in SCC. siRNA against integrin 3 or integrin 5 in stromal fibroblasts would prevent the invasion of SCC cells and Figure 4C shows that siRNA-mediated depletion of either integrin 3 or integrin 5 in stromal fibroblasts, but not in SCC cells, reduced the collective invasion of SCC cells. Several groups have shown that integrin a5 can activate Rho signalling16, 17, 18, and this result was confirmed in carcinoma-associated fibroblasts (data not shown). Integrin a3 was also important for force-mediated matrix remodelling, but we found no evidence that it regulated Rho activity (data not shown). References_end </body> </html> </notes> <label text="ITGA5"/> <bbox w="80.0" h="50.0" x="7530.0" y="2075.0"/> <glyph class="unit of information" id="_05e76028-6c33-4316-b633-f97f05e2d1aa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7547.5" y="2070.0"/> </glyph> </glyph> <glyph class="complex" id="s813_csa72" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RHOA Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:LIF CASCADE:TGFB CASCADE:EGF CASCADE:CXCL12 CASCADE:CAV PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 PMID:24857661 siRNA-mediated knockdown of RhoA expression or pharmacological inhibition of Rho-kinase (ROCK) activity resulted in blockade of both TGF-β1 and LIF-dependent proinvasive hDF activity (Figures S2B and S2C). Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity PMID:18423981 TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. References_end </body> </html> </notes> <label text="RHOA:GTP"/> <bbox w="100.0" h="120.0" x="6600.0" y="3034.0"/> <glyph class="macromolecule" id="s790_sa637"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ras homolog family member A HUGO:RHOA hgnc_id:HGNC:667 HGNC:667 ENTREZ:387 UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:LIF CASCADE:TGFB CASCADE:EGF CASCADE:CXCL12 CASCADE:CAV PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1 More detailed analysis of Rho isoforms revealed that RhoA, but not RhoB, is required for fibroblasts to promote SCC invasion PMID:24857661 siRNA-mediated knockdown of RhoA expression or pharmacological inhibition of Rho-kinase (ROCK) activity resulted in blockade of both TGF-β1 and LIF-dependent proinvasive hDF activity (Figures S2B and S2C). Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity PMID:18423981 TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. PMID:21178402 RhoA was thought to be activated mainly at the retracting tail (red) to promote tail contraction, while Rac1 was thought to be activated at the front of the cell to promote lamellipodial protrusion. PMID:17517963 caveolin-deficient MEFs showed a notable decrease in basal Rho activity and a significant increase in Rac and Cdc42 activity PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation and promotes RhoA-activation aand actin polymerisation. Rho–ROCK function is required only in stromal fibroblasts for collective SCC invasion. References_end </body> </html> </notes> <label text="RHOA"/> <bbox w="80.0" h="40.0" x="6611.0" y="3044.0"/> </glyph> <glyph class="simple chemical" id="s3134_sa638"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="6615.0" y="3091.5"/> </glyph> </glyph> <glyph class="complex" id="s810_csa73" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RHOA Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:LIF CASCADE:TGFB CASCADE:EGF CASCADE:CXCL12 CASCADE:CAV PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1 References_end </body> </html> </notes> <label text="RHOA:GDP"/> <bbox w="100.0" h="120.0" x="6790.0" y="3034.0"/> <glyph class="macromolecule" id="s3132_sa639"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ras homolog family member A HUGO:RHOA hgnc_id:HGNC:667 HGNC:667 ENTREZ:387 UNIPROT:P61586 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:LIF CASCADE:TGFB CASCADE:EGF CASCADE:CXCL12 CASCADE:CAV PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1 More detailed analysis of Rho isoforms revealed that RhoA, but not RhoB, is required for fibroblasts to promote SCC invasion PMID:24857661 siRNA-mediated knockdown of RhoA expression or pharmacological inhibition of Rho-kinase (ROCK) activity resulted in blockade of both TGF-β1 and LIF-dependent proinvasive hDF activity (Figures S2B and S2C). Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity PMID:18423981 TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. PMID:21178402 RhoA was thought to be activated mainly at the retracting tail (red) to promote tail contraction, while Rac1 was thought to be activated at the front of the cell to promote lamellipodial protrusion. PMID:17517963 caveolin-deficient MEFs showed a notable decrease in basal Rho activity and a significant increase in Rac and Cdc42 activity PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation and promotes RhoA-activation aand actin polymerisation. Rho–ROCK function is required only in stromal fibroblasts for collective SCC invasion. References_end </body> </html> </notes> <label text="RHOA"/> <bbox w="80.0" h="40.0" x="6800.0" y="3054.0"/> </glyph> <glyph class="simple chemical" id="s3133_sa640"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="6808.75" y="3100.875"/> </glyph> </glyph> <glyph class="complex" id="s4366_csa76"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LAMA*:LAMB*:LAMC* Identifiers_end References_begin: PMID:26519775 a3b1 integrin is a Laminin receptor References_end </body> </html> </notes> <label text="LAMININS"/> <bbox w="130.0" h="140.0" x="7755.0" y="1690.0"/> <glyph class="macromolecule" id="s4980_sa645"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: laminin subunit alpha 1 HUGO:LAMA1 hgnc_id:HGNC:6481 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin subunit alpha 2 HUGO:LAMA2 hgnc_id:HGNC:6482 HGNC:6482 ENTREZ:3908 UNIPROT:P24043 laminin subunit alpha 3 HUGO:LAMA3 hgnc_id:HGNC:6483 HGNC:6483 ENTREZ:3909 UNIPROT:Q16787 laminin subunit alpha 4 HUGO:LAMA4 hgnc_id:HGNC:6484 HGNC:6484 ENTREZ:3910 UNIPROT:Q16363 laminin subunit alpha 5 HUGO:LAMA5 hgnc_id:HGNC:6485 HGNC:6485 ENTREZ:3911 UNIPROT:O15230 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMA*"/> <bbox w="80.0" h="40.0" x="7775.0" y="1700.0"/> </glyph> <glyph class="macromolecule" id="s4981_sa646"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: laminin subunit beta 1 HUGO:LAMB1 hgnc_id:HGNC:6486 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin subunit beta 2 HUGO:LAMB2 hgnc_id:HGNC:6487 HGNC:6487 ENTREZ:3913 UNIPROT:P55268 laminin subunit beta 3 HUGO:LAMB3 hgnc_id:HGNC:6490 HGNC:6490 ENTREZ:3914 UNIPROT:Q13751 laminin subunit beta 4 HUGO:LAMB4 hgnc_id:HGNC:6491 HGNC:6491 ENTREZ:22798 UNIPROT:A4D0S4 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMB*"/> <bbox w="80.0" h="40.0" x="7775.0" y="1730.0"/> </glyph> <glyph class="macromolecule" id="s4982_sa647"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: laminin subunit gamma 1 HUGO:LAMC1 hgnc_id:HGNC:6492 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 laminin subunit gamma 2 HUGO:LAMC2 hgnc_id:HGNC:6493 HGNC:6493 ENTREZ:3918 UNIPROT:Q13753 laminin subunit gamma 3 HUGO:LAMC3 hgnc_id:HGNC:6494 HGNC:6494 ENTREZ:10319 UNIPROT:Q9Y6N6 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMC*"/> <bbox w="80.0" h="40.0" x="7775.0" y="1770.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4367_sa648"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: vitronectin HUGO:VTN hgnc_id:HGNC:12724 HGNC:12724 ENTREZ:7448 UNIPROT:P04004 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 vitronectin is a ligand for avb3 and avb5 integrins in CAFs. References_end </body> </html> </notes> <label text="VTN"/> <bbox w="80.0" h="40.0" x="8050.0" y="2170.0"/> </glyph> <glyph class="macromolecule" id="s4369_sa655"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1 hgnc_id:HGNC:6714 HGNC:6714 ENTREZ:4052 UNIPROT:Q14766 latent transforming growth factor beta binding protein 2 HUGO:LTBP2 hgnc_id:HGNC:6715 HGNC:6715 ENTREZ:4053 UNIPROT:Q14767 latent transforming growth factor beta binding protein 3 HUGO:LTBP3 hgnc_id:HGNC:6716 HGNC:6716 ENTREZ:4054 UNIPROT:Q9NS15 latent transforming growth factor beta binding protein 4 HUGO:LTBP4 hgnc_id:HGNC:6717 HGNC:6717 ENTREZ:8425 UNIPROT:Q8N2S1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LTBP*"/> <bbox w="80.0" h="40.0" x="3750.0" y="300.0"/> </glyph> <glyph class="macromolecule" id="s4370_sa656"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGFB induced factor homeobox 1 HUGO:TGIF1 hgnc_id:HGNC:11776 HGNC:11776 ENTREZ:7050 UNIPROT:Q15583 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LAP"/> <bbox w="80.0" h="40.0" x="3749.0" y="358.0"/> <glyph class="unit of information" id="_25986d6b-859b-4c6e-92a6-6ac69d911dce"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3764.0" y="353.0"/> </glyph> </glyph> <glyph class="complex" id="s4371_csa78"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LAP:LTBP*:TGFB* Identifiers_end References_begin: PMID:26519775; PMID:18086923; PMID:24309651 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text=" Large_Latent_Complex "/> <bbox w="105.0" h="165.0" x="3587.0" y="107.0"/> <glyph class="macromolecule" id="s4376_sa652"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1 hgnc_id:HGNC:6714 HGNC:6714 ENTREZ:4052 UNIPROT:Q14766 latent transforming growth factor beta binding protein 2 HUGO:LTBP2 hgnc_id:HGNC:6715 HGNC:6715 ENTREZ:4053 UNIPROT:Q14767 latent transforming growth factor beta binding protein 3 HUGO:LTBP3 hgnc_id:HGNC:6716 HGNC:6716 ENTREZ:4054 UNIPROT:Q9NS15 latent transforming growth factor beta binding protein 4 HUGO:LTBP4 hgnc_id:HGNC:6717 HGNC:6717 ENTREZ:8425 UNIPROT:Q8N2S1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LTBP*"/> <bbox w="80.0" h="40.0" x="3602.0" y="117.0"/> </glyph> <glyph class="macromolecule" id="s4377_sa653"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGFB induced factor homeobox 1 HUGO:TGIF1 hgnc_id:HGNC:11776 HGNC:11776 ENTREZ:7050 UNIPROT:Q15583 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LAP"/> <bbox w="80.0" h="40.0" x="3602.0" y="157.0"/> <glyph class="unit of information" id="_38dc1f33-3842-4367-9c12-b7c42628bbf5"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3617.0" y="152.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4378_sa654"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta 1 HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137 transforming growth factor beta 2 HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812 transforming growth factor beta 3 HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF PMID:21098712 Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:23784029, PMID:16572188, PMID:8515656 TGF-β1 treatment successfully transformed primary resting fibroblasts into CAFs PMID:19038247 TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3. Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1–3 and ERK inhibition reduces TGFβ-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGFβ [9]. Similarly, p38 MAPK has been shown to be central to TGFβ mediated-collagen and fibronectin expression in SSc fibroblasts [10]. PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:18423981 Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. PMID:23034983 Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects PMID:21041659 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts PMID:17768418 TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). ??? both TGF-β1 and TGF-β2 are up-regulated in CAFs PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, PMID:17979848 TGF-β promotes the generation and function of Treg cells TGF-β is able to convert CD4+CD25− non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3602.0" y="197.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4381_sa663" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. References_end </body> </html> </notes> <label text="IGF2"/> <bbox w="70.0" h="25.0" x="3975.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4382_sa664" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. References_end </body> </html> </notes> <label text="IGF2"/> <bbox w="90.0" h="25.0" x="3965.0" y="4342.5"/> <glyph class="unit of information" id="_b9d5ba5d-b314-4146-b019-2420dfed16de"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4000.0" y="4337.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4383_sa665" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: lysyl oxidase like 1 HUGO:LOXL1 hgnc_id:HGNC:6665 HGNC:6665 ENTREZ:4016 UNIPROT:Q08397 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26148229 LOX family oxidases (LOX and LOXL 1–4) are collagen cross-linking enzymes40 that influence tumor progression41 and metastasis. LOXL1 expression in CAFS is correlated with a11 expression and probably is regulated by this pathway. References_end </body> </html> </notes> <label text="LOXL1"/> <bbox w="80.0" h="40.0" x="5775.0" y="4481.625"/> </glyph> <glyph class="nucleic acid feature" id="s4384_sa666" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LOXL1 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26148229 LOX family oxidases (LOX and LOXL 1–4) are collagen cross-linking enzymes40 that influence tumor progression41 and metastasis. LOXL1 expression in CAFS is correlated with a11 expression and probably is regulated by this pathway. References_end </body> </html> </notes> <label text="LOXL1"/> <bbox w="70.0" h="25.0" x="5780.0" y="4349.125"/> </glyph> <glyph class="nucleic acid feature" id="s4385_sa667" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LOXL1 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26148229 LOX family oxidases (LOX and LOXL 1–4) are collagen cross-linking enzymes40 that influence tumor progression41 and metastasis. LOXL1 expression in CAFS is correlated with a11 expression and probably is regulated by this pathway. References_end </body> </html> </notes> <label text="LOXL1"/> <bbox w="90.0" h="25.0" x="5770.0" y="4406.5"/> <glyph class="unit of information" id="_53311647-881d-4a50-b4cb-8e5b81edcbf9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5805.0" y="4401.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4386_sa668" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LOX Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB PMID:21498085 TGF-β1 treatment significantly upregulated LOX mRNA and protein expression in cardiac fibroblasts, as well as activity in the cell-conditioned media. The increase of LOX protein in response to TGF-β1 was prevented by inhibitors of PI3K, Smad3, p38-MAPK, JNK and ERK1/2. Blockade of PI3K also decreased TGF-β1 induced phosphorylation of Smad3, suggesting that the PI3K/Akt and Smad pathways may be integrated in TGF-β1 signaling. References_end </body> </html> </notes> <label text="LOX"/> <bbox w="70.0" h="25.0" x="5375.0" y="4237.5"/> </glyph> <glyph class="nucleic acid feature" id="s4387_sa669" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LOX Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TGFB PMID:21498085 TGF-β1 treatment significantly upregulated LOX mRNA and protein expression in cardiac fibroblasts, as well as activity in the cell-conditioned media. The increase of LOX protein in response to TGF-β1 was prevented by inhibitors of PI3K, Smad3, p38-MAPK, JNK and ERK1/2. Blockade of PI3K also decreased TGF-β1 induced phosphorylation of Smad3, suggesting that the PI3K/Akt and Smad pathways may be integrated in TGF-β1 signaling. References_end </body> </html> </notes> <label text="LOX"/> <bbox w="90.0" h="25.0" x="5365.0" y="4297.5"/> <glyph class="unit of information" id="_efbff9c5-1fd7-4480-af9f-1fc4370766b9"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5400.0" y="4292.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4388_sa670" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Yes associated protein 1 HUGO:YAP1 hgnc_id:HGNC:16262 HGNC:16262 ENTREZ:10413 UNIPROT:P46937 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY MODULE:CORE Maps_Modules_end References_begin: PMID:23708000 YAP is activated in cancer-associated fibroblasts in human disease YAP is required for cancer associated fibroblast function 6 out of the 14 genes with elevated mRNA levels in CAFs were found to be consistently transcriptionally regulated by YAP (AMOTL2, ANKRD1, ANLN, CTGF, DIAPH3, SDPR). ANLN, DIAPH3 and FLNA were required for CAFs to both remodel the ECM and promote invasion PMID:25502501 yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1 (SERPINE1), which is regulated by matrix stiffness independent of transforming growth factor-β signaling. PMID:26711338 Cdc42EP3 Is Required for Mechano-transduction and YAP activation References_end </body> </html> </notes> <label text="YAP1"/> <clone/> <bbox w="80.0" h="40.0" x="6660.0" y="4190.0"/> </glyph> <glyph class="macromolecule" id="s4388_sa1160" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Yes associated protein 1 HUGO:YAP1 hgnc_id:HGNC:16262 HGNC:16262 ENTREZ:10413 UNIPROT:P46937 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY MODULE:CORE Maps_Modules_end References_begin: PMID:23708000 YAP is activated in cancer-associated fibroblasts in human disease YAP is required for cancer associated fibroblast function 6 out of the 14 genes with elevated mRNA levels in CAFs were found to be consistently transcriptionally regulated by YAP (AMOTL2, ANKRD1, ANLN, CTGF, DIAPH3, SDPR). ANLN, DIAPH3 and FLNA were required for CAFs to both remodel the ECM and promote invasion PMID:25502501 yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1 (SERPINE1), which is regulated by matrix stiffness independent of transforming growth factor-β signaling. PMID:26711338 Cdc42EP3 Is Required for Mechano-transduction and YAP activation References_end </body> </html> </notes> <label text="YAP1"/> <clone/> <bbox w="80.0" h="40.0" x="6660.0" y="4100.0"/> </glyph> <glyph class="macromolecule" id="s4389_sa671" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: RAB21, member RAS oncogene family HUGO:RAB21 hgnc_id:HGNC:18263 HGNC:18263 ENTREZ:23011 UNIPROT:Q9UL25 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:19953096 RAB21 upregulates integrin-alpha accomulation in membrans of CAFs and increases ROCK-dependent regulation of actomyosin contractility References_end </body> </html> </notes> <label text="RAB21"/> <bbox w="80.0" h="40.0" x="7180.0" y="2250.0"/> </glyph> <glyph class="macromolecule" id="s4390_sa696" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 1 HUGO:JAK1 hgnc_id:HGNC:6190 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end References_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IL6 CASCADE:PLAU CASCADE:LIF CASCADE:IFNG PMID:21840487 CAF-dependent matrix remodelling is essential for collective carcinoma cell invasion JAK kinase inhibitor P6 tested blocked remodelling (Hooper et al., 2010). P6 inhibits multiple members of the JAK family (Pedranzini et al., 2006), so we used JAK isoform-specific inhibitors to probe which JAKs are involved; neither JAK2 nor JAK3-specific inhibitors recapitulated the effect of the pan-JAK inhibitor (P6) on matrix remodelling (Figure 1A), suggesting that JAKI is the family member involved. Jak 1 regulates Actomyosin Contractility in CAFs downstream of GP130-IL6ST IL6 and oncostatin M (OSM) and via STAT3 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="490.0" y="2080.0"/> <glyph class="state variable" id="_b4939015-8f25-4bb7-96c0-426a2d723047"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="482.5" y="2095.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s3777_sa673" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin heavy chain 9 HUGO:MYH9 hgnc_id:HGNC:7579 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 myosin heavy chain 10 HUGO:MYH10 hgnc_id:HGNC:7568 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 myosin heavy chain 14 HUGO:MYH14 hgnc_id:HGNC:23212 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="MYH*"/> <bbox w="86.0" h="46.0" x="7067.0" y="3297.0"/> <glyph class="unit of information" id="_52c18999-e763-4dd2-9f6f-89191bdaffb7"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="7100.0" y="3292.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3776_sa674" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 9 HUGO:MYL9 hgnc_id:HGNC:15754 HGNC:15754 ENTREZ:10398 UNIPROT:P24844 myosin light chain 12A HUGO:MYL12A hgnc_id:HGNC:16701 HGNC:16701 ENTREZ:10627 UNIPROT:P19105 myosin light chain 12B HUGO:MYL12B hgnc_id:HGNC:29827 HGNC:29827 ENTREZ:103910 UNIPROT:O14950 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC PMID:21840487 JAK1 expression with four different siRNAs reduced MLC2 phosphorylation PMID:24857661 Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-β1 stimulation References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="7250.0" y="3210.0"/> <glyph class="state variable" id="_1cc53eb6-7943-4a1d-ba08-2e64a3c1bcb0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7245.0" y="3225.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3775_sa675" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 6 HUGO:MYL6 hgnc_id:HGNC:7587 HGNC:7587 ENTREZ:4637 UNIPROT:P60660 myosin light chain 6B HUGO:MYL6B hgnc_id:HGNC:29823 HGNC:29823 ENTREZ:140465 UNIPROT:P14649 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: B PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="7370.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s919_sa676" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin heavy chain 9 HUGO:MYH9 hgnc_id:HGNC:7579 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 myosin heavy chain 10 HUGO:MYH10 hgnc_id:HGNC:7568 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 myosin heavy chain 14 HUGO:MYH14 hgnc_id:HGNC:23212 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="MYH*"/> <bbox w="80.0" h="40.0" x="7070.0" y="3200.0"/> </glyph> <glyph class="macromolecule" id="s3786_sa678" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain kinase HUGO:MYLK hgnc_id:HGNC:7590 HGNC:7590 ENTREZ:4638 UNIPROT:Q15746 myosin light chain kinase 2 HUGO:MYLK2 hgnc_id:HGNC:16243 HGNC:16243 ENTREZ:85366 UNIPROT:Q9H1R3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: 2 PMID:11350763 Stress fiber organization is regulated by MLCK and Rho-kinase in cultured human fibroblasts PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). At the cell periphery, on the other hand, MLCK but not ROCK appears to be the kinase responsible for phosphorylating MLC. These results suggest that ROCK and MLCK play distinct roles in spatial regulation of MLC phosphorylation. References_end </body> </html> </notes> <label text="MLCK*"/> <bbox w="80.0" h="40.0" x="7470.0" y="3670.0"/> <glyph class="state variable" id="_80b44012-726f-45c1-9ba4-38e4c0b24694"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7462.5" y="3685.0"/> </glyph> </glyph> <glyph class="phenotype" id="s4398_sa692"> <label text="Actomyosin_contractility"/> <bbox w="230.0" h="55.0" x="6605.0" y="4762.5"/> </glyph> <glyph class="macromolecule" id="s3794_sa677" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain kinase HUGO:MYLK hgnc_id:HGNC:7590 HGNC:7590 ENTREZ:4638 UNIPROT:Q15746 myosin light chain kinase 2 HUGO:MYLK2 hgnc_id:HGNC:16243 HGNC:16243 ENTREZ:85366 UNIPROT:Q9H1R3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: 2 PMID:11350763 Stress fiber organization is regulated by MLCK and Rho-kinase in cultured human fibroblasts PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). At the cell periphery, on the other hand, MLCK but not ROCK appears to be the kinase responsible for phosphorylating MLC. These results suggest that ROCK and MLCK play distinct roles in spatial regulation of MLC phosphorylation. References_end </body> </html> </notes> <label text="MLCK*"/> <bbox w="80.0" h="40.0" x="7470.0" y="3560.0"/> <glyph class="state variable" id="_90a62fe7-01ec-45de-a0a5-86f16fe35b61"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7465.0" y="3575.0"/> </glyph> </glyph> <glyph class="complex" id="s4403_csa80" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ELC_MYOSIN_II*:MYH*:RLC_MYOSIN_II* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:LIF CASCADE:TGFB PMID:12194823 Rho-Kinase and Myosin-II Control Phagocytic Cup Formation during CR3, but Not FcγR, Phagocytosis inhibition of the Rho → ROK → myosin-II pathway caused a decreased accumulation of Arp2/3 complex and F-actin around bound particles, which led to a reduction in CR-mediated phagocytic engulfment. References_end </body> </html> </notes> <label text="MYOSIN_II"/> <bbox w="100.0" h="170.0" x="7251.0" y="3480.0"/> <glyph class="macromolecule multimer" id="s4573_sa679"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin heavy chain 9 HUGO:MYH9 hgnc_id:HGNC:7579 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 myosin heavy chain 10 HUGO:MYH10 hgnc_id:HGNC:7568 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 myosin heavy chain 14 HUGO:MYH14 hgnc_id:HGNC:23212 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="MYH*"/> <bbox w="86.0" h="46.0" x="7257.0" y="3497.0"/> <glyph class="unit of information" id="_31f280a5-e96d-40fa-9002-319d32432f17"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="7290.0" y="3492.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3781_sa680"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 6 HUGO:MYL6 hgnc_id:HGNC:7587 HGNC:7587 ENTREZ:4637 UNIPROT:P60660 myosin light chain 6B HUGO:MYL6B hgnc_id:HGNC:29823 HGNC:29823 ENTREZ:140465 UNIPROT:P14649 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: B PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="7261.0" y="3540.0"/> </glyph> <glyph class="macromolecule" id="s3780_sa681"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 9 HUGO:MYL9 hgnc_id:HGNC:15754 HGNC:15754 ENTREZ:10398 UNIPROT:P24844 myosin light chain 12A HUGO:MYL12A hgnc_id:HGNC:16701 HGNC:16701 ENTREZ:10627 UNIPROT:P19105 myosin light chain 12B HUGO:MYL12B hgnc_id:HGNC:29827 HGNC:29827 ENTREZ:103910 UNIPROT:O14950 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC PMID:21840487 JAK1 expression with four different siRNAs reduced MLC2 phosphorylation PMID:24857661 Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-β1 stimulation References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="7262.0" y="3580.0"/> <glyph class="state variable" id="_e96bf09c-a502-4919-a9ec-e71d96c83782"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7257.0" y="3595.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4404_csa81" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ELC_MYOSIN_II*:MYH*:RLC_MYOSIN_II* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:LIF PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1 Actomyosin contractility in CAFs, as in many other cell types, results from phosphorylation of MLC2 in myosin II downstream of the Rho kinases ROCK I and II PMID:24857661 Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-β1 stimulation References_end </body> </html> </notes> <label text="MYOSIN_II"/> <bbox w="100.0" h="170.0" x="7250.0" y="3715.0"/> <glyph class="macromolecule multimer" id="s4571_sa682"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin heavy chain 9 HUGO:MYH9 hgnc_id:HGNC:7579 HGNC:7579 ENTREZ:4627 UNIPROT:P35579 myosin heavy chain 10 HUGO:MYH10 hgnc_id:HGNC:7568 HGNC:7568 ENTREZ:4628 UNIPROT:P35580 myosin heavy chain 14 HUGO:MYH14 hgnc_id:HGNC:23212 HGNC:23212 ENTREZ:79784 UNIPROT:Q7Z406 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC References_end </body> </html> </notes> <label text="MYH*"/> <bbox w="86.0" h="46.0" x="7257.0" y="3727.0"/> <glyph class="unit of information" id="_4dbd0d30-3865-4e4e-a1cb-eacb6f71ea32"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="7290.0" y="3722.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4572_sa683"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 6 HUGO:MYL6 hgnc_id:HGNC:7587 HGNC:7587 ENTREZ:4637 UNIPROT:P60660 myosin light chain 6B HUGO:MYL6B hgnc_id:HGNC:29823 HGNC:29823 ENTREZ:140465 UNIPROT:P14649 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: B PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B References_end </body> </html> </notes> <label text="ELC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="7260.0" y="3770.0"/> </glyph> <glyph class="macromolecule" id="s3785_sa684"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: myosin light chain 9 HUGO:MYL9 hgnc_id:HGNC:15754 HGNC:15754 ENTREZ:10398 UNIPROT:P24844 myosin light chain 12A HUGO:MYL12A hgnc_id:HGNC:16701 HGNC:16701 ENTREZ:10627 UNIPROT:P19105 myosin light chain 12B HUGO:MYL12B hgnc_id:HGNC:29827 HGNC:29827 ENTREZ:103910 UNIPROT:O14950 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:25712372 In mammals, three genes (MYH9, MYH10, MYH14) encode for three non-muscle myosin-2 isoforms referred to as -2A, -2B, and - 2C, respectively. Most cells simultaneously express two or three non-muscle myosin-2 paralogs and their splice variants in a strictly regulated manner. Each mammalian non-muscle myosin-2 heavy chain associates with one ELC encoded by one of two genes (MYL6, MYL6B) and with one RLC encoded by either MYL9, MYL12A, or MYL12B. MLCK and ROCK phosphorylares RLC PMID:21840487 JAK1 expression with four different siRNAs reduced MLC2 phosphorylation PMID:24857661 Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-β1 stimulation References_end </body> </html> </notes> <label text="RLC_MYOSIN_II*"/> <bbox w="80.0" h="40.0" x="7260.0" y="3815.0"/> <glyph class="state variable" id="_817c67a0-4488-4d97-91ff-053ad72d95a1"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7252.5" y="3830.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4405_sa464" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: signal transducer and activator of transcription 3 HUGO:STAT3 hgnc_id:HGNC:11364 HGNC:11364 ENTREZ:6774 UNIPROT:P40763 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL6 CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. PMID:21840487 ROCK and JAK1/STAT3 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma downstream of IL6 pathway ROCK acts together with JAK1, in regulation of actomyosin contractility treatment with ROCK inhibitors reduced phosphorylation of STAT3 in CAFs STAT3 silencing in CAFs reduces the levels of phosphorylated and total MLC2 protein. PMID:24857661 TGF-β1 relies on a LIF/GP130-IL6ST/JAK1 signaling cascade to induce STAT3 activation. STAT3 inducec CLL2 expression downstream of this signaling. PMID:23953057 IL6 activates STAT3 in CAFs References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="80.0" h="40.0" x="960.0" y="2810.0"/> <glyph class="state variable" id="_ff87c022-bd55-4ce0-a33f-60d141ee2970"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="952.5" y="2825.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4407_sa695" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tyrosine kinase 2 HUGO:TYK2 hgnc_id:HGNC:12440 HGNC:12440 ENTREZ:7297 UNIPROT:P29597 Identifiers_end References_begin: MODUULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="430.0" y="2150.0"/> <glyph class="state variable" id="_829d778d-7c79-48e1-83fc-b0856bdba08f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="422.5" y="2165.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4406_sa694"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: oncostatin M HUGO:OSM hgnc_id:HGNC:8506 HGNC:8506 ENTREZ:5008 UNIPROT:P13725 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL6 PMID:21840487 Jak 1 regulates Actomyosin Contractility in CAFs downstream of GP130-IL6ST IL6 and oncostatin M (OSM) and via STAT3 References_end </body> </html> </notes> <label text="OSM"/> <bbox w="80.0" h="40.0" x="150.0" y="1890.0"/> </glyph> <glyph class="complex" id="s4415_csa84" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:M20*:PPP1C*:PPP1R12A Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:15124925 Phosphorylation of myosin II plays an important role in many cell functions, including smooth muscle contraction. The level of myosin II phosphorylation is determined by activities of myosin light chain kinase and myosin phosphatase (MP). MP is composed of 3 subunits: a catalytic subunit of type 1 phosphatase, PPlc; a targeting subunit, termed myosin phosphatase target subunit, MYPT; and a smaller subunit, M20, of unknown function. PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). References_end </body> </html> </notes> <label text="Myosin_Phosphatase"/> <bbox w="110.0" h="160.0" x="7035.0" y="3600.0"/> <glyph class="macromolecule" id="s4410_sa700"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein phosphatase 1 regulatory subunit 12A HUGO:PPP1R12A hgnc_id:HGNC:7618 HGNC:7618 ENTREZ:4659 UNIPROT:O14974 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). References_end </body> </html> </notes> <label text="PPP1R12A"/> <bbox w="80.0" h="40.0" x="7045.0" y="3690.0"/> <glyph class="state variable" id="_435a9d50-7beb-42d8-a9c6-666c7944719c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7040.0" y="3705.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4414_sa702"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein phosphatase 1 catalytic subunit alpha HUGO:PPP1CA hgnc_id:HGNC:9281 HGNC:9281 ENTREZ:5499 UNIPROT:P62136 protein phosphatase 1 catalytic subunit beta HUGO:PPP1CB hgnc_id:HGNC:9282 HGNC:9282 ENTREZ:5500 UNIPROT:P62140 protein phosphatase 1 catalytic subunit gamma HUGO:PPP1CC hgnc_id:HGNC:9283 HGNC:9283 ENTREZ:5501 UNIPROT:P36873 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY Maps_Modules_end </body> </html> </notes> <label text="PPP1C*"/> <bbox w="80.0" h="40.0" x="7045.0" y="3650.0"/> </glyph> <glyph class="macromolecule" id="s4422_sa705"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein phosphatase 1 regulatory subunit 12B HUGO:PPP1R12B hgnc_id:HGNC:7619 HGNC:7619 ENTREZ:4660 UNIPROT:O60237 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY Maps_Modules_end References_begin: PMID:15124925 Phosphorylation of myosin II plays an important role in many cell functions, including smooth muscle contraction. The level of myosin II phosphorylation is determined by activities of myosin light chain kinase and myosin phosphatase (MP). MP is composed of 3 subunits: a catalytic subunit of type 1 phosphatase, PPlc; a targeting subunit, termed myosin phosphatase target subunit, MYPT; and a smaller subunit, M20, of unknown function. Myosin phosphatase is a protein complex comprised of three subunits: a catalytic subunit (PP1c-delta, protein phosphatase 1, catalytic subunit delta), a large regulatory subunit (MYPT, myosin phosphatase target) and small regulatory subunit (sm-M20). Two isoforms of MYPT have been isolated--MYPT1 and MYPT2, the first of which is widely expressed, and the second of which may be specific to heart, skeletal muscle, and brain. Each of the MYPT isoforms functions to bind PP1c-delta and increase phosphatase activity. This locus (PPP1R12B)encodes both MYTP2 and M20. References_end </body> </html> </notes> <label text="M20*"/> <bbox w="80.0" h="40.0" x="7045.0" y="3610.0"/> </glyph> </glyph> <glyph class="complex" id="s4418_csa85" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:M20*:PPP1C*:PPP1R12A Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). References_end </body> </html> </notes> <label text="Myosin_Phosphatase"/> <bbox w="120.0" h="180.0" x="7030.0" y="3860.0"/> <glyph class="macromolecule" id="s4420_sa703"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein phosphatase 1 regulatory subunit 12A HUGO:PPP1R12A hgnc_id:HGNC:7618 HGNC:7618 ENTREZ:4659 UNIPROT:O14974 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). References_end </body> </html> </notes> <label text="PPP1R12A"/> <bbox w="80.0" h="40.0" x="7040.0" y="3960.0"/> <glyph class="state variable" id="_72a40b4a-a22b-47df-93fc-2488fe87abd8"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="7032.5" y="3975.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4570_sa704"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein phosphatase 1 catalytic subunit alpha HUGO:PPP1CA hgnc_id:HGNC:9281 HGNC:9281 ENTREZ:5499 UNIPROT:P62136 protein phosphatase 1 catalytic subunit beta HUGO:PPP1CB hgnc_id:HGNC:9282 HGNC:9282 ENTREZ:5500 UNIPROT:P62140 protein phosphatase 1 catalytic subunit gamma HUGO:PPP1CC hgnc_id:HGNC:9283 HGNC:9283 ENTREZ:5501 UNIPROT:P36873 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY Maps_Modules_end </body> </html> </notes> <label text="PPP1C*"/> <bbox w="80.0" h="40.0" x="7037.1484" y="3880.1072"/> </glyph> <glyph class="macromolecule" id="s4569_sa706"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein phosphatase 1 regulatory subunit 12B HUGO:PPP1R12B hgnc_id:HGNC:7619 HGNC:7619 ENTREZ:4660 UNIPROT:O60237 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY Maps_Modules_end References_begin: PMID:15124925 Phosphorylation of myosin II plays an important role in many cell functions, including smooth muscle contraction. The level of myosin II phosphorylation is determined by activities of myosin light chain kinase and myosin phosphatase (MP). MP is composed of 3 subunits: a catalytic subunit of type 1 phosphatase, PPlc; a targeting subunit, termed myosin phosphatase target subunit, MYPT; and a smaller subunit, M20, of unknown function. Myosin phosphatase is a protein complex comprised of three subunits: a catalytic subunit (PP1c-delta, protein phosphatase 1, catalytic subunit delta), a large regulatory subunit (MYPT, myosin phosphatase target) and small regulatory subunit (sm-M20). Two isoforms of MYPT have been isolated--MYPT1 and MYPT2, the first of which is widely expressed, and the second of which may be specific to heart, skeletal muscle, and brain. Each of the MYPT isoforms functions to bind PP1c-delta and increase phosphatase activity. This locus (PPP1R12B)encodes both MYTP2 and M20. References_end </body> </html> </notes> <label text="M20*"/> <bbox w="80.0" h="40.0" x="7037.1484" y="3920.1072"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4423_sa707" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LIF Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:TNF PMID:24857661 ;PMID:8432990 TGF-β1-stimulated hDF was thus assessed by quantitative real-time PCR, that disclosed a 100-fold increase of LIF and 5-fold increase of IL6 mRNA steady-state levels ( Figure 2B). PMID:8432990 TNF, IL1A induces LIF gene expression and protein level. References_end </body> </html> </notes> <label text="LIF"/> <bbox w="70.0" h="25.0" x="475.0" y="3168.5"/> </glyph> <glyph class="nucleic acid feature" id="s4424_sa708" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LIF Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:TNF References_end </body> </html> </notes> <label text="LIF"/> <bbox w="90.0" h="25.0" x="465.0" y="3248.5"/> <glyph class="unit of information" id="_3c02bf77-3112-4465-b1a2-b191daf1b749"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="500.0" y="3243.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4425_sa709" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LIF receptor alpha HUGO:LIFR hgnc_id:HGNC:6597 HGNC:6597 ENTREZ:3977 UNIPROT:P42702 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:LIF PMID:22595692 The structure of receptors of IL6 like cytokines References_end </body> </html> </notes> <label text="LIFR"/> <bbox w="80.0" h="50.0" x="820.0" y="2475.0"/> <glyph class="unit of information" id="_3cfe70f3-1d0c-4e73-a7e2-8896fe1949d0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="837.5" y="2470.0"/> </glyph> </glyph> <glyph class="complex" id="s4426_csa86" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LIFR:gp130* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4426"/> <bbox w="100.0" h="130.0" x="650.0" y="2155.0"/> <glyph class="macromolecule" id="s4427_sa710"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LIF receptor alpha HUGO:LIFR hgnc_id:HGNC:6597 HGNC:6597 ENTREZ:3977 UNIPROT:P42702 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:LIF PMID:22595692 The structure of receptors of IL6 like cytokines References_end </body> </html> </notes> <label text="LIFR"/> <bbox w="80.0" h="50.0" x="660.0" y="2160.0"/> <glyph class="unit of information" id="_2db8ebf6-08e4-429a-9179-404c7fc07892"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="677.5" y="2155.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4428_sa711"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="660.0" y="2210.0"/> <glyph class="state variable" id="_8f748399-5527-4a91-8674-c758e4dfcfbc"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="722.5" y="2207.541"/> </glyph> <glyph class="unit of information" id="_57e0b126-7d8c-4a0b-8440-6020ebf194aa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="677.5" y="2205.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4429_sa712"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LIF, interleukin 6 family cytokine HUGO:LIF hgnc_id:HGNC:6596 HGNC:6596 ENTREZ:3976 UNIPROT:P15018 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:TNF CASCADE:LIF PMID:24857661 LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, LIF as the major cytokine mediating STAT3 phosphorylation upon TGF-β1 stimulation. TGF-β1 relies on a LIF/GP130-IL6ST/JAK1 signaling cascade to induce STAT3 activation. LIF signaling mediates onset of a proinvasive microenvironment by proinvasive fibroblast activation and actomyosin contractility regulation independent of α-SMA expression. References_end </body> </html> </notes> <label text="LIF"/> <bbox w="80.0" h="40.0" x="220.0" y="1630.0"/> </glyph> <glyph class="complex" id="s4430_csa87" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:JAK1:LIF:LIFR:gp130* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:LIF PMID:22595692 The structure of receptors of IL6 like cytokines References_end </body> </html> </notes> <label text="s4426"/> <bbox w="210.0" h="175.0" x="535.0" y="2342.0"/> <glyph class="macromolecule" id="s4431_sa713"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LIF receptor alpha HUGO:LIFR hgnc_id:HGNC:6597 HGNC:6597 ENTREZ:3977 UNIPROT:P42702 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:LIF PMID:22595692 The structure of receptors of IL6 like cytokines References_end </body> </html> </notes> <label text="LIFR"/> <bbox w="80.0" h="50.0" x="555.0" y="2347.0"/> <glyph class="unit of information" id="_ea0ff1f0-3c7e-4e03-9d73-236e408722fd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="572.5" y="2342.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4432_sa714"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="555.0" y="2397.0"/> <glyph class="state variable" id="_b1bb4ce5-6f1c-41f7-b39e-bfec425f061c"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="617.5" y="2394.541"/> </glyph> <glyph class="unit of information" id="_27b2f3c2-a9e8-4ce9-9a4c-7ac5d23a671b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="572.5" y="2392.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4433_sa715"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 1 HUGO:JAK1 hgnc_id:HGNC:6190 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end References_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IL6 CASCADE:PLAU CASCADE:LIF CASCADE:IFNG PMID:21840487 CAF-dependent matrix remodelling is essential for collective carcinoma cell invasion JAK kinase inhibitor P6 tested blocked remodelling (Hooper et al., 2010). P6 inhibits multiple members of the JAK family (Pedranzini et al., 2006), so we used JAK isoform-specific inhibitors to probe which JAKs are involved; neither JAK2 nor JAK3-specific inhibitors recapitulated the effect of the pan-JAK inhibitor (P6) on matrix remodelling (Figure 1A), suggesting that JAKI is the family member involved. Jak 1 regulates Actomyosin Contractility in CAFs downstream of GP130-IL6ST IL6 and oncostatin M (OSM) and via STAT3 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="555.0" y="2457.0"/> <glyph class="state variable" id="_8b563e04-8768-4d47-9f01-23dedf6682e9"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="547.5" y="2472.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4434_sa719"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LIF, interleukin 6 family cytokine HUGO:LIF hgnc_id:HGNC:6596 HGNC:6596 ENTREZ:3976 UNIPROT:P15018 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:TNF CASCADE:LIF PMID:24857661 LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, LIF as the major cytokine mediating STAT3 phosphorylation upon TGF-β1 stimulation. TGF-β1 relies on a LIF/GP130-IL6ST/JAK1 signaling cascade to induce STAT3 activation. LIF signaling mediates onset of a proinvasive microenvironment by proinvasive fibroblast activation and actomyosin contractility regulation independent of α-SMA expression. References_end </body> </html> </notes> <label text="LIF"/> <bbox w="80.0" h="40.0" x="645.0" y="2347.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s529_sa413" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma receptor 2 HUGO:IFNGR2 hgnc_id:HGNC:5440 HGNC:5440 ENTREZ:3460 UNIPROT:P38484 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CZSCZDE:IFNG Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR2"/> <bbox w="80.0" h="50.0" x="2490.0" y="1305.0"/> <glyph class="unit of information" id="_af4d7ccf-fe60-49b0-b61f-da46ab837a32"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2507.5" y="1300.0"/> </glyph> </glyph> <glyph class="macromolecule multimer" id="s711_sa412"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma HUGO:IFNG hgnc_id:HGNC:5438 HGNC:5438 ENTREZ:3458 UNIPROT:P01579 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IFNG Maps_Modules_end References_begin: PMID:17559085 The Th1 cytokine interferon-γ (IFN-γ) inhibits collagen gene transcription, and blocks stimulation induced by TGF-β (Varga et al., 1990). Negative regulation of collagen gene by IFN-γ plays an important homeostatic role in preventing excessive scar formation. Transcription factors implicated in mediating IFN-γ-induced inhibition of collagen gene expression include STAT1α (Ghosh et al., 2001), class II transactivator (CIITA) (Zhu and Ting, 2001), the RFX5 complex (Sengupta et al., 2002), YB-1 (Higashi et al., 2003), and C/EBP-β (Ghosh et al., 2006). In our studies focusing on the role of p300 in IFN-γ modulation of collagen synthesis, we found that IFN-γ induced a direct interaction between activated STAT1α and p300 in normal skin fibroblasts (Ghosh et al., 2001). Furthermore, ectopic expression of p300 overcame the inhibition by IFN-γ and rescued stimulation by TGF-β, suggesting that in response to IFN-γ, activated STAT1α and/or downstream factor(s) sequestered p300, preventing its recruitment to the transcriptional machinery and thereby inhibiting collagen gene transcription (Ghosh et al., 2001). Similarly, IFN-γ suppression of COL1A2 promoter activation by YB-1 also appears to involve p300 sequestration (Higashi et al., 2003). References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="86.0" h="46.0" x="2697.0" y="587.0"/> <glyph class="unit of information" id="_11162389-15d5-41a8-8bdc-3a8403c5b618"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2730.0" y="582.0"/> </glyph> </glyph> <glyph class="complex" id="s527_csa45" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IFNGR1:IFNGR2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: 17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. 19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2. Ligand engagement of the IFNG receptor leads to activation of receptor-associated Jak1 and Jak2 and phosphorylation of a receptor tyrosine residue (Y440) that serves as a docking site for STAT1, which exists in a latent state in the cytoplasm. References_end </body> </html> </notes> <label text="IFNGR"/> <bbox w="120.0" h="130.0" x="2560.0" y="995.0"/> <glyph class="macromolecule" id="s709_sa421"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma receptor 1 HUGO:IFNGR1 hgnc_id:HGNC:5439 HGNC:5439 ENTREZ:3459 UNIPROT:P15260 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IFNG Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="2580.0" y="1010.0"/> <glyph class="state variable" id="_5c5feafb-aba8-4096-9723-4243212e8935"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2575.0" y="1029.9602"/> </glyph> <glyph class="unit of information" id="_6a59d4e9-c875-47f1-a3b3-be943bb0a8f4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2597.5" y="1005.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s710_sa420"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma receptor 2 HUGO:IFNGR2 hgnc_id:HGNC:5440 HGNC:5440 ENTREZ:3460 UNIPROT:P38484 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CZSCZDE:IFNG Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR2"/> <bbox w="80.0" h="50.0" x="2580.0" y="1050.0"/> <glyph class="unit of information" id="_f2944fea-d8c2-4c7f-b3a8-7b030e020dd2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2597.5" y="1045.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4121_csa44" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IFNG:IFNGR1:IFNGR2:JAK1:JAK2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: 17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. 19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2. Ligand engagement of the IFNG receptor leads to activation of receptor-associated Jak1 and Jak2 and phosphorylation of a receptor tyrosine residue (Y440) that serves as a docking site for STAT1, which exists in a latent state in the cytoplasm. References_end </body> </html> </notes> <label text="IFNGR"/> <bbox w="199.5" h="207.0" x="2707.0" y="1195.0"/> <glyph class="macromolecule multimer" id="s4126_sa419"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma HUGO:IFNG hgnc_id:HGNC:5438 HGNC:5438 ENTREZ:3458 UNIPROT:P01579 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IFNG Maps_Modules_end References_begin: PMID:17559085 The Th1 cytokine interferon-γ (IFN-γ) inhibits collagen gene transcription, and blocks stimulation induced by TGF-β (Varga et al., 1990). Negative regulation of collagen gene by IFN-γ plays an important homeostatic role in preventing excessive scar formation. Transcription factors implicated in mediating IFN-γ-induced inhibition of collagen gene expression include STAT1α (Ghosh et al., 2001), class II transactivator (CIITA) (Zhu and Ting, 2001), the RFX5 complex (Sengupta et al., 2002), YB-1 (Higashi et al., 2003), and C/EBP-β (Ghosh et al., 2006). In our studies focusing on the role of p300 in IFN-γ modulation of collagen synthesis, we found that IFN-γ induced a direct interaction between activated STAT1α and p300 in normal skin fibroblasts (Ghosh et al., 2001). Furthermore, ectopic expression of p300 overcame the inhibition by IFN-γ and rescued stimulation by TGF-β, suggesting that in response to IFN-γ, activated STAT1α and/or downstream factor(s) sequestered p300, preventing its recruitment to the transcriptional machinery and thereby inhibiting collagen gene transcription (Ghosh et al., 2001). Similarly, IFN-γ suppression of COL1A2 promoter activation by YB-1 also appears to involve p300 sequestration (Higashi et al., 2003). References_end </body> </html> </notes> <label text="IFNG"/> <bbox w="86.0" h="46.0" x="2766.5" y="1207.0"/> <glyph class="unit of information" id="_aa79cfe5-f6d7-49f0-a782-1f0b1e1b390a"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="2799.5" y="1202.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4125_sa418"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 2 HUGO:JAK2 hgnc_id:HGNC:6192 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:PLAU CASCADE:IFNG Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="2817.0" y="1295.0"/> <glyph class="state variable" id="_d3cf7050-2053-4557-b5ab-20fc066b69b1"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2812.0" y="1310.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4124_sa417"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 1 HUGO:JAK1 hgnc_id:HGNC:6190 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end References_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IL6 CASCADE:PLAU CASCADE:LIF CASCADE:IFNG PMID:21840487 CAF-dependent matrix remodelling is essential for collective carcinoma cell invasion JAK kinase inhibitor P6 tested blocked remodelling (Hooper et al., 2010). P6 inhibits multiple members of the JAK family (Pedranzini et al., 2006), so we used JAK isoform-specific inhibitors to probe which JAKs are involved; neither JAK2 nor JAK3-specific inhibitors recapitulated the effect of the pan-JAK inhibitor (P6) on matrix remodelling (Figure 1A), suggesting that JAKI is the family member involved. Jak 1 regulates Actomyosin Contractility in CAFs downstream of GP130-IL6ST IL6 and oncostatin M (OSM) and via STAT3 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="2819.5" y="1340.0"/> <glyph class="state variable" id="_c91e7d2a-8cbb-43bb-87db-0c43e488105e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2814.5" y="1355.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4123_sa416"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma receptor 2 HUGO:IFNGR2 hgnc_id:HGNC:5440 HGNC:5440 ENTREZ:3460 UNIPROT:P38484 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CZSCZDE:IFNG Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR2"/> <bbox w="80.0" h="50.0" x="2719.5" y="1285.0"/> <glyph class="unit of information" id="_85b1f74a-f449-490c-b3de-fe4090a8e2a8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2737.0" y="1280.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4122_sa415"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma receptor 1 HUGO:IFNGR1 hgnc_id:HGNC:5439 HGNC:5439 ENTREZ:3459 UNIPROT:P15260 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IFNG Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="2719.5" y="1335.0"/> <glyph class="state variable" id="_f7fd7bdc-af19-405c-869b-ee62d5bf5ed4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2712.0" y="1354.9602"/> </glyph> <glyph class="unit of information" id="_2140a176-52db-4bed-97e3-0ecddbe21825"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2737.0" y="1330.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4435_csa88" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PLAUR:gp130* Identifiers_end References_begin: PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. References_end </body> </html> </notes> <label text="s4171"/> <bbox w="100.0" h="147.5" x="870.0" y="1716.0"/> <glyph class="macromolecule" id="s4772_sa716"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase receptor HUGO:PLAUR hgnc_id:HGNC:9053 HGNC:9053 ENTREZ:5329 UNIPROT:Q03405 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="PLAUR"/> <bbox w="80.0" h="50.0" x="880.0" y="1733.5"/> <glyph class="unit of information" id="_f413ed54-f5cb-4fab-b0b6-5b4b01604db6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="897.5" y="1728.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4437_sa718"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="880.0" y="1778.5"/> <glyph class="state variable" id="_649027d8-ae56-4a55-9fce-61136f87f2e2"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="942.5" y="1776.041"/> </glyph> <glyph class="unit of information" id="_9e3bac30-0387-4bbb-9e07-e7978ca5eff1"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="897.5" y="1773.5"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4181_sa693" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: signal transducer and activator of transcription 3 HUGO:STAT3 hgnc_id:HGNC:11364 HGNC:11364 ENTREZ:6774 UNIPROT:P40763 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL6 CASCADE:PLAU PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. PMID:21840487 ROCK and JAK1/STAT3 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma downstream of IL6 pathway ROCK acts together with JAK1, in regulation of actomyosin contractility treatment with ROCK inhibitors reduced phosphorylation of STAT3 in CAFs STAT3 silencing in CAFs reduces the levels of phosphorylated and total MLC2 protein. PMID:24857661 TGF-β1 relies on a LIF/GP130-IL6ST/JAK1 signaling cascade to induce STAT3 activation. STAT3 inducec CLL2 expression downstream of this signaling. PMID:23953057 IL6 activates STAT3 in CAFs References_end </body> </html> </notes> <label text="STAT3"/> <bbox w="80.0" h="40.0" x="960.0" y="2690.0"/> <glyph class="state variable" id="_78c392fd-9567-4eb0-ba5d-8610ad43d25b"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="955.0" y="2705.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4441_sa722" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL11 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TGFB PMID:8133053 IL1a and TGFB induce IL11 gene expression and protein accamulation in fibroblasts. References_end </body> </html> </notes> <label text="IL11"/> <bbox w="70.0" h="25.0" x="715.0" y="3168.5"/> </glyph> <glyph class="nucleic acid feature" id="s4442_sa723" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL11 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TGFB PMID:8133053 IL1a and TGFB induce gene expression and protein accamulation in fibroblasts. References_end </body> </html> </notes> <label text="IL11"/> <bbox w="90.0" h="25.0" x="705.0" y="3248.5"/> <glyph class="unit of information" id="_7783b250-fd35-4624-baf8-d244ebfe0c5c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="740.0" y="3243.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4443_sa726" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 2 HUGO:JAK2 hgnc_id:HGNC:6192 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:PLAU CASCADE:IFNG Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="JAK2"/> <clone/> <bbox w="80.0" h="40.0" x="940.0" y="2450.0"/> <glyph class="state variable" id="_939698f5-3bcc-43a5-b4cc-116cd87b2189"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="935.0" y="2465.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4443_sa1168" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 2 HUGO:JAK2 hgnc_id:HGNC:6192 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:PLAU CASCADE:IFNG Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="JAK2"/> <clone/> <bbox w="80.0" h="40.0" x="2833.5962" y="925.96155"/> <glyph class="state variable" id="_b14b3a2a-4d10-4f65-873c-d138be8d8a2c"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2828.5962" y="940.96155"/> </glyph> </glyph> <glyph class="macromolecule" id="s4446_sa728"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase HUGO:PLAU hgnc_id:HGNC:9052 HGNC:9052 ENTREZ:5328 UNIPROT:P00749 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGF PMID:11021826 Fibroblastic expression (immunohistocheemistry) of both uPA and uPAR were positively correlated with tumor size. fibroblastic expression of PAI1 was related to the presence of invasion PMID:19631971 co-culturing fibroblasts with ovarian cancer cells (ES-2) led to induction of uPA in fibroblasts; the same effect was observed when the fibroblasts were grown in ES-2 cell-conditioned medium. The basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) were the cancer cell-derived paracrine factors inducing uPA transcription in the fibroblasts. References_end </body> </html> </notes> <label text="proPLAU*"/> <bbox w="80.0" h="40.0" x="480.0" y="1510.0"/> </glyph> <glyph class="complex" id="s3968_csa37" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL6R:JAK1:JAK2:TYK2:gp130* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: 1439146 IL6 signaling acts through IL6 receptor and receptor-associated signal transducer, gp130 22595692 The structure of receptors of IL6 like cytokines 9716487 IL6 signaling acts through jak/stat pathway, probably via Jak1, Jak2 and Tyk2 References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="185.0" h="182.85156" x="237.0" y="2418.0"/> <glyph class="macromolecule" id="s3974_sa378"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 2 HUGO:JAK2 hgnc_id:HGNC:6192 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:PLAU CASCADE:IFNG Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="JAK2"/> <bbox w="80.0" h="40.0" x="332.0" y="2528.0"/> <glyph class="state variable" id="_533f0b02-1a22-4bf7-a9bb-e71abcb36c92"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="324.5" y="2543.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3973_sa377"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tyrosine kinase 2 HUGO:TYK2 hgnc_id:HGNC:12440 HGNC:12440 ENTREZ:7297 UNIPROT:P29597 Identifiers_end References_begin: MODUULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 PMID:14610620 TYK2 is a member of the Janus kinase family. TYK2 associated with IL13RA1 participates in signal transduction. PMID:‭21115385, PMID:7543512 ‭The binding of IL-10 to its receptor activates two members of the Janus kinase family: Jak1 (associated with the IL-1OR1 and Tyk2 (associated with the IL-10R2) IL-10 treatment of monocytes results in the tyrosine phosphorylation of tyk2 and Jakl References_end </body> </html> </notes> <label text="TYK2"/> <bbox w="80.0" h="40.0" x="332.0" y="2478.0"/> <glyph class="state variable" id="_59fa9757-4102-4a84-80a0-329db8e29cd5"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="324.5" y="2493.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3972_sa376"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 1 HUGO:JAK1 hgnc_id:HGNC:6190 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end References_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IL6 CASCADE:PLAU CASCADE:LIF CASCADE:IFNG PMID:21840487 CAF-dependent matrix remodelling is essential for collective carcinoma cell invasion JAK kinase inhibitor P6 tested blocked remodelling (Hooper et al., 2010). P6 inhibits multiple members of the JAK family (Pedranzini et al., 2006), so we used JAK isoform-specific inhibitors to probe which JAKs are involved; neither JAK2 nor JAK3-specific inhibitors recapitulated the effect of the pan-JAK inhibitor (P6) on matrix remodelling (Figure 1A), suggesting that JAKI is the family member involved. Jak 1 regulates Actomyosin Contractility in CAFs downstream of GP130-IL6ST IL6 and oncostatin M (OSM) and via STAT3 References_end </body> </html> </notes> <label text="JAK1"/> <bbox w="80.0" h="40.0" x="332.0" y="2428.0"/> <glyph class="state variable" id="_5332bc31-4d2e-4a58-a707-789fcde35736"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="324.5" y="2443.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3970_sa374"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 receptor HUGO:IL6R hgnc_id:HGNC:6019 HGNC:6019 ENTREZ:3570 UNIPROT:P08887 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL6 Maps_Modules_end References_begin: PMID:12754507, PMID:24418198 SOCS3 binds with high affinity to the phosphorylated Tyr759 (Y759) Of gp130 to suppress IL-6 signaling. References_end </body> </html> </notes> <label text="IL6R"/> <bbox w="80.0" h="50.0" x="239.5" y="2474.4258"/> <glyph class="unit of information" id="_6d3d24da-c421-4466-83ea-728088664432"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="257.0" y="2469.4258"/> </glyph> </glyph> <glyph class="macromolecule" id="s3896_sa368"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 signal transducer HUGO:IL6ST hgnc_id:HGNC:6021 HGNC:6021 ENTREZ:3572 UNIPROT:P40189 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:LIF CASCADE:TGFB CASCADE:IL6 CASCADE:PLAU Maps_Modules_end References_begin: PMID:11306493 IL4 signaling prevents CSF2RA(CD116) lost on DC surface in tumor microenviroment. and blocks gp130 and CSF1R (CD115)surface expression. References_end </body> </html> </notes> <label text="gp130*"/> <bbox w="80.0" h="50.0" x="239.5" y="2524.4258"/> <glyph class="state variable" id="_aaaa346d-2183-4568-8393-b7e370f58179"> <state value="P" variable="Y759"/> <bbox w="35.0" h="10.0" x="302.0" y="2521.9668"/> </glyph> <glyph class="unit of information" id="_41ac929f-1857-4165-9658-8a0188a73fad"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="257.0" y="2519.4258"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4447_sa729" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA hgnc_id:HGNC:12680 HGNC:12680 ENTREZ:7422 UNIPROT:P15692 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:IL6 PMID:24346288 IL-6 promoted VEGF expression by fibroblasts but not by cancer cell lines PMID:12629515; PMID:11960372 Probably IL6 induces VEGF expression in fibroblasts via STAT3 pathway (data from non fibroblasts only) PMID:16572188; PMID:9753319 Vascular endothelial growth factor (VEGF, also known as vascular permeability factor (VPF)) has a central role in the emergence of the reactive stroma27. VEGF can be released by cancer cells themselves, but fibroblasts and inflammatory cells are the principal source of host-derived VEGF28. VEGF induces microvascular permeability, which leads to the extravasation of plasma proteins such as fibrin, which in turn attract an influx of fibroblasts, inflammatory cells and endothelial cells27, 29, 30. These cells produce ECM that is rich in fibronectin and type I collagen, both of which are conducive to initiating tumour angiogenesis PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:19414323 overexpression of VEGF activity in tumours can lead to increased infiltration of TReg cells and MDSCs, which as discussed above are key cell types that trigger immunosuppression. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="80.0" h="40.0" x="4310.0" y="4431.0"/> </glyph> <glyph class="nucleic acid feature" id="s4448_sa730" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:VEGFA Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL6 PMID:24346288 IL-6 promoted VEGF expression by fibroblasts but not by cancer cell lines PMID:12629515; PMID:11960372 Probably IL6 induces VEGF expression in fibroblasts via STAT3 References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="70.0" h="25.0" x="4315.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4449_sa731" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:VEGFA Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:IL6 PMID:24346288 IL-6 promoted VEGF expression by fibroblasts but not by cancer cell lines PMID:12629515; PMID:11960372 Probably IL6 induces VEGF expression in fibroblasts via STAT3 References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="90.0" h="25.0" x="4305.0" y="4342.5"/> <glyph class="unit of information" id="_6644e0c5-da4a-4eb9-baf6-b4d20a97f50b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4340.0" y="4337.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4450_sa732" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR205 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:23924028 miR-205 blocks tumor-driven activation of surrounding fibroblasts by reducing pro-inflammatory cytokine secretion. References_end </body> </html> </notes> <label text="MIR205"/> <bbox w="90.0" h="25.0" x="2735.0" y="2987.5"/> <glyph class="unit of information" id="_c36c1214-f30d-4345-9666-d7ff2bf6d029"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2765.0" y="2982.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4455_sa739" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SPP1 Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:PDGF PMID:19118022 fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts probably via PDGFR-α. References_end </body> </html> </notes> <label text="SPP1"/> <bbox w="70.0" h="25.0" x="4095.0" y="3427.5"/> </glyph> <glyph class="nucleic acid feature" id="s4456_sa740" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SPP1 Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:PDGF PMID:19118022 fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts. References_end </body> </html> </notes> <label text="SPP1"/> <bbox w="90.0" h="25.0" x="4085.0" y="3517.5"/> <glyph class="unit of information" id="_c8e31ffa-b353-49f5-b994-96c449044b4d"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4120.0" y="3512.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4457_sa742" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PDGFRA HUGO:PDGFRB Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:LIF CASCADE:TGFB PMID:19118022 Fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts probably via PDGFR-α. PMID:24857661 we noted an increased expression of PDGFRα after LIF stimulation in hPDF PMID:26921338 TGFB induces expression of PDGFB and PDGFR in CAFs and indirectly suppresses PEDF expression via PDGFB signaling References_end </body> </html> </notes> <label text="PDGFR*"/> <bbox w="70.0" h="25.0" x="4515.0" y="1317.5"/> </glyph> <glyph class="nucleic acid feature" id="s4458_sa743" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PDGFRA HUGO:PDGFRB Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:TGFB CASCADE:LIF PMID:19118022 Fibroblasts expressed high amounts of osteopontin, and stimulation with PDGF-CC for 6 h increased the production even further, by 2.4-fold compared to unstimulated fibroblasts, demonstrating that the expression of osteopontin is directly regulated by signaling induced by PDGF-CC in fibroblasts probably via PDGFR-α. PMID:24857661 we noted an increased expression of PDGFRα after LIF stimulation in hPDF References_end </body> </html> </notes> <label text="PDGFR*"/> <bbox w="90.0" h="25.0" x="4505.0" y="1247.5"/> <glyph class="unit of information" id="_57ec9aa9-6e31-4978-a802-85fbec35b3cf"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4540.0" y="1242.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s1309_sa255" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TGFB1 HUGO:TGFB2 HUGO:TGFB3 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:TGFB PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:21098712 Exosomal TGF-β, resulted in an enhanced induction of TGF-β-mRNA in fibroblasts via TGFBR1 References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="70.0" h="25.0" x="3655.0" y="4537.5"/> </glyph> <glyph class="macromolecule" id="s4460_sa746" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 7 HUGO:FGF7 hgnc_id:HGNC:3685 HGNC:3685 ENTREZ:2252 UNIPROT:P21781 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling References_end </body> </html> </notes> <label text="FGF7"/> <bbox w="80.0" h="40.0" x="3700.0" y="4431.0"/> </glyph> <glyph class="nucleic acid feature" id="s4461_sa747" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF7 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling References_end </body> </html> </notes> <label text="FGF7"/> <bbox w="70.0" h="25.0" x="3695.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4462_sa748" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF7 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling References_end </body> </html> </notes> <label text="FGF7"/> <bbox w="90.0" h="25.0" x="3685.0" y="4342.5"/> <glyph class="unit of information" id="_44c558e7-5d50-48e1-830a-6df30848cee6"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3720.0" y="4337.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4463_sa749" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF2 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling PMID:21098712; PMID:22652804; PMID:17637743; PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways (erk,p38) References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="70.0" h="25.0" x="3585.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4464_sa750" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:FGF2 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF CASCADE:TGFB PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling PMID:21098712; PMID:22652804; PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="90.0" h="25.0" x="3575.0" y="4342.5"/> <glyph class="unit of information" id="_df6cb9c3-239e-4901-844c-5f0c8d701594"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3610.0" y="4337.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s4466_sa100" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:22101652; PMID:19923890 The M1 or M2 splice isoforms of pyruvate kinase (PK), a mandatory regulatory glycolytic enzyme, shift glucose metabolism towards aerobic glycolysis (PKM2) or oxidative phosphorylation (PKM1) PKM2 and lactate dehydrogenase are highly expressed in the stroma of breast cancer lacking caveolin-1 expression CASCADE:TGFB CASCADE:PDGF References_end </body> </html> </notes> <label text="glucose"/> <bbox w="70.0" h="25.0" x="2975.0" y="4537.5"/> </glyph> <glyph class="macromolecule" id="s4468_sa751"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: hepatocyte growth factor HUGO:HGF hgnc_id:HGNC:4893 HGNC:4893 ENTREZ:3082 UNIPROT:P14210 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:FGF CASCADE:PDGF CASCADE:HGF PMID:9242465; PMID:19631971 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts PMID:27474009 HGF is a activation factor for fibroblasts PMID:23667593 Cancer-Associated Fibroblasts from Hepatocellular Carcinoma Promote Malignant Cell Proliferation by HGF Secretion PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15059978 Proinvasive factors secreted by myofibroblasts are identified as TNC and SF/HGF, each of which is necessary but not sufficient for stimulation of invasion of human colon cancer cells PMID:22763439 HGF is present in the stromal cells of melanoma and correlates with poor response to therapy References_end </body> </html> </notes> <label text="HGF"/> <bbox w="80.0" h="40.0" x="5750.0" y="690.0"/> </glyph> <glyph class="macromolecule" id="s4469_sa752" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein tyrosine phosphatase, non-receptor type 6 HUGO:PTPN6 hgnc_id:HGNC:9658 HGNC:9658 ENTREZ:5777 UNIPROT:P29350 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:27474009; PMID:26667266 STAT3 acetylation and phosphorylation are inversely correlated with SHP-1 expression. References_end </body> </html> </notes> <label text="PTPN6"/> <bbox w="80.0" h="40.0" x="1430.0" y="2760.0"/> </glyph> <glyph class="macromolecule" id="s4470_sa754" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: signal transducer and activator of transcription 1 HUGO:STAT1 hgnc_id:HGNC:11362 HGNC:11362 ENTREZ:6772 UNIPROT:P42224 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR CASCADE:IFNG PMID:17559085, PMID:11134049 IFN-γ induced a direct interaction between activated STAT1α and p300 in normal skin fibroblasts (Ghosh et al., 2001). Furthermore, ectopic expression of p300 overcame the inhibition by IFN-γ and rescued stimulation by TGF-β, suggesting that in response to IFN-γ, activated STAT1α and/or downstream factor(s) sequestered p300, preventing its recruitment to the transcriptional machinery and thereby inhibiting collagen gene transcription (Ghosh et al., 2001). Similarly, IFN-γ suppression of COL1A2 promoter activation by YB-1 also appears to involve p300 sequestration (Higashi et al., 2003). References_end </body> </html> </notes> <label text="STAT1"/> <bbox w="80.0" h="40.0" x="2860.0" y="1730.0"/> <glyph class="state variable" id="_318df1d4-29df-4554-9f2b-ccab24b24983"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2852.5" y="1745.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4323_sa595"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibronectin 1 HUGO:FN1 hgnc_id:HGNC:3778 HGNC:3778 ENTREZ:2335 UNIPROT:P02751 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH CASCADE:INTEGRIN PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. PMID:18353785 TGFβ1-inducedαvβ3 expression is dependent on integrin-mediated cell adhesion; FN strongly potentiated the effect of TGFβ1. PMID:26519775 fibronectin is a ligand fo a5b1, avb3, avb5 integrins in CAFs References_end </body> </html> </notes> <label text="FN*"/> <bbox w="80.0" h="40.0" x="7960.0" y="1960.0"/> </glyph> <glyph class="phenotype" id="s4175_sa447"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12118074 , PMID:3491869 p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration PMID:23505219 Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma In fibroblasts, PDGF-D activated the Rac1 and Cdc42 Rho GTPases and c-Jun N-terminal kinase (JNK). Selective inhibition of Rho GTPases (particularly Rac1) and of JNK strongly reduced PDGF-D-induced fibroblast migration. PMID:20861157 MIF inhibits in CXCR2/CD74-dependent manner recruitment of CAFs to the growing tumor. References_end </body> </html> </notes> <label text="MIGRATION_INTO_THE_TUMOR"/> <bbox w="390.0" h="125.0" x="6485.0" y="5067.5"/> </glyph> <glyph class="complex" id="s4474_csa89" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:Alpha_tubulin*:Beta-tubulin* Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:PDGF References_end </body> </html> </notes> <label text="s4474"/> <bbox w="100.0" h="140.0" x="6080.0" y="4060.0"/> <glyph class="macromolecule" id="s4472_sa755"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tubulin alpha 1a HUGO:TUBA1A hgnc_id:HGNC:20766 HGNC:20766 ENTREZ:7846 UNIPROT:Q71U36 tubulin alpha 1b HUGO:TUBA1B hgnc_id:HGNC:18809 HGNC:18809 ENTREZ:10376 UNIPROT:P68363 tubulin alpha 1c HUGO:TUBA1C hgnc_id:HGNC:20768 HGNC:20768 ENTREZ:84790 UNIPROT:Q9BQE3 tubulin alpha 3c HUGO:TUBA3C hgnc_id:HGNC:12408 HGNC:12408 ENTREZ:7278 UNIPROT:Q13748 tubulin alpha 3d HUGO:TUBA3D hgnc_id:HGNC:24071 HGNC:24071 ENTREZ:113457 UNIPROT:Q13748 tubulin alpha 3e HUGO:TUBA3E hgnc_id:HGNC:20765 HGNC:20765 ENTREZ:112714 UNIPROT:Q6PEY2 tubulin alpha 4a HUGO:TUBA4A hgnc_id:HGNC:12407 HGNC:12407 ENTREZ:7277 UNIPROT:P68366 tubulin alpha 8 HUGO:TUBA8 hgnc_id:HGNC:12410 HGNC:12410 ENTREZ:51807 UNIPROT:Q9NY65 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:PDGF PMID:17397400 PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling References_end </body> </html> </notes> <label text="Alpha_tubulin*"/> <bbox w="80.0" h="40.0" x="6090.0" y="4130.0"/> </glyph> <glyph class="macromolecule" id="s4473_sa756"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tubulin beta class I HUGO:TUBB hgnc_id:HGNC:20778 HGNC:20778 ENTREZ:203068 UNIPROT:P07437 tubulin beta 1 class VI HUGO:TUBB1 hgnc_id:HGNC:16257 HGNC:16257 ENTREZ:81027 UNIPROT:Q9H4B7 tubulin beta 2A class IIa HUGO:TUBB2A hgnc_id:HGNC:12412 HGNC:12412 ENTREZ:7280 UNIPROT:Q13885 tubulin beta 2B class IIb HUGO:TUBB2B hgnc_id:HGNC:30829 HGNC:30829 ENTREZ:347733 UNIPROT:Q9BVA1 tubulin beta 4B class IVb HUGO:TUBB4B hgnc_id:HGNC:20771 HGNC:20771 ENTREZ:10383 UNIPROT:P68371 tubulin beta 3 class III HUGO:TUBB3 hgnc_id:HGNC:20772 HGNC:20772 ENTREZ:10381 UNIPROT:Q13509 tubulin beta 4A class IVa HUGO:TUBB4A hgnc_id:HGNC:20774 HGNC:20774 ENTREZ:10382 UNIPROT:P04350 tubulin beta 7 pseudogene HUGO:TUBB7P hgnc_id:HGNC:12413 HGNC:12413 ENTREZ:56604 tubulin beta 6 class V HUGO:TUBB6 hgnc_id:HGNC:20776 HGNC:20776 ENTREZ:84617 UNIPROT:Q9BUF5 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:PDGF PMID:17397400 PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling References_end </body> </html> </notes> <label text="Beta-tubulin*"/> <bbox w="80.0" h="40.0" x="6090.0" y="4070.0"/> </glyph> </glyph> <glyph class="phenotype" id="s4475_sa757" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:17397400 PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling Microtubule network itself is polarized in migrating cells. References_end </body> </html> </notes> <label text="Microtubule_polymerization"/> <bbox w="270.0" h="45.0" x="6005.0" y="4317.5"/> </glyph> <glyph class="macromolecule" id="s1895_sa758" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: actin, alpha 1, skeletal muscle HUGO:ACTA1 hgnc_id:HGNC:129 HGNC:129 ENTREZ:58 UNIPROT:P68133 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 hgnc_id:HGNC:130 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin beta HUGO:ACTB hgnc_id:HGNC:132 HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 HUGO:ACTC1 hgnc_id:HGNC:143 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin gamma 1 HUGO:ACTG1 hgnc_id:HGNC:144 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 CASCADE:PDGF GASCADE:TGFB CASCADE:EGF CASCADE:HH CASCADE:CXCL12 PMID:25732845 PMID:16139227 Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression, probably via regulation of fibroblast migration. Phosphorylation of Girdin by Akt Is Required for Cell Migration. Girdin Is Required for the Formation of Actin Stress Fibers and Cell Migration PMID:18423981 Opposing roles of EGF and TGF-β on F-actin reorganization and Rho- GTPase activity EGF treatment stimulated the bi-polarization and formation of dendritic-like cellular extensions of fibroblasts. TGF-β treatment, with reduction of polarized iHDFs from 40% to 12% and upregulation of stress fiber-positive fibroblasts from 30% to 84%. PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation and promotes RhoA-activation aand actin polymerisation. PMID:26711338 CAFs Have Enhanced Actin and Septin Cytoskeletal Networks regulated by Cdc42EP3/BORG2 References_end </body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="130.0" h="50.0" x="6305.0" y="4075.0"/> </glyph> <glyph class="macromolecule multimer" id="s1918_sa759" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: actin, alpha 1, skeletal muscle HUGO:ACTA1 hgnc_id:HGNC:129 HGNC:129 ENTREZ:58 UNIPROT:P68133 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 actin, alpha 2, smooth muscle, aorta HUGO:ACTA2 hgnc_id:HGNC:130 HGNC:130 ENTREZ:59 UNIPROT:P62736 actin beta HUGO:ACTB hgnc_id:HGNC:132 HGNC:132 ENTREZ:60 UNIPROT:P60709 actin, alpha, cardiac muscle 1 HUGO:ACTC1 hgnc_id:HGNC:143 HGNC:143 ENTREZ:70 UNIPROT:P68032 actin gamma 1 HUGO:ACTG1 hgnc_id:HGNC:144 HGNC:144 ENTREZ:71 UNIPROT:P63261 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: REACTOME:49626 KEGG:58 ATLASONC:GC_ACTA1 WIKI:ACTA1 REACTOME:49566 KEGG:59 ATLASONC:GC_ACTA2 WIKI:ACTA2 REACTOME:49576 KEGG:60 ATLASONC:ACTBID42959ch7p22 WIKI:ACTB REACTOME:49595 KEGG:70 ATLASONC:GC_ACTC1 WIKI:ACTC1 REACTOME:49603 KEGG:71 ATLASONC:GC_ACTG1 WIKI:ACTG1 CASCADE:PDGF GASCADE:TGFB CASCADE:EGF CASCADE:HH CASCADE:CXCL12 PMID:25732845 PMID:16139227 Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression, probably via regulation of fibroblast migration. Phosphorylation of Girdin by Akt Is Required for Cell Migration. Girdin Is Required for the Formation of Actin Stress Fibers and Cell Migration PMID:18423981 Opposing roles of EGF and TGF-β on F-actin reorganization and Rho- GTPase activity EGF treatment stimulated the bi-polarization and formation of dendritic-like cellular extensions of fibroblasts. TGF-β treatment, with reduction of polarized iHDFs from 40% to 12% and upregulation of stress fiber-positive fibroblasts from 30% to 84%. PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation and promotes RhoA-activation aand actin polymerisation. PMID:26711338 CAFs Have Enhanced Actin and Septin Cytoskeletal Networks regulated by Cdc42EP3/BORG2 References_end </body> </html> </notes> <label text="Actin cytoskeletal*"/> <bbox w="136.0" h="56.0" x="6302.0" y="4172.0"/> <glyph class="unit of information" id="_9a208207-cd40-425a-9874-07eef32d068e"> <label text="N:2"/> <bbox w="20.0" h="10.0" x="6360.0" y="4167.0"/> </glyph> </glyph> <glyph class="phenotype" id="s858_sa760" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:DC MODULE:CROSS_ACTIVATION_OF_IMMUNE_CELLS MODULE:ANTIGEN_PRESENTATION_AND_ACTIVATING_CHEKPOINTS MODULE:EFFECTOR_ACTIVATION Maps_Modules_end </body> </html> </notes> <label text="Actin polymerization"/> <bbox w="160.0" h="35.0" x="6300.0" y="4282.5"/> </glyph> <glyph class="complex" id="s94_csa90" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RAC1_2* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:PDGF CASCAFE:EGF CASCADE:CAV References_end </body> </html> </notes> <label text="s94"/> <bbox w="100.0" h="110.0" x="5779.0" y="3034.0"/> <glyph class="simple chemical" id="s4476_sa763"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="5797.75" y="3090.875"/> </glyph> <glyph class="macromolecule" id="s3771_sa764"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Rac family small GTPase 1 HUGO:RAC1 hgnc_id:HGNC:9801 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Rac family small GTPase 2 HUGO:RAC2 hgnc_id:HGNC:9802 HGNC:9802 ENTREZ:5880 UNIPROT:P15153 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:PDGF CASCAFE:EGF CASCADE:CAV PMID:17517963 caveolin-deficient MEFs showed a notable decrease in basal Rho activity and a significant increase in Rac and Cdc42 activity PMID:11747822 Rac and Cdc42 are capable of inducing phosphorylation of Akt and that PDGF induces phosphorylation of Akt at least in part through Rac in fibroblasts. Expression of Rac V12 or Cdc42 V12 stimulated cell motility Figure 2 and Figure 3[14]. Coexpression of dominant-negative Akt suppressed cell motility stimulated by active Rac and Cdc42 to the basal levels (Figure 2d), suggesting that Akt is an essential downstream effector of Rac and Cdc42 in stimulating cell motility PMID:18423981 TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. PMID:21178402 RhoA was thought to be activated mainly at the retracting tail (red) to promote tail contraction, while Rac1 was thought to be activated at the front of the cell to promote lamellipodial protrusion. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="5789.0" y="3039.0"/> </glyph> </glyph> <glyph class="complex" id="s97_csa91" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RAC1_2* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:PDGF CASCAFE:EGF CASCADE:CAV PMID:11747822 Rac and Cdc42 are capable of inducing phosphorylation of Akt and that PDGF induces phosphorylation of Akt at least in part through Rac in fibroblasts. Expression of Rac V12 or Cdc42 V12 stimulated cell motility Figure 2 and Figure 3[14]. Coexpression of dominant-negative Akt suppressed cell motility stimulated by active Rac and Cdc42 to the basal levels (Figure 2d), suggesting that Akt is an essential downstream effector of Rac and Cdc42 in stimulating cell motility PMID:10753747 Pten regulates PI3K pathway via its phosphatase activity on phosphatidylinositol (PI) 3,4,5-trisphosphate (PI(3,4,5)P3), a product of PI 3-kinase. Pten-deficient fibroblasts migrate faster than wild type. there are marked increases of the GTP-bound forms of Rac1 and Cdc42 in logarithmically growing Pten−/− cells compared to wild-type cells, although the total protein levels are not affected by the Pten status. similar to Akt, Rac1 and Cdc42 activation in Pten−/− cells is downstream of PI 3-kinase. References_end </body> </html> </notes> <label text="s94"/> <bbox w="90.0" h="105.0" x="5965.0" y="3034.0"/> <glyph class="simple chemical" id="s2985_sa765"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="5980.0" y="3086.5"/> </glyph> <glyph class="macromolecule" id="s3772_sa766"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Rac family small GTPase 1 HUGO:RAC1 hgnc_id:HGNC:9801 HGNC:9801 ENTREZ:5879 UNIPROT:P63000 Rac family small GTPase 2 HUGO:RAC2 hgnc_id:HGNC:9802 HGNC:9802 ENTREZ:5880 UNIPROT:P15153 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:PDGF CASCAFE:EGF CASCADE:CAV PMID:17517963 caveolin-deficient MEFs showed a notable decrease in basal Rho activity and a significant increase in Rac and Cdc42 activity PMID:11747822 Rac and Cdc42 are capable of inducing phosphorylation of Akt and that PDGF induces phosphorylation of Akt at least in part through Rac in fibroblasts. Expression of Rac V12 or Cdc42 V12 stimulated cell motility Figure 2 and Figure 3[14]. Coexpression of dominant-negative Akt suppressed cell motility stimulated by active Rac and Cdc42 to the basal levels (Figure 2d), suggesting that Akt is an essential downstream effector of Rac and Cdc42 in stimulating cell motility PMID:18423981 TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. PMID:21178402 RhoA was thought to be activated mainly at the retracting tail (red) to promote tail contraction, while Rac1 was thought to be activated at the front of the cell to promote lamellipodial protrusion. References_end </body> </html> </notes> <label text="RAC1_2*"/> <bbox w="80.0" h="40.0" x="5970.0" y="3036.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4477_sa768" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ETS proto-oncogene 2, transcription factor HUGO:ETS2 hgnc_id:HGNC:3489 HGNC:3489 ENTREZ:2114 UNIPROT:P15036 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. PMID:23977064 Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer References_end </body> </html> </notes> <label text="ETS2"/> <bbox w="80.0" h="40.0" x="3840.0" y="3570.0"/> <glyph class="state variable" id="_9b033532-9d80-4d24-b12e-799aa7f19d55"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3835.0" y="3585.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4478_sa769" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ETS2 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="ETS2"/> <bbox w="70.0" h="25.0" x="3845.0" y="3437.5"/> </glyph> <glyph class="nucleic acid feature" id="s4479_sa770" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ETS2 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="ETS2"/> <bbox w="90.0" h="25.0" x="3835.0" y="3507.5"/> <glyph class="unit of information" id="_9e362d5f-219b-4d15-8d9e-f9cfe22f2ad7"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3870.0" y="3502.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4480_sa771" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ETS proto-oncogene 2, transcription factor HUGO:ETS2 hgnc_id:HGNC:3489 HGNC:3489 ENTREZ:2114 UNIPROT:P15036 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. PMID:23977064 Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer References_end </body> </html> </notes> <label text="ETS2"/> <bbox w="80.0" h="40.0" x="3850.0" y="3690.0"/> <glyph class="state variable" id="_de80cf3c-f024-45ad-9383-73efce9abb9c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3842.5" y="3705.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4481_sa772" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP9 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="70.0" h="25.0" x="5005.0" y="4427.5"/> </glyph> <glyph class="nucleic acid feature" id="s4482_sa773" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP9 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="90.0" h="25.0" x="4990.0" y="4507.5"/> <glyph class="unit of information" id="_74532bda-c71e-4e4f-8716-f300d8369071"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5025.0" y="4502.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4483_sa774" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: matrix metallopeptidase 9 HUGO:MMP9 hgnc_id:HGNC:7176 HGNC:7176 ENTREZ:4318 UNIPROT:P14780 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="80.0" h="40.0" x="5000.0" y="4590.0"/> </glyph> <glyph class="nucleic acid feature" id="s4484_sa775" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR320A Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="MIR320A"/> <bbox w="70.0" h="25.0" x="2745.0" y="2728.5"/> </glyph> <glyph class="complex" id="s4486_csa92" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ETS2:MIR320A Identifiers_end </body> </html> </notes> <label text="s4486"/> <bbox w="100.0" h="120.0" x="3670.0" y="3510.0"/> <glyph class="nucleic acid feature" id="s4487_sa777"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR320A Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="MIR320A"/> <bbox w="90.0" h="25.0" x="3675.0" y="3567.5"/> <glyph class="unit of information" id="_66cb7c77-4ad7-4cf7-beef-82c7c5810efe"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3705.0" y="3562.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4494_sa785"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ETS2 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="ETS2"/> <bbox w="90.0" h="25.0" x="3675.0" y="3537.5"/> <glyph class="unit of information" id="_8d18c2f5-6287-4fc8-9516-7da009e125da"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3710.0" y="3532.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s4489_sa779" compartmentRef="c5_ca5"> <label text="csa92_degraded"/> <bbox w="30.0" h="30.0" x="3635.0" y="3685.0"/> </glyph> <glyph class="nucleic acid feature" id="s4490_sa782" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EMILIN2 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="EMILIN2"/> <bbox w="70.0" h="25.0" x="4930.0" y="4246.25"/> </glyph> <glyph class="nucleic acid feature" id="s4491_sa783" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EMILIN2 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="EMILIN2"/> <bbox w="90.0" h="25.0" x="4920.0" y="4306.25"/> <glyph class="unit of information" id="_bfb72827-e923-4f62-8e45-0427ad1f50d0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4955.0" y="4301.25"/> </glyph> </glyph> <glyph class="macromolecule" id="s4492_sa784" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: elastin microfibril interfacer 2 HUGO:EMILIN2 hgnc_id:HGNC:19881 HGNC:19881 ENTREZ:84034 UNIPROT:Q9BXX0 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 (Elastin Microfibril Interfacer 2) are directly regulated by miR-320 via their 3′ UTR target sequences PMID:20360940 EMILIN2 is an extracellular matrix (ECM) glycoprotein, triggers cell death through a direct binding to death receptors. using either the full molecule or the active fragment, for the first time, we demonstrate a significant antitumoral effect in vivo, likely due to a decrease in tumor cell viability. Unexpectedly, tumors treated with EMILIN2 or the deletion mutant display a significant increase of tumor angiogenesis. References_end </body> </html> </notes> <label text="EMILIN2"/> <bbox w="80.0" h="40.0" x="4930.0" y="4380.0"/> </glyph> <glyph class="complex" id="s4493_csa93" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:EMILIN2 Identifiers_end </body> </html> </notes> <label text="s4493"/> <bbox w="105.0" h="89.0" x="4695.0" y="4351.0"/> <glyph class="nucleic acid feature" id="s4986_sa786"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EMILIN2 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="EMILIN2"/> <bbox w="90.0" h="25.0" x="4705.0" y="4397.5"/> <glyph class="unit of information" id="_05f65d44-23f5-4eba-b2f8-0f4999a540ae"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4740.0" y="4392.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4987_sa787"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR320A Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="MIR320A"/> <bbox w="90.0" h="25.0" x="4705.0" y="4367.5"/> <glyph class="unit of information" id="_8e0dfd3b-d54c-4a65-a48e-d2b66e3aa49d"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4735.0" y="4362.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4496_csa94" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR320A:MMP9 Identifiers_end </body> </html> </notes> <label text="s4496"/> <bbox w="100.0" h="120.0" x="4795.0" y="4531.0"/> <glyph class="nucleic acid feature" id="s4567_sa788"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR320A Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="MIR320A"/> <bbox w="90.0" h="25.0" x="4800.0" y="4548.5"/> <glyph class="unit of information" id="_6bae15d4-6cfa-4647-96f2-405554c70206"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4830.0" y="4543.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4566_sa789"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP9 Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: PMID:19847259 In fibroblasts PTEN inhibit ETS2 expression; and AKT and JNK induce phosphorylqtion of ETS2. MMP9 and CCL3 are the direct targets of this transcription factor. References_end </body> </html> </notes> <label text="MMP9"/> <bbox w="90.0" h="25.0" x="4800.0" y="4578.5"/> <glyph class="unit of information" id="_cddf18cc-f978-4299-a1d8-9b98c5e0ba95"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4835.0" y="4573.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s4497_sa790" compartmentRef="c5_ca5"> <label text="csa93_degraded"/> <bbox w="30.0" h="30.0" x="4715.0" y="4575.0"/> </glyph> <glyph class="source and sink" id="s4498_sa791" compartmentRef="c5_ca5"> <label text="csa94_degraded"/> <bbox w="30.0" h="30.0" x="4840.0" y="4716.25"/> </glyph> <glyph class="macromolecule" id="s4197_sa462" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase 8 HUGO:MAPK8 hgnc_id:HGNC:6881 HGNC:6881 ENTREZ:5599 UNIPROT:P45983 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 mitogen-activated protein kinase 9 HUGO:MAPK9 hgnc_id:HGNC:6886 HGNC:6886 ENTREZ:5601 UNIPROT:P45984 mitogen-activated protein kinase 10 HUGO:MAPK10 hgnc_id:HGNC:6872 HGNC:6872 ENTREZ:5602 UNIPROT:P53779 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: REACTOME:59293 KEGG:5599 ATLASONC:JNK1ID196 WIKI:MAPK8 mitogen-activated protein kinase 9 REACTOME:59295 KEGG:5601 ATLASONC:JNK2ID426 WIKI:MAPK9 mitogen-activated protein kinase 10 REACTOME:59297 KEGG:5602 ATLASONC:JNK3ID427 WIKI:MAPK10 CADCADE:TNF CASCADE:IL1 CASCADE:PDGFB PMID:15653932 TNF signaling activates ERK,JNK and p38 kinases in fibroblasts and induses TGFB expression via ERK PMID:26921338 PDGFB inhibits PEDF expression via p38 and JNK References_end </body> </html> </notes> <label text="JNK*"/> <bbox w="80.0" h="40.0" x="5090.0" y="3320.0"/> <glyph class="state variable" id="_1ee202c9-0ac1-48e6-9413-5336cf4f69cf"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5082.5" y="3335.0"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4500_sa793" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EGFR Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:25987127 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation References_end </body> </html> </notes> <label text="EGFR"/> <bbox w="70.0" h="25.0" x="5194.0" y="1347.5"/> </glyph> <glyph class="nucleic acid feature" id="s4501_sa794" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EGFR Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:25987127 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation References_end </body> </html> </notes> <label text="EGFR"/> <bbox w="90.0" h="25.0" x="5185.0" y="1277.5"/> <glyph class="unit of information" id="_e694eacd-f59a-409a-98a9-84edef1f592e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5220.0" y="1272.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4503_sa796" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: HUGO:AREG MODULE:GROWTH_FACTORS_PRODUCTION PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist; EGF signaling induces AREG release. References_end </body> </html> </notes> <label text="AREG"/> <bbox w="70.0" h="25.0" x="3475.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4504_sa797" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: HUGO:AREG MODULE:GROWTH_FACTORS_PRODUCTION PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist; EGF signaling induces AREG release. References_end </body> </html> </notes> <label text="AREG"/> <bbox w="90.0" h="25.0" x="3465.0" y="4342.5"/> <glyph class="unit of information" id="_eeabf78e-9d1b-4f4a-aa69-8be7dd9cce7a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3500.0" y="4337.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4506_sa799"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: amphiregulin HUGO:AREG hgnc_id:HGNC:651 HGNC:651 ENTREZ:374 UNIPROT:P15514 Identifiers_end References_begin: MODULE:GROWTH_FACTORS_PRODUCTION PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist; EGF signaling induces AREG release. References_end </body> </html> </notes> <label text="AREG"/> <bbox w="80.0" h="40.0" x="4960.0" y="560.0"/> </glyph> <glyph class="macromolecule" id="s4507_sa800" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TIMP metallopeptidase inhibitor 2 HUGO:TIMP2 hgnc_id:HGNC:11821 HGNC:11821 ENTREZ:7077 UNIPROT:P16035 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:1323219 MMP2 and TIMP2 are axpressed by CAFS References_end </body> </html> </notes> <label text="TIMP2"/> <bbox w="80.0" h="40.0" x="5680.0" y="4590.0"/> </glyph> <glyph class="macromolecule" id="s4508_sa801"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 2 HUGO:IGF2 hgnc_id:HGNC:5466 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. PMID:24668028 IGF2 expressed by CAFs promotes tumor growth PMID:11237532 In breast cancers, both IGF-I and IGF-II are expressed in the stromal ﬁbroblasts and expression of IGF-II in particular correlates with tumor progression PMID:15003992 TGF-β induced the myofibroblast phenotype via a CTGF-dependent pathway, CTGF mediates EGF-stimulated proliferation and IGF-2-induced differentiation of fibroblasts References_end </body> </html> </notes> <label text="IGF2"/> <bbox w="80.0" h="40.0" x="5290.0" y="590.0"/> </glyph> <glyph class="macromolecule" id="s4509_sa152" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: connective tissue growth factor HUGO:CTGF hgnc_id:HGNC:2500 HGNC:2500 ENTREZ:1490 UNIPROT:P29279 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:23259531 CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. PMID:11013125 ; PMID:11376132 CTGF expression is induced by TGF- beta in fibroblasts via SMAD3 and SMAD4 pathway PMID:15003992 TGF-β induced the myofibroblast phenotype via a CTGF-dependent pathway, CTGF mediates EGF-stimulated proliferation and IGF-2-induced differentiation of fibroblasts, probably via activation of EGFR and IGFR. References_end </body> </html> </notes> <label text="CTGF"/> <clone/> <bbox w="80.0" h="40.0" x="4310.0" y="4746.0"/> </glyph> <glyph class="macromolecule" id="s4509_sa802" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: connective tissue growth factor HUGO:CTGF hgnc_id:HGNC:2500 HGNC:2500 ENTREZ:1490 UNIPROT:P29279 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:23259531 CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. PMID:11013125 ; PMID:11376132 CTGF expression is induced by TGF- beta in fibroblasts via SMAD3 and SMAD4 pathway PMID:15003992 TGF-β induced the myofibroblast phenotype via a CTGF-dependent pathway, CTGF mediates EGF-stimulated proliferation and IGF-2-induced differentiation of fibroblasts, probably via activation of EGFR and IGFR. References_end </body> </html> </notes> <label text="CTGF"/> <clone/> <bbox w="80.0" h="40.0" x="4750.0" y="1480.0"/> </glyph> <glyph class="nucleic acid feature" id="s4510_sa803" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CTGF References_begin: CASCADE:TGFB PMID:11013125 ; PMID:11376132; PMID:24412104; PMID:21098712 CTGF expression is induced by TGF- beta in fibroblasts via SMAD3 and SMAD4 pathway PMID:23204521 CTGF expression induced by TGF is ROS dependent References_end </body> </html> </notes> <label text="CTGF"/> <bbox w="70.0" h="25.0" x="4315.0" y="4593.5"/> </glyph> <glyph class="nucleic acid feature" id="s4511_sa804" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CTGF References_begin: CASCADE:TGFB PMID:11013125 ; PMID:11376132 CTGF expression is induced by TGF- beta in fibroblasts via SMAD3 and SMAD4 pathway References_end </body> </html> </notes> <label text="CTGF"/> <bbox w="90.0" h="25.0" x="4305.0" y="4673.5"/> <glyph class="unit of information" id="_69ff9482-baff-41c9-b5f8-5e39bf1af9de"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4340.0" y="4668.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4512_sa806" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: prolyl 4-hydroxylase, transmembrane HUGO:P4HTM hgnc_id:HGNC:28858 HGNC:28858 ENTREZ:54681 UNIPROT:Q9NXG6 Identifiers_end References_begin: CASCADE:TGFB PMID:18423981 Collagen type I maturation enzyme prolyl-4-hydroxylase (P4H) is induced by TGFB signaling on protein level.. References_end </body> </html> </notes> <label text="P4HTM"/> <bbox w="80.0" h="40.0" x="5260.0" y="4380.0"/> </glyph> <glyph class="nucleic acid feature" id="s4513_sa807" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:P4HTM References_begin: CASCADE:TGFB PMID:18423981 Collagen type I maturation enzyme prolyl-4-hydroxylase (P4H) is induced by TGFB signaling on protein level.. References_end </body> </html> </notes> <label text="P4HTM"/> <bbox w="70.0" h="25.0" x="5265.0" y="4227.5"/> </glyph> <glyph class="nucleic acid feature" id="s4514_sa808" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:P4HTM References_begin: CASCADE:TGFB PMID:18423981 Collagen type I maturation enzyme prolyl-4-hydroxylase (P4H) is induced by TGFB signaling on protein level.. References_end </body> </html> </notes> <label text="P4HTM"/> <bbox w="90.0" h="25.0" x="5249.0" y="4308.75"/> <glyph class="unit of information" id="_f80b9d9f-2aae-4500-bfa1-8ba1ff0061e5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5284.0" y="4303.75"/> </glyph> </glyph> <glyph class="macromolecule" id="s4515_sa809" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 1 receptor HUGO:IGF1R hgnc_id:HGNC:5465 HGNC:5465 ENTREZ:3480 UNIPROT:P08069 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: GASCADE:IGF1R PMID:24103846 ; PMID:24782617 IGFR pathway is imporatnd for fibroblast activation. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. In contrast, IGF-1 treatment on soft substrate resulted in upregulation of αSMA gene and protein expression, as well as Col1a1 and Col3a1 transcripts. In conclusion, IGF-1 stimulates differentiation of fibroblasts into a myofibroblast phenotype in a soft matrix environment and has a modest effect on αSMA stress fiber organization in mouse lung fibroblasts. IGF-1-induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. IGF-1 significantly increased levels of phospho-IGF-1R and ERK1/2 in a time-dependent manner in both MIFs and CCD-18Co cells. PMID:12175651; PMID:10086337 Upon IGF-IR autophosphorylation the protein Shc is recruited to the receptor and becomes phosphorylated on tyrosine residues.36 Activated Shc then binds the adaptor Grb2 in an IRS-1-independent manner, leading to activation of the Ras-ERK pathway.36 This pathway of IGF-IR signaling has been most closely associated with cell differentiation and migration, but in some cases also can regulate the machinery of apoptosis, for example, in detachment-induced death, or anoikis, in fibroblasts. References_end </body> </html> </notes> <label text="IGF1R"/> <bbox w="80.0" h="50.0" x="5360.0" y="1055.0"/> <glyph class="state variable" id="_5320bd01-d363-4901-83d0-103b57466023"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5355.0" y="1075.0"/> </glyph> <glyph class="unit of information" id="_85b11fac-7a03-4441-8b5f-975cc0b32218"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5377.5" y="1050.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4519_sa812"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 1 HUGO:IGF1 hgnc_id:HGNC:5464 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 Identifiers_end References_begin: CASCADE:TGFB PMID:11237532 ; PMID:19631971 In breast cancers, both IGF-I and IGF-II are expressed in the stromal ﬁbroblasts and expression of IGF-II in particular correlates with tumor progression PMID:12181198 IGF-I potently stimulated proliferation of TGF-β1-activated myofibroblasts without reversing activated fibrogenic phenotype. We conclude that TGF-β1 and IGF-I both stimulate type I collagen synthesis but have differential effects on activated phenotype and proliferation. TGF-β1 induces IGF-I expression in CCD-18Co fibroblast cells. References_end </body> </html> </notes> <label text="IGF1"/> <bbox w="80.0" h="40.0" x="5440.0" y="640.0"/> </glyph> <glyph class="nucleic acid feature" id="s4520_sa814" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF1 Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:12181198 TGF-β1 induces IGF-I expression in CCD-18Co fibroblast cells. References_end </body> </html> </notes> <label text="IGF1"/> <bbox w="70.0" h="25.0" x="3855.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4521_sa815" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF1 Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:12181198 TGF-β1 induces IGF-I expression in CCD-18Co fibroblast cells. References_end </body> </html> </notes> <label text="IGF1"/> <bbox w="90.0" h="25.0" x="3845.0" y="4342.5"/> <glyph class="unit of information" id="_5b5273e1-049d-428c-836e-00e059ccbef2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3880.0" y="4337.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4522_sa816"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor binding protein 3 HUGO:IGFBP3 hgnc_id:HGNC:5472 HGNC:5472 ENTREZ:3486 UNIPROT:P17936 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:12181198 IGFBP-3 and IGFBP-4 significantly inhibited IGF-I-stimulated DNA synthesis in fibroblasts References_end </body> </html> </notes> <label text="IGFBP3"/> <bbox w="80.0" h="40.0" x="5570.0" y="570.0"/> </glyph> <glyph class="macromolecule" id="s4523_sa817"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor binding protein 4 HUGO:IGFBP4 hgnc_id:HGNC:5473 HGNC:5473 ENTREZ:3487 UNIPROT:P22692 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:12181198 IGFBP-3 and IGFBP-4 significantly inhibited IGF-I-stimulated DNA synthesis in fibroblasts References_end </body> </html> </notes> <label text="IGFBP4"/> <bbox w="80.0" h="40.0" x="5390.0" y="510.0"/> </glyph> <glyph class="nucleic acid feature" id="s4524_sa818" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HGF Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:FGF CASCADE:PDGF CASCADE:HGF PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="HGF"/> <bbox w="70.0" h="25.0" x="4065.0" y="4242.5"/> </glyph> <glyph class="nucleic acid feature" id="s4525_sa819" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HGF Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:FGF CASCADE:PDGF CASCADE:HGF PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="HGF"/> <bbox w="90.0" h="25.0" x="4055.0" y="4342.5"/> <glyph class="unit of information" id="_c0bf6365-9802-46f2-b55e-f91ef9e034f3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4090.0" y="4337.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4526_sa820"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 1 HUGO:FGF1 hgnc_id:HGNC:3665 HGNC:3665 ENTREZ:2246 UNIPROT:P05230 Identifiers_end References_begin: PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts PMID:26183471 CAFs secrete more FGF-1/-3 than normal fibroblasts References_end </body> </html> </notes> <label text="FGF1"/> <bbox w="80.0" h="40.0" x="4520.0" y="510.0"/> </glyph> <glyph class="macromolecule" id="s4527_sa821"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 4 HUGO:FGF4 hgnc_id:HGNC:3682 HGNC:3682 ENTREZ:2249 UNIPROT:P08620 Identifiers_end References_begin: PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="FGF4"/> <bbox w="80.0" h="40.0" x="4750.0" y="540.0"/> </glyph> <glyph class="macromolecule" id="s4535_sa827"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 3 HUGO:FGF3 hgnc_id:HGNC:3681 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Identifiers_end References_begin: PMID:26183471 CAFs secrete more FGF-1/-3 than normal fibroblasts References_end </body> </html> </notes> <label text="FGF3"/> <bbox w="80.0" h="40.0" x="4850.0" y="550.0"/> </glyph> <glyph class="macromolecule" id="s4529_sa823" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: MET proto-oncogene, receptor tyrosine kinase HUGO:MET hgnc_id:HGNC:7029 HGNC:7029 ENTREZ:4233 UNIPROT:P08581 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:11290563 Human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein Proliferation of myofibroblasts was stimulated in a dose-dependent manner by exogenously added recombinant human HGF whereas it was inhibited in a dose-dependent manner by neutralizing antibody to HGF. The addition of HGF in the culture medium stimulated tyrosine phosphorylation of c-MET. A significant relationship between myofibroblast c-MET expression and shortened patient survival was observed. References_end </body> </html> </notes> <label text="MET"/> <bbox w="80.0" h="50.0" x="5660.0" y="1075.0"/> <glyph class="state variable" id="_a8393b68-0326-4cce-a858-56c710c282df"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5655.0" y="1095.0"/> </glyph> <glyph class="unit of information" id="_9b7ec071-4359-4f74-9403-8d66d76ca0af"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5677.5" y="1070.0"/> </glyph> </glyph> <glyph class="complex" id="s4530_csa96" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:HGF:MET Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4530"/> <bbox w="100.0" h="120.0" x="5730.0" y="1160.0"/> <glyph class="macromolecule" id="s4825_sa825"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: hepatocyte growth factor HUGO:HGF hgnc_id:HGNC:4893 HGNC:4893 ENTREZ:3082 UNIPROT:P14210 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:FGF CASCADE:PDGF CASCADE:HGF PMID:9242465; PMID:19631971 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts PMID:27474009 HGF is a activation factor for fibroblasts PMID:23667593 Cancer-Associated Fibroblasts from Hepatocellular Carcinoma Promote Malignant Cell Proliferation by HGF Secretion PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15059978 Proinvasive factors secreted by myofibroblasts are identified as TNC and SF/HGF, each of which is necessary but not sufficient for stimulation of invasion of human colon cancer cells PMID:22763439 HGF is present in the stromal cells of melanoma and correlates with poor response to therapy References_end </body> </html> </notes> <label text="HGF"/> <bbox w="80.0" h="40.0" x="5740.0" y="1170.0"/> </glyph> <glyph class="macromolecule" id="s4826_sa824"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: MET proto-oncogene, receptor tyrosine kinase HUGO:MET hgnc_id:HGNC:7029 HGNC:7029 ENTREZ:4233 UNIPROT:P08581 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:11290563 Human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein Proliferation of myofibroblasts was stimulated in a dose-dependent manner by exogenously added recombinant human HGF whereas it was inhibited in a dose-dependent manner by neutralizing antibody to HGF. The addition of HGF in the culture medium stimulated tyrosine phosphorylation of c-MET. A significant relationship between myofibroblast c-MET expression and shortened patient survival was observed. References_end </body> </html> </notes> <label text="MET"/> <bbox w="80.0" h="50.0" x="5740.0" y="1215.0"/> <glyph class="state variable" id="_b3bb3f9d-12cd-4f4c-831d-14652f6dd7bc"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5732.5" y="1235.0"/> </glyph> <glyph class="unit of information" id="_12962617-aac4-43fc-b947-131b95152fbc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5757.5" y="1210.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4541_sa832" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Rho GTPase activating protein 35 HUGO:ARHGAP35 hgnc_id:HGNC:4591 HGNC:4591 ENTREZ:2909 UNIPROT:Q9NRY4 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:CAV CASCADE:INTEGRIN PMID:17517963 Src is involved in activation of Rac (Servitja et al., 2003; Kawakatsu et al., 2005) and Cdc42 (Miyamoto et al., 2003; Tu et al., 2003; Fukuyama et al., 2005) and can inhibit Rho through activation of p190RhoGAP PMID:22411312 ARHGAP35 (p190RhoGAP) inhibits RhoA. Engagement of integrins triggers Src‑dependent p190GAP phosphorylation which when activated inhibits RhoA enabling Rac1 activation that promotes lamellipodia formation, cell spreading and nascent focal adhesions.1 References_end </body> </html> </notes> <label text="ARHGAP35"/> <bbox w="80.0" h="40.0" x="6710.0" y="2820.0"/> <glyph class="state variable" id="_605703f1-7306-417b-8b3c-e802db58c7d6"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6705.0" y="2835.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4546_sa857" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase kinase 1 HUGO:MAP2K1 hgnc_id:HGNC:6840 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 mitogen-activated protein kinase kinase 2 HUGO:MAP2K2 hgnc_id:HGNC:6842 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 Identifiers_end Maps_Modules_begin: MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:16227978 Ras GTPases comprise a large family of mostly membrane-resident proteins that shuttle between an inactive GDP-bound and active GTP-bound conformation105. The best-characterized family members are K-Ras, H-Ras and N-Ras. RasGTP can bind to a number of effector molecules, including the serine/threonine kinase Raf, phosphatidylinositol 3-kinase, RalGDS and others106. RasGTP recruits these proteins to the membrane compartment, which is crucial for their activation and signalling function. All three Raf family members, A-Raf, B-Raf and Raf-1, bind RasGTP as the first step in their activation process. Whereas RasGTP association might suffice to activate B-Raf, both Raf-1 and A-Raf undergo a complex series of activation steps that have not been entirely elucidated and involve changes in phosphorylation levels and protein interactions. For recent reviews on Raf isoforms and their activation mechanisms see Refs 1–3. All Raf isoforms can activate MAPK and ERK kinase (MEK) by phosphorylating two serines in the MEK ACTIVATION LOOP, PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="MEK1/2*"/> <bbox w="80.0" h="40.0" x="4980.0" y="2980.0"/> <glyph class="state variable" id="_ee407378-8178-4da2-bb2f-96266fb000d9"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4975.0" y="2995.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4547_sa838" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor receptor substrate 2 HUGO:FRS2 hgnc_id:HGNC:16971 HGNC:16971 ENTREZ:10818 UNIPROT:Q8WU20 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:FGF PMID:11447289 Experiments with FRS2 alpha-deficient fibroblasts demonstrate that FRS2 alpha plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. FRS2α has been implicated as a critical link between FGF stimulation and the Ras/MAP kinase signaling pathway References_end </body> </html> </notes> <label text="FRS2"/> <bbox w="80.0" h="40.0" x="4749.0" y="1400.0"/> <glyph class="state variable" id="_cfb09306-480a-41c8-b254-abccc5cb5ce2"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4744.0" y="1415.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4549_sa841" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein tyrosine phosphatase, non-receptor type 11 HUGO:PTPN11 hgnc_id:HGNC:9644 HGNC:9644 ENTREZ:5781 UNIPROT:Q06124 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF PMID:11447289 Tyrosine-phosphorylated Shp2 molecules have not been detected in FRS2α mutant cell lysates, indicating that FRS2α is required for tyrosine phosphorylation of Shp2 leading to complex formation between Shp2 and Grb2. FGF-induced tyrosine phosphorylation of Shp2 as well as FRS2α/Grb2 complex formation were completely restored by ectopic expression of FRS2α in mutant cells. These findings demonstrate that expression of functional FRS2α is indeed crucial for the recruitment and tyrosine phosphorylation of these two effector proteins References_end </body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="4790.0" y="2140.0"/> <glyph class="state variable" id="_8b489aa8-bc47-4eb1-b491-0130c3b9fadb"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4785.0" y="2155.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4550_sa844" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: protein tyrosine phosphatase, non-receptor type 11 HUGO:PTPN11 hgnc_id:HGNC:9644 HGNC:9644 ENTREZ:5781 UNIPROT:Q06124 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF PMID:11447289 Tyrosine-phosphorylated Shp2 molecules have not been detected in FRS2α mutant cell lysates, indicating that FRS2α is required for tyrosine phosphorylation of Shp2 leading to complex formation between Shp2 and Grb2. FGF-induced tyrosine phosphorylation of Shp2 as well as FRS2α/Grb2 complex formation were completely restored by ectopic expression of FRS2α in mutant cells. These findings demonstrate that expression of functional FRS2α is indeed crucial for the recruitment and tyrosine phosphorylation of these two effector proteins References_end </body> </html> </notes> <label text="PTPN11"/> <bbox w="80.0" h="40.0" x="4790.0" y="2240.0"/> <glyph class="state variable" id="_6cc9e208-2319-43b6-b6ab-7d706e30ac6f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4782.5" y="2255.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4551_sa845" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: GRB2 associated binding protein 1 HUGO:GAB1 hgnc_id:HGNC:4066 HGNC:4066 ENTREZ:2549 UNIPROT:Q13480 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:11447289 FGF-induced tyrosine phosphorylation of Gab1 was detected in lysates from wild-type fibroblasts, tyrosine phosphorylation of Gab1 could not be detected in FRS2α-deficient fibroblasts. FRS2α Is Required for Recruitment of PI-3 Kinase via the Docking Protein Gab1. References_end </body> </html> </notes> <label text="GAB1"/> <bbox w="80.0" h="40.0" x="4255.0" y="2415.0"/> <glyph class="state variable" id="_8c2a3ae3-319a-4212-ad73-e8958ee3c83a"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="4250.0" y="2430.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4552_sa846" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: GRB2 associated binding protein 1 HUGO:GAB1 hgnc_id:HGNC:4066 HGNC:4066 ENTREZ:2549 UNIPROT:Q13480 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:11447289 FGF-induced tyrosine phosphorylation of Gab1 was detected in lysates from wild-type fibroblasts, tyrosine phosphorylation of Gab1 could not be detected in FRS2α-deficient fibroblasts. FRS2α Is Required for Recruitment of PI-3 Kinase via the Docking Protein Gab1. References_end </body> </html> </notes> <label text="GAB1"/> <bbox w="70.0" h="40.0" x="4250.0" y="2245.0"/> <glyph class="state variable" id="_4d64144b-9db7-4857-a3d2-40401b89bc0a"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4242.5" y="2260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1679_sa848" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SHC adaptor protein 1 HUGO:SHC1 hgnc_id:HGNC:10840 HGNC:10840 ENTREZ:6464 UNIPROT:P29353 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR PMID:11447289 Grb2 forms a complex with tyrosine-phosphorylated Shc in FGF-stimulated fibroblasts in an FRS2α-independent manner PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway EGFR induces SHC phosphorylation, directly interacts with GRB2 and induces formation of SHC:GRB2:SOS activated complex. References_end </body> </html> </notes> <label text="SHC1"/> <bbox w="80.0" h="40.0" x="5490.0" y="2270.0"/> <glyph class="state variable" id="_f575b503-8321-4ca7-96b5-71ea8607a293"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5485.0" y="2285.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4553_sa839" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SHC adaptor protein 1 HUGO:SHC1 hgnc_id:HGNC:10840 HGNC:10840 ENTREZ:6464 UNIPROT:P29353 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR PMID:11447289 Grb2 forms a complex with tyrosine-phosphorylated Shc in FGF-stimulated fibroblasts in an FRS2α-independent manner PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway EGFR induces SHC phosphorylation, directly interacts with GRB2 and induces formation of SHC:GRB2:SOS activated complex. References_end </body> </html> </notes> <label text="SHC1"/> <bbox w="80.0" h="40.0" x="5490.0" y="2370.0"/> <glyph class="state variable" id="_855d7d9d-472c-4970-aed1-ef940b57901f"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5482.5" y="2385.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4554_sa843" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor receptor substrate 2 HUGO:FRS2 hgnc_id:HGNC:16971 HGNC:16971 ENTREZ:10818 UNIPROT:Q8WU20 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:FGF PMID:11447289 Experiments with FRS2 alpha-deficient fibroblasts demonstrate that FRS2 alpha plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. FRS2α has been implicated as a critical link between FGF stimulation and the Ras/MAP kinase signaling pathway References_end </body> </html> </notes> <label text="FRS2"/> <bbox w="80.0" h="40.0" x="4750.0" y="1480.0"/> <glyph class="state variable" id="_1e68cad7-7bd8-44ce-8b78-d82c6904c10d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4742.5" y="1495.0"/> </glyph> </glyph> <glyph class="complex" id="s4556_csa97" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GDP:RAS* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s4556"/> <bbox w="100.0" h="120.0" x="4830.0" y="2630.0"/> <glyph class="macromolecule" id="s4557_sa850"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NRAS proto-oncogene, GTPase HUGO:NRAS hgnc_id:HGNC:7989 HGNC:7989 ENTREZ:4893 UNIPROT:P01111 KRAS proto-oncogene, GTPase HUGO:KRAS hgnc_id:HGNC:6407 HGNC:6407 ENTREZ:3845 UNIPROT:P01116 HRas proto-oncogene, GTPase HUGO:HRAS hgnc_id:HGNC:5173 HGNC:5173 ENTREZ:3265 UNIPROT:P01112 Identifiers_end Maps_Modules_begin: MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:12419216 FGF activares RAS in fibroblasts PMID:16227978 Ras GTPases comprise a large family of mostly membrane-resident proteins that shuttle between an inactive GDP-bound and active GTP-bound conformation105. The best-characterized family members are K-Ras, H-Ras and N-Ras. RasGTP can bind to a number of effector molecules, including the serine/threonine kinase Raf, phosphatidylinositol 3-kinase, RalGDS and others106. RasGTP recruits these proteins to the membrane compartment, which is crucial for their activation and signalling function. All three Raf family members, A-Raf, B-Raf and Raf-1, bind RasGTP as the first step in their activation process. Whereas RasGTP association might suffice to activate B-Raf, both Raf-1 and A-Raf undergo a complex series of activation steps that have not been entirely elucidated and involve changes in phosphorylation levels and protein interactions. For recent reviews on Raf isoforms and their activation mechanisms see Refs 1–3. All Raf isoforms can activate MAPK and ERK kinase (MEK) by phosphorylating two serines in the MEK ACTIVATION LOOP, PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="RAS*"/> <bbox w="80.0" h="40.0" x="4840.0" y="2650.0"/> </glyph> <glyph class="simple chemical" id="s4559_sa856"> <label text="GDP"/> <bbox w="62.5" h="26.25" x="4858.75" y="2706.875"/> </glyph> </glyph> <glyph class="complex" id="s4558_csa98" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:GTP:RAS* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s4558"/> <bbox w="100.0" h="120.0" x="5000.0" y="2630.0"/> <glyph class="macromolecule" id="s4555_sa852"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: NRAS proto-oncogene, GTPase HUGO:NRAS hgnc_id:HGNC:7989 HGNC:7989 ENTREZ:4893 UNIPROT:P01111 KRAS proto-oncogene, GTPase HUGO:KRAS hgnc_id:HGNC:6407 HGNC:6407 ENTREZ:3845 UNIPROT:P01116 HRas proto-oncogene, GTPase HUGO:HRAS hgnc_id:HGNC:5173 HGNC:5173 ENTREZ:3265 UNIPROT:P01112 Identifiers_end Maps_Modules_begin: MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:12419216 FGF activares RAS in fibroblasts PMID:16227978 Ras GTPases comprise a large family of mostly membrane-resident proteins that shuttle between an inactive GDP-bound and active GTP-bound conformation105. The best-characterized family members are K-Ras, H-Ras and N-Ras. RasGTP can bind to a number of effector molecules, including the serine/threonine kinase Raf, phosphatidylinositol 3-kinase, RalGDS and others106. RasGTP recruits these proteins to the membrane compartment, which is crucial for their activation and signalling function. All three Raf family members, A-Raf, B-Raf and Raf-1, bind RasGTP as the first step in their activation process. Whereas RasGTP association might suffice to activate B-Raf, both Raf-1 and A-Raf undergo a complex series of activation steps that have not been entirely elucidated and involve changes in phosphorylation levels and protein interactions. For recent reviews on Raf isoforms and their activation mechanisms see Refs 1–3. All Raf isoforms can activate MAPK and ERK kinase (MEK) by phosphorylating two serines in the MEK ACTIVATION LOOP, PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="RAS*"/> <bbox w="80.0" h="40.0" x="5010.0" y="2640.0"/> </glyph> <glyph class="simple chemical" id="s4560_sa855"> <label text="GTP"/> <bbox w="70.0" h="25.0" x="5015.0" y="2697.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4561_sa837" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: mitogen-activated protein kinase kinase 1 HUGO:MAP2K1 hgnc_id:HGNC:6840 HGNC:6840 ENTREZ:5604 UNIPROT:Q02750 mitogen-activated protein kinase kinase 2 HUGO:MAP2K2 hgnc_id:HGNC:6842 HGNC:6842 ENTREZ:5605 UNIPROT:P36507 Identifiers_end Maps_Modules_begin: MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:16227978 Ras GTPases comprise a large family of mostly membrane-resident proteins that shuttle between an inactive GDP-bound and active GTP-bound conformation105. The best-characterized family members are K-Ras, H-Ras and N-Ras. RasGTP can bind to a number of effector molecules, including the serine/threonine kinase Raf, phosphatidylinositol 3-kinase, RalGDS and others106. RasGTP recruits these proteins to the membrane compartment, which is crucial for their activation and signalling function. All three Raf family members, A-Raf, B-Raf and Raf-1, bind RasGTP as the first step in their activation process. Whereas RasGTP association might suffice to activate B-Raf, both Raf-1 and A-Raf undergo a complex series of activation steps that have not been entirely elucidated and involve changes in phosphorylation levels and protein interactions. For recent reviews on Raf isoforms and their activation mechanisms see Refs 1–3. All Raf isoforms can activate MAPK and ERK kinase (MEK) by phosphorylating two serines in the MEK ACTIVATION LOOP, PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="MEK1/2*"/> <bbox w="80.0" h="40.0" x="4980.0" y="3090.0"/> <glyph class="state variable" id="_e53438ac-6897-4017-b83e-09bdde5296bb"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="4972.5" y="3105.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4563_sa860" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin receptor substrate 1 HUGO:IRS1 hgnc_id:HGNC:6125 HGNC:6125 ENTREZ:3667 UNIPROT:P35568 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: GASCADE:IGF1R PMID:8621421 Grb2- and Shc-SH2 domain binding to phosphopeptides from rat IRS-1 PMID:12175651; PMID:10086337 Upon IGF-IR autophosphorylation the protein Shc is recruited to the receptor and becomes phosphorylated on tyrosine residues.36 Activated Shc then binds the adaptor Grb2 in an IRS-1-independent manner, leading to activation of the Ras-ERK pathway.36 This pathway of IGF-IR signaling has been most closely associated with cell differentiation and migration, but in some cases also can regulate the machinery of apoptosis, for example, in detachment-induced death, or anoikis, in fibroblasts. References_end </body> </html> </notes> <label text="IRS1"/> <bbox w="80.0" h="40.0" x="5340.0" y="1390.0"/> <glyph class="state variable" id="_274d1433-a21a-45a5-bf44-b1fffe015159"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5335.0" y="1405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4564_sa861" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin receptor substrate 1 HUGO:IRS1 hgnc_id:HGNC:6125 HGNC:6125 ENTREZ:3667 UNIPROT:P35568 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: GASCADE:IGF1R PMID:8621421 Grb2- and Shc-SH2 domain binding to phosphopeptides from rat IRS-1 PMID:12175651; PMID:10086337 Upon IGF-IR autophosphorylation the protein Shc is recruited to the receptor and becomes phosphorylated on tyrosine residues.36 Activated Shc then binds the adaptor Grb2 in an IRS-1-independent manner, leading to activation of the Ras-ERK pathway.36 This pathway of IGF-IR signaling has been most closely associated with cell differentiation and migration, but in some cases also can regulate the machinery of apoptosis, for example, in detachment-induced death, or anoikis, in fibroblasts. References_end </body> </html> </notes> <label text="IRS1"/> <bbox w="80.0" h="40.0" x="5340.0" y="1490.0"/> <glyph class="state variable" id="_60e73167-1957-4ff9-a486-b3e4d009c92b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5332.5" y="1505.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4565_sa863" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 1 receptor HUGO:IGF1R hgnc_id:HGNC:5465 HGNC:5465 ENTREZ:3480 UNIPROT:P08069 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: GASCADE:IGF1R PMID:24103846 ; PMID:24782617 IGFR pathway is imporatnd for fibroblast activation. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. In contrast, IGF-1 treatment on soft substrate resulted in upregulation of αSMA gene and protein expression, as well as Col1a1 and Col3a1 transcripts. In conclusion, IGF-1 stimulates differentiation of fibroblasts into a myofibroblast phenotype in a soft matrix environment and has a modest effect on αSMA stress fiber organization in mouse lung fibroblasts. IGF-1-induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. IGF-1 significantly increased levels of phospho-IGF-1R and ERK1/2 in a time-dependent manner in both MIFs and CCD-18Co cells. PMID:12175651; PMID:10086337 Upon IGF-IR autophosphorylation the protein Shc is recruited to the receptor and becomes phosphorylated on tyrosine residues.36 Activated Shc then binds the adaptor Grb2 in an IRS-1-independent manner, leading to activation of the Ras-ERK pathway.36 This pathway of IGF-IR signaling has been most closely associated with cell differentiation and migration, but in some cases also can regulate the machinery of apoptosis, for example, in detachment-induced death, or anoikis, in fibroblasts. References_end </body> </html> </notes> <label text="IGF1R"/> <bbox w="80.0" h="50.0" x="5360.0" y="1165.0"/> <glyph class="state variable" id="_1f6b3b87-262a-4d3e-a4db-80821d20416c"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5352.5" y="1185.0"/> </glyph> <glyph class="unit of information" id="_78adb402-a521-4fed-8886-eb8739510dc8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5377.5" y="1160.0"/> </glyph> </glyph> <glyph class="phenotype" id="s4568_sa864" compartmentRef="c5_ca5"> <label text="Stress_fibrilles_formation"/> <bbox w="195.0" h="47.5" x="6282.5" y="4376.25"/> </glyph> <glyph class="macromolecule" id="s865_sa865" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Wiskott-Aldrich syndrome HUGO:WAS hgnc_id:HGNC:12731 HGNC:12731 ENTREZ:7454 UNIPROT:P42768 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: L PMID:21178402 Rac1 and Cdc42 activate ARP2/3 complex; Rac1 and Cdc42 activate Wiskott-Aldrich Syndrome family of proteins including WASP, N-WASP and WAVE1/2. PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. PMID:23212475 WAve and WASP proteins activate Arp2/3 complex References_end </body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="6360.0" y="3260.0"/> <glyph class="state variable" id="_c411c6e5-75a8-4527-859a-cb55caa79179"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6355.0" y="3275.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s1705_sa866" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Wiskott-Aldrich syndrome HUGO:WAS hgnc_id:HGNC:12731 HGNC:12731 ENTREZ:7454 UNIPROT:P42768 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: L PMID:21178402 Rac1 and Cdc42 activate ARP2/3 complex; Rac1 and Cdc42 activate Wiskott-Aldrich Syndrome family of proteins including WASP, N-WASP and WAVE1/2. PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. PMID:23212475 WAve and WASP proteins activate Arp2/3 complex References_end </body> </html> </notes> <label text="WASP*"/> <bbox w="80.0" h="40.0" x="6360.0" y="3380.0"/> <glyph class="state variable" id="_2fe854b9-6f9f-44a4-888e-3802573e54cd"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6352.5" y="3395.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2447_sa882" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LIMK1 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21178402 Activation of LIMK by ROCK has been linked to the phosphoregulation of ADF/cofilin.52,54–56 ADF/cofilin has been shown to be one of the key regulators of actin severing, nucleation and capping within the protrusive machinery References_end </body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="6700.0" y="3870.0"/> <glyph class="state variable" id="_f279fa4d-05d2-4b87-a736-1b33e08d320d"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6695.0" y="3885.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2445_sa883" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LIMK1 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21178402 Activation of LIMK by ROCK has been linked to the phosphoregulation of ADF/cofilin.52,54–56 ADF/cofilin has been shown to be one of the key regulators of actin severing, nucleation and capping within the protrusive machinery References_end </body> </html> </notes> <label text="LIMK1"/> <bbox w="80.0" h="40.0" x="6700.0" y="4000.0"/> <glyph class="state variable" id="_5f39b855-ae03-40be-a604-6438d4ff81c6"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6692.5" y="4015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s863_sa884" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CFL1 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21178402 Activation of LIMK by ROCK has been linked to the phosphoregulation of ADF/cofilin.52,54–56 ADF/cofilin has been shown to be one of the key regulators of actin severing, nucleation and capping within the protrusive machinery References_end </body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="6550.0" y="3950.0"/> <glyph class="state variable" id="_027ab87b-9c6b-421c-8e6c-d22734f278ed"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6542.5" y="3965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s857_sa885" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CFL1 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:21178402 Activation of LIMK by ROCK has been linked to the phosphoregulation of ADF/cofilin.52,54–56 ADF/cofilin has been shown to be one of the key regulators of actin severing, nucleation and capping within the protrusive machinery References_end </body> </html> </notes> <label text="CFL1"/> <bbox w="80.0" h="40.0" x="6550.0" y="4040.0"/> <glyph class="state variable" id="_142e2d2b-8ac6-485b-9411-b8e40b1edd79"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="6545.0" y="4055.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4574_sa886" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:WASF1 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:23212475 WAve and WASP proteins activate Arp2/3 complex References_end </body> </html> </notes> <label text="WAVE*"/> <bbox w="80.0" h="40.0" x="6720.0" y="3570.0"/> </glyph> <glyph class="nucleic acid feature" id="s4576_sa887" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR155 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. PMID:26589288 MiR-155 knockout also inhibits cardiac fibroblast proliferation and differentiation into myofibroblasts. PMID:26195069 Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. References_end </body> </html> </notes> <label text="MIR155"/> <bbox w="90.0" h="25.0" x="4535.0" y="3687.5"/> <glyph class="unit of information" id="_5b76f5a8-ba58-4da7-8b9e-91e283f9a8a9"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="4565.0" y="3682.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4577_sa888" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR214 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. References_end </body> </html> </notes> <label text="MIR214"/> <bbox w="90.0" h="25.0" x="2705.0" y="2937.5"/> <glyph class="unit of information" id="_7afd0297-9c47-49f6-a28c-e308b142e938"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2735.0" y="2932.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4578_sa889" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR31 Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. PMID:20980827 miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knock-down of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. References_end </body> </html> </notes> <label text="MIR31"/> <bbox w="90.0" h="25.0" x="2875.0" y="2807.5"/> <glyph class="unit of information" id="_5861cc2f-6399-411c-9634-d0c0ecac84d8"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2905.0" y="2802.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4580_sa891" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: HUGO:SATB2 MODULE:FIBROBLAST_ACTIVATION_MARKERS PMID:20980827 miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knock-down of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. References_end </body> </html> </notes> <label text="SATB2"/> <bbox w="90.0" h="25.0" x="2465.0" y="4077.5"/> <glyph class="unit of information" id="_cf440768-e462-4ae5-9d7a-d26653455ce5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2500.0" y="4072.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4581_sa892"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR211 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:27548915 melanosomal miR-211 induces primary fibroblast reprogramming as demonstrated by elevation of the pro-inflammatory gene signature, cell proliferation and migration. Finally, we demonstrate that melanosomal miR-211 directly targets IGF2R and thus induces MAPK signalling. References_end </body> </html> </notes> <label text="MIR211"/> <bbox w="90.0" h="25.0" x="5585.0" y="687.5"/> <glyph class="unit of information" id="_15ea62bc-6855-453d-a563-c3abdd2e5dc9"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5615.0" y="682.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4582_sa893" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR221 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:22964023 miR-221-5p is upregulated in CAFS and , miR-141, miR-200b, miR-101-3p are downregulated SARA (ZFYVE16) is predicted as a target of miR-221-3p References_end </body> </html> </notes> <label text="MIR221"/> <bbox w="90.0" h="25.0" x="1745.0" y="4427.5"/> <glyph class="unit of information" id="_3de89e17-850e-426f-89c2-82abe285f12b"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1775.0" y="4422.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4583_sa896" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR141 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:22964023 miR-221-5p is upregulated in CAFS and , miR-141, miR-200b, miR-101-3p are downregulated TGF-β, IL-6 and RPS6KB1 are predicted as targets for miR-200b/c, IL-6, GRB2 are predicted as targets for miR-141 References_end </body> </html> </notes> <label text="MIR141"/> <bbox w="90.0" h="25.0" x="2835.0" y="2562.25"/> <glyph class="unit of information" id="_a3bda735-160f-4bf7-9642-b7842c37ed6e"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2865.0" y="2557.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4584_sa897" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR200B Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:22964023 miR-221-5p is upregulated in CAFS and , miR-141, miR-200b, miR-101-3p are downregulated TGF-β, IL-6 and RPS6KB1 are predicted as targets for miR-200b/c, IL-6, GRB2 are predicted as targets for miR-141 References_end </body> </html> </notes> <label text="MIR200B"/> <bbox w="90.0" h="25.0" x="3015.0" y="2562.25"/> <glyph class="unit of information" id="_0f23e892-4d5c-4955-8777-ac29d13e1f09"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="3045.0" y="2557.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4585_sa898" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR101-2 HUGO:MIR101-1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:22964023 miR-221-5p is upregulated in CAFS and , miR-141, miR-200b, miR-101-3p are downregulated References_end </body> </html> </notes> <label text="MIR101*"/> <bbox w="90.0" h="25.0" x="2925.0" y="2562.25"/> <glyph class="unit of information" id="_22b7ecb5-2345-41af-9627-03722f4d24f0"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2955.0" y="2557.25"/> </glyph> </glyph> <glyph class="complex" id="s4586_csa101" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR31:SATB2 Identifiers_end </body> </html> </notes> <label text="s4586"/> <bbox w="100.0" h="100.0" x="2310.0" y="3960.0"/> <glyph class="nucleic acid feature" id="s4587_sa900"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: HUGO:SATB2 MODULE:FIBROBLAST_ACTIVATION_MARKERS PMID:20980827 miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knock-down of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. References_end </body> </html> </notes> <label text="SATB2"/> <bbox w="90.0" h="25.0" x="2315.0" y="3997.5"/> <glyph class="unit of information" id="_db6256a5-876d-421c-ac85-dbd037887569"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2350.0" y="3992.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4588_sa901"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR31 Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. PMID:20980827 miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knock-down of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. References_end </body> </html> </notes> <label text="MIR31"/> <bbox w="90.0" h="25.0" x="2315.0" y="3966.5"/> <glyph class="unit of information" id="_5165dcbd-5304-4b68-a96a-7b4df0bd1af5"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2345.0" y="3961.5"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4589_sa902" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: HUGO:SATB2 MODULE:FIBROBLAST_ACTIVATION_MARKERS PMID:20980827 miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knock-down of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. References_end </body> </html> </notes> <label text="SATB2"/> <bbox w="70.0" h="25.0" x="2475.0" y="4007.5"/> </glyph> <glyph class="macromolecule" id="s4590_sa903" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: HUGO:SATB2 MODULE:FIBROBLAST_ACTIVATION_MARKERS PMID:20980827 SATB2 is a nuclear matrixattachment protein, involved in chromatin remodeling. In addition, through interaction with other transcription factors, it stimulates a cooperative increase of the transcription activation of their target genes. miR-31 directly targets the homeobox gene SATB2, which is responsible for chromatin remodeling and regulation of gene expression, and was significantly elevated in CAFs. The functional relevance of miR-31 and SATB2 were tested in in vitro models of endometrial cancer. Overexpression of miR-31 significantly impaired the ability of CAFs to stimulate tumor cell migration and invasion, without affecting tumor cell proliferation. Genetic manipulation of SATB2 levels in normal fibroblasts or CAFs showed that, reciprocally to miR-31, SATB2 increased tumor cell migration and invasion, while knock-down of endogenous SATB2 in CAFs reversed this phenotype. Introduction of SATB2 into normal fibroblasts stimulated expression of a number of genes involved in cell invasion, migration and scattering. References_end </body> </html> </notes> <label text="SATB2"/> <bbox w="80.0" h="40.0" x="2470.0" y="4140.0"/> </glyph> <glyph class="nucleic acid feature" id="s4592_sa905" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR31 Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:21051947 bone marrow-derived stromal cells from Cav-1(-/-) mice had elevated levels of miR-31 References_end </body> </html> </notes> <label text="MIR31"/> <bbox w="70.0" h="25.0" x="2885.0" y="2728.5"/> </glyph> <glyph class="macromolecule" id="s4593_sa907" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2R Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:27548915 One function of IGF2R is to bind to the ligand IGF2, leading to IGF2 degradation and consequently an inhibition of the growth stimulation that results from the interaction between IGF2 and IGF1R48, 49. IGF2 is upregulated in CAFs50, suggesting that IGF2R is inhibited. Therefore, reduction in IGF2R following treatment with miR-211 or melanosomes may increase IGF2 levels, promoting its binding to IGF1R, and thus leading to hyperactivation of this pathway and increased proliferation. References_end </body> </html> </notes> <label text="IGF2R"/> <bbox w="80.0" h="50.0" x="5260.0" y="975.0"/> <glyph class="unit of information" id="_f590220e-6616-4f10-b617-362b6fc11158"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5277.5" y="970.0"/> </glyph> </glyph> <glyph class="complex" id="s4594_csa102" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IGF2:IGF2R Identifiers_end </body> </html> </notes> <label text="s4594"/> <bbox w="100.0" h="120.0" x="5510.0" y="1050.0"/> <glyph class="macromolecule" id="s4807_sa908"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2R Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:27548915 One function of IGF2R is to bind to the ligand IGF2, leading to IGF2 degradation and consequently an inhibition of the growth stimulation that results from the interaction between IGF2 and IGF1R48, 49. IGF2 is upregulated in CAFs50, suggesting that IGF2R is inhibited. Therefore, reduction in IGF2R following treatment with miR-211 or melanosomes may increase IGF2 levels, promoting its binding to IGF1R, and thus leading to hyperactivation of this pathway and increased proliferation. References_end </body> </html> </notes> <label text="IGF2R"/> <bbox w="80.0" h="50.0" x="5520.0" y="1115.0"/> <glyph class="unit of information" id="_dcca9db3-f82f-4a83-a95a-36a522794788"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5537.5" y="1110.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4596_sa909"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 2 HUGO:IGF2 hgnc_id:HGNC:5466 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. PMID:24668028 IGF2 expressed by CAFs promotes tumor growth PMID:11237532 In breast cancers, both IGF-I and IGF-II are expressed in the stromal ﬁbroblasts and expression of IGF-II in particular correlates with tumor progression PMID:15003992 TGF-β induced the myofibroblast phenotype via a CTGF-dependent pathway, CTGF mediates EGF-stimulated proliferation and IGF-2-induced differentiation of fibroblasts References_end </body> </html> </notes> <label text="IGF2"/> <bbox w="80.0" h="40.0" x="5520.0" y="1070.0"/> </glyph> </glyph> <glyph class="source and sink" id="s4597_sa910" compartmentRef="c5_ca5"> <label text="csa102_degraded"/> <bbox w="30.0" h="30.0" x="5605.0" y="1205.0"/> </glyph> <glyph class="nucleic acid feature" id="s4598_sa911" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2R Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:27548915 One function of IGF2R is to bind to the ligand IGF2, leading to IGF2 degradation and consequently an inhibition of the growth stimulation that results from the interaction between IGF2 and IGF1R48, 49. IGF2 is upregulated in CAFs50, suggesting that IGF2R is inhibited. Therefore, reduction in IGF2R following treatment with miR-211 or melanosomes may increase IGF2 levels, promoting its binding to IGF1R, and thus leading to hyperactivation of this pathway and increased proliferation. References_end </body> </html> </notes> <label text="IGF2R"/> <bbox w="70.0" h="25.0" x="3115.0" y="2807.5"/> </glyph> <glyph class="nucleic acid feature" id="s4599_sa912" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2R Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:27548915 One function of IGF2R is to bind to the ligand IGF2, leading to IGF2 degradation and consequently an inhibition of the growth stimulation that results from the interaction between IGF2 and IGF1R48, 49. IGF2 is upregulated in CAFs50, suggesting that IGF2R is inhibited. Therefore, reduction in IGF2R following treatment with miR-211 or melanosomes may increase IGF2 levels, promoting its binding to IGF1R, and thus leading to hyperactivation of this pathway and increased proliferation. References_end </body> </html> </notes> <label text="IGF2R"/> <bbox w="90.0" h="25.0" x="3105.0" y="2717.5"/> <glyph class="unit of information" id="_28ad3168-5372-4c48-8f76-ff6a76bf2cb2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3140.0" y="2712.5"/> </glyph> </glyph> <glyph class="complex" id="s4600_csa103" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IGF2R:MIR211 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4600"/> <bbox w="100.0" h="120.0" x="5510.0" y="1230.0"/> <glyph class="nucleic acid feature" id="s4601_sa913"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR211 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: PMID:27548915 melanosomal miR-211 induces primary fibroblast reprogramming as demonstrated by elevation of the pro-inflammatory gene signature, cell proliferation and migration. Finally, we demonstrate that melanosomal miR-211 directly targets IGF2R and thus induces MAPK signalling. References_end </body> </html> </notes> <label text="MIR211"/> <bbox w="90.0" h="25.0" x="5515.0" y="1277.5"/> <glyph class="unit of information" id="_96978f30-b254-4220-a385-7de85d771ddb"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="5545.0" y="1272.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4602_sa914"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IGF2R Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:27548915 One function of IGF2R is to bind to the ligand IGF2, leading to IGF2 degradation and consequently an inhibition of the growth stimulation that results from the interaction between IGF2 and IGF1R48, 49. IGF2 is upregulated in CAFs50, suggesting that IGF2R is inhibited. Therefore, reduction in IGF2R following treatment with miR-211 or melanosomes may increase IGF2 levels, promoting its binding to IGF1R, and thus leading to hyperactivation of this pathway and increased proliferation. References_end </body> </html> </notes> <label text="IGF2R"/> <bbox w="90.0" h="25.0" x="5515.0" y="1247.5"/> <glyph class="unit of information" id="_42849434-6466-4f6b-a185-08c58a27ca43"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5550.0" y="1242.5"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4604_csa104" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CCL5:MIR214 Identifiers_end </body> </html> </notes> <label text="s4604"/> <bbox w="100.0" h="120.0" x="1530.0" y="3780.0"/> <glyph class="nucleic acid feature" id="s4606_sa916"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR214 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. References_end </body> </html> </notes> <label text="MIR214"/> <bbox w="90.0" h="25.0" x="1535.0" y="3797.5"/> <glyph class="unit of information" id="_1f83377e-07b6-46c0-a659-74e986515d8c"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1565.0" y="3792.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4605_sa917"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL5 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="90.0" h="25.0" x="1535.0" y="3827.5"/> <glyph class="unit of information" id="_c554d1d4-14ae-45d6-ab18-a18217dd55fc"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1570.0" y="3822.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s4607_sa918" compartmentRef="c5_ca5"> <label text="csa104_degraded"/> <bbox w="30.0" h="30.0" x="1685.0" y="3765.0"/> </glyph> <glyph class="phenotype" id="s4608_sa920" compartmentRef="c5_ca5"> <label text="NEGATIVE_REGULATORS OF_CAF"/> <bbox w="280.0" h="35.0" x="2880.0" y="2922.5"/> </glyph> <glyph class="nucleic acid feature" id="s4609_sa921" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI1 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH CASCADE:TGFB PMID:20215540 Shh ligand induces expression of Gli1 mRNA in pancreatic CAFs siRNA knockdown of SMO expression blocks GLI1 induction in pancreatic CAFs PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 References_end </body> </html> </notes> <label text="GLI1"/> <bbox w="70.0" h="25.0" x="5955.0" y="1717.5"/> </glyph> <glyph class="nucleic acid feature" id="s4610_sa922" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI1 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH CASCADE:TGFB PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 References_end </body> </html> </notes> <label text="GLI1"/> <bbox w="90.0" h="25.0" x="5945.0" y="1777.5"/> <glyph class="unit of information" id="_1f53c6e2-a87f-4a08-85f7-53dde3565b83"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5980.0" y="1772.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4611_sa923" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTCH1 HUGO:PTCH2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:22354771; PMID:17638910 Stimulation of cultured normal fibroblasts with TGFβ in the absence of SHH increased the mRNA levels of the hedgehog target genes Ptch1, Ptch2 (probably via GLI1 and GLI2) References_end </body> </html> </notes> <label text="PTCH*"/> <bbox w="70.0" h="25.0" x="6255.0" y="1637.5"/> </glyph> <glyph class="nucleic acid feature" id="s4612_sa925" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTCH1 HUGO:PTCH2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:22354771; PMID:17638910 Stimulation of cultured normal fibroblasts with TGFβ in the absence of SHH increased the mRNA levels of the hedgehog target genes Ptch1, Ptch2 (probably via GLI1 and GLI2) References_end </body> </html> </notes> <label text="PTCH*"/> <bbox w="90.0" h="25.0" x="6255.0" y="1487.5"/> <glyph class="unit of information" id="_faa0ff38-44f2-4a01-a09b-f5d006066933"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6290.0" y="1482.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4613_sa926" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTCH1 HUGO:PTCH2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:19081070 The Hh reception system consists of a 12-span transmembrane protein, Patched (Ptc), as the Hh receptor and a 7-span transmembrane protein, Smoothened (Smo), as the obligatory signal transducer across the plasma membrane (Ingham and McMahon, 2001). In the absence of Hh, Ptc blocks Smo activity, and full-length Gli proteins are proteolytically processed to generate C-terminally truncated GliR that actively represses a subset of Hh target genes. Hh binding to Ptc unleashes Smo activity, which blocks GliR production and promotes GliA activation. References_end </body> </html> </notes> <label text="PTCH*"/> <bbox w="80.0" h="50.0" x="6260.0" y="1355.0"/> <glyph class="unit of information" id="_db49dbae-8b2d-46ee-9e85-e6aa7c04ddd9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6277.5" y="1350.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4614_sa927" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMO Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:20215540 SMO is upregulated in pancreatic CAFs AFs expressing SMO could transduce the Sonic hedgehog signal to activate Gli1 expression, and small interfering RNA knockdown of SMO blocked the induction of Gli1 in these cells. PMID:23031257 TGF-β1–Induced Fibroblast Differentiation Depends on SMO in Control Fibroblasts Expression of collagen and actin (alphaSMA) and FN1 are SMO and GLI1/GLI2 dependent PMID:19081070 The Hh reception system consists of a 12-span transmembrane protein, Patched (Ptc), as the Hh receptor and a 7-span transmembrane protein, Smoothened (Smo), as the obligatory signal transducer across the plasma membrane (Ingham and McMahon, 2001). In the absence of Hh, Ptc blocks Smo activity, and full-length Gli proteins are proteolytically processed to generate C-terminally truncated GliR that actively represses a subset of Hh target genes. Hh binding to Ptc unleashes Smo activity, which blocks GliR production and promotes GliA activation. References_end </body> </html> </notes> <label text="SMO"/> <bbox w="80.0" h="50.0" x="6090.0" y="1455.0"/> <glyph class="unit of information" id="_35f6fa04-27f9-497e-a8c0-dcab9a018229"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6107.5" y="1450.0"/> </glyph> </glyph> <glyph class="complex" id="s4615_csa105" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:PTCH*:SMO Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4615"/> <bbox w="100.0" h="120.0" x="6110.0" y="1190.0"/> <glyph class="macromolecule" id="s4616_sa928"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SMO Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:20215540 SMO is upregulated in pancreatic CAFs AFs expressing SMO could transduce the Sonic hedgehog signal to activate Gli1 expression, and small interfering RNA knockdown of SMO blocked the induction of Gli1 in these cells. PMID:23031257 TGF-β1–Induced Fibroblast Differentiation Depends on SMO in Control Fibroblasts Expression of collagen and actin (alphaSMA) and FN1 are SMO and GLI1/GLI2 dependent PMID:19081070 The Hh reception system consists of a 12-span transmembrane protein, Patched (Ptc), as the Hh receptor and a 7-span transmembrane protein, Smoothened (Smo), as the obligatory signal transducer across the plasma membrane (Ingham and McMahon, 2001). In the absence of Hh, Ptc blocks Smo activity, and full-length Gli proteins are proteolytically processed to generate C-terminally truncated GliR that actively represses a subset of Hh target genes. Hh binding to Ptc unleashes Smo activity, which blocks GliR production and promotes GliA activation. References_end </body> </html> </notes> <label text="SMO"/> <bbox w="80.0" h="50.0" x="6120.0" y="1195.0"/> <glyph class="unit of information" id="_f25223e3-8961-4b93-8542-642f327d9451"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6137.5" y="1190.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4617_sa929"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTCH1 HUGO:PTCH2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:19081070 The Hh reception system consists of a 12-span transmembrane protein, Patched (Ptc), as the Hh receptor and a 7-span transmembrane protein, Smoothened (Smo), as the obligatory signal transducer across the plasma membrane (Ingham and McMahon, 2001). In the absence of Hh, Ptc blocks Smo activity, and full-length Gli proteins are proteolytically processed to generate C-terminally truncated GliR that actively represses a subset of Hh target genes. Hh binding to Ptc unleashes Smo activity, which blocks GliR production and promotes GliA activation. References_end </body> </html> </notes> <label text="PTCH*"/> <bbox w="80.0" h="50.0" x="6120.0" y="1235.0"/> <glyph class="unit of information" id="_0f053b33-3fda-4a75-be13-53e070b1069b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6137.5" y="1230.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4618_sa930" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI12 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HH PMID:17638910; PMID:22354771 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 Double-staining for α-SMA and GLI1 or GLI2 demonstrated a prominent accumulation of both GLI transcription factors in myofibroblasts PMID:19081070 The vertebrate GliRepressor function is largely derived from Gli3 while the primary GliActivator activity is largely contributed by Gli2. Gli1 is a transcriptional target of Hh signaling and acts as a transcriptional activator to reinforce GliA function PMID:23031257 TGF-β1–Induced Fibroblast Differentiation Depends on SMO in Control Fibroblasts Expression of collagen and actin (alphaSMA) and FN1 are SMO and GLI1/GLI2 dependent References_end </body> </html> </notes> <label text="GLI2"/> <bbox w="80.0" h="40.0" x="6130.0" y="1850.0"/> </glyph> <glyph class="macromolecule" id="s4619_sa931" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI3 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 PMID:19081070; PMID:22354771 The vertebrate GliRepressor function is largely derived from Gli3 while the primary GliActivator activity is largely contributed by Gli2. Gli1 is a transcriptional target of Hh signaling and acts as a transcriptional activator to reinforce GliA function References_end </body> </html> </notes> <label text="GLI3"/> <bbox w="80.0" h="40.0" x="5840.0" y="1620.0"/> </glyph> <glyph class="nucleic acid feature" id="s4620_sa932" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HH PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 References_end </body> </html> </notes> <label text="GLI2"/> <bbox w="70.0" h="25.0" x="6136.0" y="1727.5"/> </glyph> <glyph class="nucleic acid feature" id="s4621_sa934" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI2 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:HH PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, GLI1 and GLI2 expression is upregulated by TGFB via SMAD3 References_end </body> </html> </notes> <label text="GLI2"/> <bbox w="90.0" h="25.0" x="6126.0" y="1777.5"/> <glyph class="unit of information" id="_ddd6f4d2-4162-413b-8afc-b792e93e851e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="6161.0" y="1772.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4622_sa935" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI3 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:11731473 Gli3 repressed in response to Hh signals PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, References_end </body> </html> </notes> <label text="GLI3"/> <bbox w="70.0" h="25.0" x="5845.0" y="1487.5"/> </glyph> <glyph class="nucleic acid feature" id="s4623_sa936" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLI3 Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH PMID:17638910 GLI1, GLI2, GLI3 proteins are expressed in fibroblasts, References_end </body> </html> </notes> <label text="GLI3"/> <bbox w="90.0" h="25.0" x="5835.0" y="1547.5"/> <glyph class="unit of information" id="_7e0c10cb-2f9c-4077-81a4-b4f66ef7368e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5870.0" y="1542.5"/> </glyph> </glyph> <glyph class="source and sink" id="s4214_sa483" compartmentRef="c5_ca5"> <label text="csa53_degraded"/> <bbox w="30.0" h="30.0" x="3385.0" y="1345.0"/> </glyph> <glyph class="macromolecule" id="s4624_sa937" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Rho GTPase activating protein 35 HUGO:ARHGAP35 hgnc_id:HGNC:4591 HGNC:4591 ENTREZ:2909 UNIPROT:Q9NRY4 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: CASCADE:CAV CASCADE:INTEGRIN PMID:17517963 Src is involved in activation of Rac (Servitja et al., 2003; Kawakatsu et al., 2005) and Cdc42 (Miyamoto et al., 2003; Tu et al., 2003; Fukuyama et al., 2005) and can inhibit Rho through activation of p190RhoGAP PMID:22411312 ARHGAP35 (p190RhoGAP) inhibits RhoA. Engagement of integrins triggers Src‑dependent p190GAP phosphorylation which when activated inhibits RhoA enabling Rac1 activation that promotes lamellipodia formation, cell spreading and nascent focal adhesions.1 References_end </body> </html> </notes> <label text="ARHGAP35"/> <bbox w="80.0" h="40.0" x="6710.0" y="2950.0"/> <glyph class="state variable" id="_9f47553b-876a-402f-bd2e-9c0378e4389d"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6702.5" y="2965.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4625_sa599" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SRC proto-oncogene, non-receptor tyrosine kinase HUGO:SRC hgnc_id:HGNC:11283 HGNC:11283 ENTREZ:6714 UNIPROT:P12931 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:CAV PMID:11476890 Src kinases participate in PTK2 (FAK) phosphorylation downstream of integrin signaling Src−/− fibroblasts are slightly defective and fibroblasts deficient for the src, fyn and yes genes exhibit a dramatic defect in the cell adhesion-dependent tyrosine phosphorylation of FAK. hese observations suggest that cell adhesion-dependent tyrosine phosphorylation of FAK occurs in two phases. The first, autophosphorylation phase, occurs in the absence of Src and results in the tyrosine phosphorylation of FAK residue 397. The second phase occurs following recruitment of Src into complex with FAK and results in phosphorylation of FAK at other tyrosine residues leading to the full activation of FAK and transmission of downstream signals. PMID:16919435 Integrin-stimulated FAK phosphorylation at Y397 creates a high-affinity binding site for the Src-homology 2 (SH2) domain of SFKs. The binding of Src to FAK can lead to the conformational activation of SFKs and the formation of a transient FAK–Src signaling complex in fibroblasts and epithelial cells PMID:25572304 FAK undergoes autophosphorylation that leads to its association with Src, resulting in activation of both kinases. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. PMID:17517963 Src is involved in activation of Rac (Servitja et al., 2003; Kawakatsu et al., 2005) and Cdc42 (Miyamoto et al., 2003; Tu et al., 2003; Fukuyama et al., 2005) and can inhibit Rho through activation of p190RhoGAP caveolin-1 stimulates normal Rho GTP loading through inactivation of the Src–p190RhoGAP pathway. References_end </body> </html> </notes> <label text="SRC"/> <bbox w="80.0" h="40.0" x="6620.0" y="2560.0"/> <glyph class="state variable" id="_c832214d-c602-41ee-91f0-c9581908f7c4"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="6612.5" y="2575.0"/> </glyph> </glyph> <glyph class="phenotype" id="s4626_sa938" compartmentRef="c5_ca5"> <label text="Hypoxia"/> <bbox w="80.0" h="30.0" x="3320.0" y="3565.0"/> </glyph> <glyph class="source and sink" id="s4627_sa939" compartmentRef="c5_ca5"> <label text="sa469_degraded"/> <bbox w="30.0" h="30.0" x="3155.0" y="3265.0"/> </glyph> <glyph class="nucleic acid feature" id="s4628_sa940" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CAV1 Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:25364523 We cultured cardiac fibroblasts of mice were in hypoxia or normoxia conditions for 12, 24 and 48 hours. At all the time points, caveolin-1 and PTEN expression were gradually reduced, whereas, α-SMA was gradually increased. References_end </body> </html> </notes> <label text="CAV1"/> <bbox w="90.0" h="25.0" x="3115.0" y="3027.5"/> <glyph class="unit of information" id="_d985e62a-69d5-47f1-8f61-e9feff7b8a31"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3150.0" y="3022.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4629_sa941" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTEN Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: PMID:25364523 We cultured cardiac fibroblasts of mice were in hypoxia or normoxia conditions for 12, 24 and 48 hours. At all the time points, caveolin-1 and PTEN expression were gradually reduced, whereas, α-SMA was gradually increased. References_end </body> </html> </notes> <label text="PTEN"/> <bbox w="90.0" h="25.0" x="3325.0" y="2457.5"/> <glyph class="unit of information" id="_5e4b6506-b3f9-480a-bf51-b24211bee17f"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3360.0" y="2452.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4631_sa943" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PLAU Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGF PMID:19631971 co-culturing fibroblasts with ovarian cancer cells (ES-2) led to induction of uPA in fibroblasts; the same effect was observed when the fibroblasts were grown in ES-2 cell-conditioned medium. The basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) were the cancer cell-derived paracrine factors inducing uPA transcription in the fibroblasts. References_end </body> </html> </notes> <label text="PLAU"/> <bbox w="70.0" h="25.0" x="845.0" y="3168.5"/> </glyph> <glyph class="nucleic acid feature" id="s4632_sa944" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PLAU Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGF PMID:19631971 co-culturing fibroblasts with ovarian cancer cells (ES-2) led to induction of uPA in fibroblasts; the same effect was observed when the fibroblasts were grown in ES-2 cell-conditioned medium. The basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) were the cancer cell-derived paracrine factors inducing uPA transcription in the fibroblasts. References_end </body> </html> </notes> <label text="PLAU"/> <bbox w="90.0" h="25.0" x="835.0" y="3248.5"/> <glyph class="unit of information" id="_e10ddc3e-2d77-4333-ac35-94a66760a3de"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="870.0" y="3243.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4634_sa946" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SERPINF1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26921338 (PEDF, SERPINF1) normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. PEDF treatment strongly elevated cytoplasmic PEDF levels in the activated fibroblasts, suggesting a positive feedback loop. References_end </body> </html> </notes> <label text="SERPINF1"/> <bbox w="70.0" h="25.0" x="2845.0" y="2297.5"/> </glyph> <glyph class="nucleic acid feature" id="s4635_sa947" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SERPINF1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26921338 (PEDF, SERPINF1) normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. PEDF treatment strongly elevated cytoplasmic PEDF levels in the activated fibroblasts, suggesting a positive feedback loop. References_end </body> </html> </notes> <label text="SERPINF1"/> <bbox w="90.0" h="25.0" x="2835.0" y="2357.5"/> <glyph class="unit of information" id="_60953fe3-a8c2-435c-9fc8-a14937c78e5b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2870.0" y="2352.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4637_sa949" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> platelet derived growth factor subunit A HUGO:PDGFA hgnc_id:HGNC:8799 HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet derived growth factor subunit B HUGO:PDGFB hgnc_id:HGNC:8800 HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC hgnc_id:HGNC:8801 HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 References_begin: CASCADE:TGFB PMID:26921338 TGFB induces expression of PDGFB and PDGFR in CAFs and indirectly suppresses PEDF expression via PDGFB signaling References_end </body> </html> </notes> <label text="PDGF*"/> <bbox w="70.0" h="25.0" x="4205.0" y="4593.5"/> </glyph> <glyph class="nucleic acid feature" id="s4638_sa950" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> platelet derived growth factor subunit A HUGO:PDGFA hgnc_id:HGNC:8799 HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet derived growth factor subunit B HUGO:PDGFB hgnc_id:HGNC:8800 HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC hgnc_id:HGNC:8801 HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 References_begin: CASCADE:TGFB PMID:26921338 TGFB induces expression of PDGFB and PDGFR in CAFs and indirectly suppresses PEDF expression via PDGFB signaling References_end </body> </html> </notes> <label text="PDGF*"/> <bbox w="90.0" h="25.0" x="4195.0" y="4673.5"/> <glyph class="unit of information" id="_99a00de2-f430-443e-b5de-0cea63fe0c10"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4230.0" y="4668.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4639_sa951"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:POSTN Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:TGFB PMID:20096135 Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker. PN promotes proliferation and invasion of CCA cells Knockdown of ITGα5 attenuates PN-induced proliferation and invasion PMID:22158103 Postn expression in fibroblast is activated by TGFB signaling, probably via SMAD. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. References_end </body> </html> </notes> <label text="POSTN"/> <bbox w="80.0" h="40.0" x="7540.0" y="1550.0"/> </glyph> <glyph class="macromolecule" id="s4640_sa952" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CA9 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:19365853 CA IX expression by CAFs was found to be significantly correlated with conventional prognostic factors, including pathologic tumor classification and lymph node involvement. References_end </body> </html> </notes> <label text="CA9"/> <bbox w="80.0" h="40.0" x="1830.0" y="4510.0"/> </glyph> <glyph class="macromolecule" id="s4643_sa955" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP1 References_begin: PMID:20015200 Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin which activates matrix metalloproteinases (MMPs) involved in degradation of the extracellular matrix. Its secretion in the tumour microenvironment makes TFPI-2 a potential inhibitor of tumour invasion and metastasis TFPI-2 down-regulation enhanced cell adhesion to collagen IV and laminin via an increase in α(1) integrin on cell surface, and increased MMP expression (mainly MMP-1 and -3) contributing to cancer cell invasion through basement membrane components. References_end </body> </html> </notes> <label text="MMP1"/> <bbox w="80.0" h="40.0" x="5170.0" y="4690.0"/> </glyph> <glyph class="macromolecule" id="s4644_sa956" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP3 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:20015200 Tissue factor pathway inhibitor-2 (TFPI-2) is a potent inhibitor of plasmin which activates matrix metalloproteinases (MMPs) involved in degradation of the extracellular matrix. Its secretion in the tumour microenvironment makes TFPI-2 a potential inhibitor of tumour invasion and metastasis TFPI-2 down-regulation enhanced cell adhesion to collagen IV and laminin via an increase in α(1) integrin on cell surface, and increased MMP expression (mainly MMP-1 and -3) contributing to cancer cell invasion through basement membrane components. References_end </body> </html> </notes> <label text="MMP3"/> <bbox w="80.0" h="40.0" x="5460.0" y="4590.0"/> </glyph> <glyph class="macromolecule" id="s4645_sa957" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP7 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:20015200 MMP7 is expressed in CAFs References_end </body> </html> </notes> <label text="MMP7"/> <bbox w="80.0" h="40.0" x="5180.0" y="4780.0"/> </glyph> <glyph class="macromolecule" id="s4646_sa958" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HBEGF References_begin: PMID:19631971 Fibroblasts cultivated in cancer cell CM express different growth factors, bFGF mRNA and IL-1α mRNA was increased after 12 h, whereas mRNA for bFGF, HB-EGF, HGF, IGF-1, and IL-1α was increased after 24 h. EGF mRNA was not increased by the CM at any time point. References_end </body> </html> </notes> <label text="HBEGF"/> <bbox w="80.0" h="40.0" x="3880.0" y="4840.0"/> </glyph> <glyph class="complex" id="s4669_csa62" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA1:ITGB1 Identifiers_end References_begin: PMID:26148229 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins PMID:19397781 alpha(1)beta(1) integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth. References_end </body> </html> </notes> <label text="s76"/> <clone/> <bbox w="100.0" h="120.0" x="6780.0" y="2150.0"/> <glyph class="macromolecule" id="s4670_sa580"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 1 HUGO:ITGA1 hgnc_id:HGNC:6134 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26148229 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins PMID:19397781 alpha(1)beta(1) integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth. References_end </body> </html> </notes> <label text="ITGA1"/> <clone/> <bbox w="80.0" h="40.0" x="6790.0" y="2160.0"/> <glyph class="unit of information" id="_351b4871-3b1d-4f60-bbc2-a7a280ba4947"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6807.5" y="2155.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4671_sa581"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="6790.0" y="2200.0"/> <glyph class="unit of information" id="_b303d6cc-3ed8-4fc5-924f-2d0830769aff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6807.5" y="2195.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4669_csa2" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA1:ITGB1 Identifiers_end References_begin: PMID:26148229 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins PMID:19397781 alpha(1)beta(1) integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth. References_end </body> </html> </notes> <label text="s76"/> <clone/> <bbox w="100.0" h="120.0" x="6770.0" y="1920.0"/> <glyph class="macromolecule" id="s4670_sa76"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 1 HUGO:ITGA1 hgnc_id:HGNC:6134 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26148229 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins PMID:19397781 alpha(1)beta(1) integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth. References_end </body> </html> </notes> <label text="ITGA1"/> <clone/> <bbox w="80.0" h="40.0" x="6780.0" y="1930.0"/> <glyph class="unit of information" id="_1fa472bd-b435-48a0-bc45-afdad7fdae0a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6797.5" y="1925.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4671_sa77"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="6780.0" y="1970.0"/> <glyph class="unit of information" id="_cf56d5cd-9827-47b8-a81e-56dc18b7ef8d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6797.5" y="1965.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4672_csa61" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA2:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:9456329;PMID:11112697 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor PMID:25100717 Probably colagen signaling activates NFkB via ILK ILK is involved in an alternative activation of NF-κB signaling by modulating the phosphorylation of p65 at Ser-536 (Cre-mediated ILK deletion in ilkfl/fl MEFs demonstrates that LPS-induced p65 Ser-536 phosphorylation was inhibited by ILK deficiency). PMID:11112697 Collagen signaking together with TNF induses MMP14 expression and MMP2 activation in fibroblasts References_end </body> </html> </notes> <label text="s4295"/> <clone/> <bbox w="100.0" h="120.0" x="6490.0" y="2020.0"/> <glyph class="macromolecule" id="s4673_sa570"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 2 HUGO:ITGA2 hgnc_id:HGNC:6137 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor References_end </body> </html> </notes> <label text="ITGA2"/> <clone/> <bbox w="80.0" h="40.0" x="6500.0" y="2040.0"/> <glyph class="unit of information" id="_0f096d85-3e0d-4e19-8658-242edcc3039d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6517.5" y="2035.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4674_sa571"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="6500.0" y="2090.0"/> <glyph class="unit of information" id="_bf5ff739-be42-4f04-9797-d22576ee5641"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6517.5" y="2085.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4672_csa60" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA2:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:9456329;PMID:11112697 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor PMID:25100717 Probably colagen signaling activates NFkB via ILK ILK is involved in an alternative activation of NF-κB signaling by modulating the phosphorylation of p65 at Ser-536 (Cre-mediated ILK deletion in ilkfl/fl MEFs demonstrates that LPS-induced p65 Ser-536 phosphorylation was inhibited by ILK deficiency). PMID:11112697 Collagen signaking together with TNF induses MMP14 expression and MMP2 activation in fibroblasts References_end </body> </html> </notes> <label text="s4295"/> <clone/> <bbox w="100.0" h="120.0" x="6510.0" y="1790.0"/> <glyph class="macromolecule" id="s4673_sa566"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 2 HUGO:ITGA2 hgnc_id:HGNC:6137 HGNC:6137 ENTREZ:3673 UNIPROT:P17301 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor References_end </body> </html> </notes> <label text="ITGA2"/> <clone/> <bbox w="80.0" h="40.0" x="6520.0" y="1800.0"/> <glyph class="unit of information" id="_f5c1a9e9-de9d-431a-94ff-1220c33dbd0b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6537.5" y="1795.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4674_sa567"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="6520.0" y="1840.0"/> <glyph class="unit of information" id="_27f4aa69-f950-4ea7-bbeb-75d364578fc4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6537.5" y="1835.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4687_csa74" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA5:ITGB1 Identifiers_end </body> </html> </notes> <label text="s4356"/> <clone/> <bbox w="100.0" h="120.0" x="7170.0" y="2500.0"/> <glyph class="macromolecule" id="s4688_sa641"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="7180.0" y="2510.0"/> <glyph class="unit of information" id="_90c43a74-5bf6-4b27-ac18-6a40f6800400"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7197.5" y="2505.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4689_sa642"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 5 HUGO:ITGA5 hgnc_id:HGNC:6141 HGNC:6141 ENTREZ:3678 UNIPROT:P08648 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18037882 Integrin a3 and a5 are important in leading fibroblasts in SCC. siRNA against integrin 3 or integrin 5 in stromal fibroblasts would prevent the invasion of SCC cells and Figure 4C shows that siRNA-mediated depletion of either integrin 3 or integrin 5 in stromal fibroblasts, but not in SCC cells, reduced the collective invasion of SCC cells. Several groups have shown that integrin a5 can activate Rho signalling16, 17, 18, and this result was confirmed in carcinoma-associated fibroblasts (data not shown). Integrin a3 was also important for force-mediated matrix remodelling, but we found no evidence that it regulated Rho activity (data not shown). References_end </body> </html> </notes> <label text="ITGA5"/> <clone/> <bbox w="80.0" h="50.0" x="7180.0" y="2545.0"/> <glyph class="unit of information" id="_67113eae-61db-402e-a959-f4da9dcbaf20"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7197.5" y="2540.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4687_csa70" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA5:ITGB1 Identifiers_end </body> </html> </notes> <label text="s4356"/> <clone/> <bbox w="100.0" h="120.0" x="7360.0" y="2230.0"/> <glyph class="macromolecule" id="s4688_sa629"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="7370.0" y="2240.0"/> <glyph class="unit of information" id="_a9bdd1c6-b58d-4f42-b44e-a94784905647"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7387.5" y="2235.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4689_sa631"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 5 HUGO:ITGA5 hgnc_id:HGNC:6141 HGNC:6141 ENTREZ:3678 UNIPROT:P08648 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18037882 Integrin a3 and a5 are important in leading fibroblasts in SCC. siRNA against integrin 3 or integrin 5 in stromal fibroblasts would prevent the invasion of SCC cells and Figure 4C shows that siRNA-mediated depletion of either integrin 3 or integrin 5 in stromal fibroblasts, but not in SCC cells, reduced the collective invasion of SCC cells. Several groups have shown that integrin a5 can activate Rho signalling16, 17, 18, and this result was confirmed in carcinoma-associated fibroblasts (data not shown). Integrin a3 was also important for force-mediated matrix remodelling, but we found no evidence that it regulated Rho activity (data not shown). References_end </body> </html> </notes> <label text="ITGA5"/> <clone/> <bbox w="80.0" h="50.0" x="7370.0" y="2275.0"/> <glyph class="unit of information" id="_f5bfac86-bf85-41ac-a410-bab28d5bdc59"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7387.5" y="2270.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4707_csa68" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA11:ITGB1 Identifiers_end References_begin: 20129924 Integrin alpha11beta1 is a collagen receptor on fibroblasts Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins alpha11beta1 can act as a mechanosensor to promote the myofibroblast phenotype human corneal fibroblasts were transfected with small interfering RNA to alpha11, which decreased alpha-smooth muscle actin expression and myofibroblast differentiation. 26148229 Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs) 25076207; 26148229 Fibroblast expression of α11β1 integrin stimulates tumor cell growth. 19913614 The human alpha11 integrin promoter drives fibroblast-restricted expression in vivo and is regulated by TGF-beta1 in a Smad- and Sp1-dependent manner. 17420280 Analysis of matrix metalloproteinase in vitro and in vivo revealed disturbed MMP13 and MMP14 synthesis in alpha11(-/-) cells. References_end </body> </html> </notes> <label text="s4340"/> <clone/> <bbox w="100.0" h="120.0" x="7030.0" y="1930.0"/> <glyph class="macromolecule" id="s4708_sa616"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="7040.0" y="1980.0"/> <glyph class="unit of information" id="_8c2fe7bb-2e84-4218-b115-566bf2c5c491"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7057.5" y="1975.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4709_sa617"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 11 HUGO:ITGA11 hgnc_id:HGNC:6136 HGNC:6136 ENTREZ:22801 UNIPROT:Q9UKX5 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:TGFB PMID:20129924 Integrin alpha11beta1 is a collagen receptor on fibroblasts alpha11beta1 can act as a mechanosensor to promote the myofibroblast phenotype PMID:25076207 fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. References_end </body> </html> </notes> <label text="ITGA11"/> <clone/> <bbox w="80.0" h="50.0" x="7040.0" y="1935.0"/> <glyph class="unit of information" id="_64f194b7-7ffc-4b5c-8ee3-819b52a5e125"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7057.5" y="1930.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4707_csa69" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA11:ITGB1 Identifiers_end References_begin: 20129924 Integrin alpha11beta1 is a collagen receptor on fibroblasts Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins alpha11beta1 can act as a mechanosensor to promote the myofibroblast phenotype human corneal fibroblasts were transfected with small interfering RNA to alpha11, which decreased alpha-smooth muscle actin expression and myofibroblast differentiation. 26148229 Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs) 25076207; 26148229 Fibroblast expression of α11β1 integrin stimulates tumor cell growth. 19913614 The human alpha11 integrin promoter drives fibroblast-restricted expression in vivo and is regulated by TGF-beta1 in a Smad- and Sp1-dependent manner. 17420280 Analysis of matrix metalloproteinase in vitro and in vivo revealed disturbed MMP13 and MMP14 synthesis in alpha11(-/-) cells. References_end </body> </html> </notes> <label text="s4340"/> <clone/> <bbox w="100.0" h="120.0" x="6940.0" y="2310.0"/> <glyph class="macromolecule" id="s4708_sa618"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="6950.0" y="2360.0"/> <glyph class="unit of information" id="_94399e8e-d4f9-4e54-b90f-5e90c6b3d6d3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6967.5" y="2355.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4709_sa619"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 11 HUGO:ITGA11 hgnc_id:HGNC:6136 HGNC:6136 ENTREZ:22801 UNIPROT:Q9UKX5 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:TGFB PMID:20129924 Integrin alpha11beta1 is a collagen receptor on fibroblasts alpha11beta1 can act as a mechanosensor to promote the myofibroblast phenotype PMID:25076207 fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. References_end </body> </html> </notes> <label text="ITGA11"/> <clone/> <bbox w="80.0" h="50.0" x="6950.0" y="2315.0"/> <glyph class="unit of information" id="_bee17e96-fa42-4200-9623-4c713bde2a55"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6967.5" y="2310.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4710_csa99" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ACTR2:ACTR3:ARPC1*:ARPC2:ARPC3:ARPC4:ARPC5 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="Arp2/3"/> <clone/> <bbox w="190.0" h="210.0" x="6515.0" y="3345.0"/> <glyph class="macromolecule" id="s4715_sa867"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC3 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC3"/> <clone/> <bbox w="80.0" h="40.0" x="6610.0" y="3360.0"/> </glyph> <glyph class="macromolecule" id="s4716_sa868"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC4 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC4"/> <clone/> <bbox w="80.0" h="40.0" x="6610.0" y="3400.0"/> </glyph> <glyph class="macromolecule" id="s4717_sa869"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC5 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC5"/> <clone/> <bbox w="80.0" h="40.0" x="6610.0" y="3440.0"/> </glyph> <glyph class="macromolecule" id="s4712_sa870"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTR3 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ACTR3"/> <clone/> <bbox w="80.0" h="40.0" x="6520.0" y="3480.0"/> </glyph> <glyph class="macromolecule" id="s4711_sa871"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTR2 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ACTR2"/> <clone/> <bbox w="80.0" h="40.0" x="6520.0" y="3440.0"/> </glyph> <glyph class="macromolecule" id="s4713_sa872"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC2 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC2"/> <clone/> <bbox w="80.0" h="40.0" x="6520.0" y="3400.0"/> </glyph> <glyph class="macromolecule" id="s4714_sa873"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC1A HUGO:ARPC1B Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC1*"/> <clone/> <bbox w="80.0" h="40.0" x="6520.0" y="3360.0"/> </glyph> </glyph> <glyph class="complex" id="s4710_csa100" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ACTR2:ACTR3:ARPC1*:ARPC2:ARPC3:ARPC4:ARPC5 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="Arp2/3"/> <clone/> <bbox w="220.0" h="205.0" x="6500.0" y="3627.5"/> <glyph class="macromolecule" id="s4711_sa874"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTR2 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ACTR2"/> <clone/> <bbox w="80.0" h="40.0" x="6510.0" y="3720.0"/> </glyph> <glyph class="macromolecule" id="s4712_sa875"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ACTR3 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ACTR3"/> <clone/> <bbox w="80.0" h="40.0" x="6510.0" y="3762.5"/> </glyph> <glyph class="macromolecule" id="s4713_sa876"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC2 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC2"/> <clone/> <bbox w="80.0" h="40.0" x="6510.0" y="3682.5"/> </glyph> <glyph class="macromolecule" id="s4714_sa877"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC1A HUGO:ARPC1B Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC1*"/> <clone/> <bbox w="80.0" h="40.0" x="6510.0" y="3642.5"/> </glyph> <glyph class="macromolecule" id="s4715_sa878"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC3 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC3"/> <clone/> <bbox w="80.0" h="40.0" x="6610.0" y="3642.5"/> </glyph> <glyph class="macromolecule" id="s4716_sa879"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC4 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC4"/> <clone/> <bbox w="80.0" h="40.0" x="6610.0" y="3690.0"/> </glyph> <glyph class="macromolecule" id="s4717_sa880"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:ARPC5 Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: PMID:11395419 Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. References_end </body> </html> </notes> <label text="ARPC5"/> <clone/> <bbox w="80.0" h="40.0" x="6610.0" y="3722.5"/> </glyph> </glyph> <glyph class="complex" id="s4718_csa79" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LAP:LTBP*:TGFB* Identifiers_end References_begin: PMID:26519775; PMID:18086923; PMID:24309651 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text=" Large_Latent_Complex "/> <bbox w="105.0" h="165.0" x="3737.0" y="4677.0"/> <glyph class="macromolecule" id="s4843_sa657"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1 hgnc_id:HGNC:6714 HGNC:6714 ENTREZ:4052 UNIPROT:Q14766 latent transforming growth factor beta binding protein 2 HUGO:LTBP2 hgnc_id:HGNC:6715 HGNC:6715 ENTREZ:4053 UNIPROT:Q14767 latent transforming growth factor beta binding protein 3 HUGO:LTBP3 hgnc_id:HGNC:6716 HGNC:6716 ENTREZ:4054 UNIPROT:Q9NS15 latent transforming growth factor beta binding protein 4 HUGO:LTBP4 hgnc_id:HGNC:6717 HGNC:6717 ENTREZ:8425 UNIPROT:Q8N2S1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LTBP*"/> <bbox w="80.0" h="40.0" x="3752.0" y="4687.0"/> </glyph> <glyph class="macromolecule" id="s4844_sa658"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGFB induced factor homeobox 1 HUGO:TGIF1 hgnc_id:HGNC:11776 HGNC:11776 ENTREZ:7050 UNIPROT:Q15583 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LAP"/> <bbox w="80.0" h="40.0" x="3752.0" y="4727.0"/> <glyph class="unit of information" id="_ba175bf5-befd-4eaf-a03f-d99f1ae91876"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3767.0" y="4722.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4845_sa659"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta 1 HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137 transforming growth factor beta 2 HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812 transforming growth factor beta 3 HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF PMID:21098712 Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:23784029, PMID:16572188, PMID:8515656 TGF-β1 treatment successfully transformed primary resting fibroblasts into CAFs PMID:19038247 TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3. Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1–3 and ERK inhibition reduces TGFβ-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGFβ [9]. Similarly, p38 MAPK has been shown to be central to TGFβ mediated-collagen and fibronectin expression in SSc fibroblasts [10]. PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:18423981 Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. PMID:23034983 Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects PMID:21041659 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts PMID:17768418 TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). ??? both TGF-β1 and TGF-β2 are up-regulated in CAFs PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, PMID:17979848 TGF-β promotes the generation and function of Treg cells TGF-β is able to convert CD4+CD25− non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3752.0" y="4767.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4722_sa7" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast activation protein alpha HUGO:FAP hgnc_id:HGNC:3590 HGNC:3590 ENTREZ:2191 UNIPROT:Q12884 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HGF CASCADE:TGFB CASCADE:PLAU PMID:25593080 Fibroblast activation protein α in tumor microenvironment: Recent progression and implications (Review) FAPα expression may be elevated under the influence of an altered tumor microenvironment or inflammation. In vitro FAPα expression was observed in fibroblasts and melanocytes cultured in fibroblast growth factor (FGF) and phorbol ester (33). Treatment of FB20 cells with human transforming growth factor-βl (TGF-β1), 12-o-tetradecanoyl phorbol-13-acetate (TPA), retinol or retinoic acid for 24–48 h increased FAPα expression in the cells (34). FAPα expression in CD strictured myofibroblasts under the stimulation of 10 ng/ml tumor necrosis factor α (TNF-α) or TGF-β1 for 48 h was significantly increased (59). TNF-α, produced by macrophages, was also able to induce FAPα expression in cultured human aortic smooth muscle cells (60). Further to the cytokines and chemical substances which induce FAPα expression, physical stimulants, including ultraviolet radiation, also induce upregulation of FAPα expression in fibroblasts, melanocytes and primary melanoma cells to facilitate invasion and migration of the cells (69). FAPα is a tumor promoter. Silencing FAPα with short interfering RNA transfected using a lentiviral vector inhibited growth and resulted in cell cycle arrest at the G2 and S phases of cancer-associated fibroblasts in vitro (73). FAPα displays DPP and gelatinolytic activity as proved by gelatin zymography and can cleave native ECM proteins, including collagen I, collagen IV, fibronectin, laminin and gelatin (38–40,49,86). These enzyme activities depend on the mutation at position Ser624, which abrogates the DPP and collagenase activity of FAPα (49). These enzymatic activities indicate that FAPα may have a prominent role in tumor invasion, metastasis and angiogenesis (86–88). Clinical observation revealed that the overexpression of FAPα by ductal carcinomas is congruent with the invasion and metastasis of infiltrating ductal carcinomas (IDC) of the breast (55). Using an in vivo-like three-dimensional matrix system, Lee et al (89) observed that FAPα remodeled the ECM and increased the invasive capability and metastasis of pancreatic tumors, mediated by β1-integrin/focal adhesion kinase. PMID:7911242 FAP is originally identified as a membrane-bound serine protease implicated in extracellular matrix remodeling PMID:27216177 PlAUR induces FAK activation downstream of FAP, which directly interacts with PLAUR. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:24778314 Review about FAP PMID:21051638 FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment. References_end </body> </html> </notes> <label text="FAP"/> <clone/> <bbox w="80.0" h="40.0" x="2170.0" y="4360.0"/> </glyph> <glyph class="macromolecule" id="s4722_sa724" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast activation protein alpha HUGO:FAP hgnc_id:HGNC:3590 HGNC:3590 ENTREZ:2191 UNIPROT:Q12884 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:FIBROBLAST_ACTIVATION_MARKERS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HGF CASCADE:TGFB CASCADE:PLAU PMID:25593080 Fibroblast activation protein α in tumor microenvironment: Recent progression and implications (Review) FAPα expression may be elevated under the influence of an altered tumor microenvironment or inflammation. In vitro FAPα expression was observed in fibroblasts and melanocytes cultured in fibroblast growth factor (FGF) and phorbol ester (33). Treatment of FB20 cells with human transforming growth factor-βl (TGF-β1), 12-o-tetradecanoyl phorbol-13-acetate (TPA), retinol or retinoic acid for 24–48 h increased FAPα expression in the cells (34). FAPα expression in CD strictured myofibroblasts under the stimulation of 10 ng/ml tumor necrosis factor α (TNF-α) or TGF-β1 for 48 h was significantly increased (59). TNF-α, produced by macrophages, was also able to induce FAPα expression in cultured human aortic smooth muscle cells (60). Further to the cytokines and chemical substances which induce FAPα expression, physical stimulants, including ultraviolet radiation, also induce upregulation of FAPα expression in fibroblasts, melanocytes and primary melanoma cells to facilitate invasion and migration of the cells (69). FAPα is a tumor promoter. Silencing FAPα with short interfering RNA transfected using a lentiviral vector inhibited growth and resulted in cell cycle arrest at the G2 and S phases of cancer-associated fibroblasts in vitro (73). FAPα displays DPP and gelatinolytic activity as proved by gelatin zymography and can cleave native ECM proteins, including collagen I, collagen IV, fibronectin, laminin and gelatin (38–40,49,86). These enzyme activities depend on the mutation at position Ser624, which abrogates the DPP and collagenase activity of FAPα (49). These enzymatic activities indicate that FAPα may have a prominent role in tumor invasion, metastasis and angiogenesis (86–88). Clinical observation revealed that the overexpression of FAPα by ductal carcinomas is congruent with the invasion and metastasis of infiltrating ductal carcinomas (IDC) of the breast (55). Using an in vivo-like three-dimensional matrix system, Lee et al (89) observed that FAPα remodeled the ECM and increased the invasive capability and metastasis of pancreatic tumors, mediated by β1-integrin/focal adhesion kinase. PMID:7911242 FAP is originally identified as a membrane-bound serine protease implicated in extracellular matrix remodeling PMID:27216177 PlAUR induces FAK activation downstream of FAP, which directly interacts with PLAUR. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:24778314 Review about FAP PMID:21051638 FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment. References_end </body> </html> </notes> <label text="FAP"/> <clone/> <bbox w="80.0" h="40.0" x="830.0" y="1940.0"/> </glyph> <glyph class="macromolecule" id="s4723_sa24" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: epidermal growth factor HUGO:EGF hgnc_id:HGNC:3229 HGNC:3229 ENTREZ:1950 UNIPROT:P01133 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:15175028 Epidermal growth factor induces fibronectin expression in human dermal fibroblasts via protein kinase C δ signaling pathway PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. PMID:18423981 EGF stimulates invasion of iHDF fibroblasts in collagen 3D-culture conditions, provbably via RAC activation. EGF down-regulated Rho-GTP levels in fibroblasts, giving permissive signals for Rac1 activation, fibroblast polarization, and invasion. PMID:19631971 Fibroblasts cultivated in cancer cell CM express different growth factors, bFGF mRNA and IL-1α mRNA was increased after 12 h, whereas mRNA for bFGF, HB-EGF, HGF, IGF-1, and IL-1α was increased after 24 h. EGF mRNA was not increased by the CM at any time point. PMID:21098712; TGFB induces EGF expression and secretion in fibroblasts References_end </body> </html> </notes> <label text="EGF"/> <bbox w="80.0" h="40.0" x="4070.0" y="4746.0"/> </glyph> <glyph class="macromolecule" id="s4724_sa25" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 2 HUGO:FGF2 hgnc_id:HGNC:3676 HGNC:3676 ENTREZ:2247 UNIPROT:P09038 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PGDF CASCADE:FGF CASCADE:TGFB PMID:23123598 paracrine PDGF stimulation of CAFs induces production of the prototypical pro-angiogenic inducer fibroblast growth factor (FGF)-2 in both cervical carcinomas and melanoma [11] and [85]. PMID:18232728 FGF-2 Functionally Contributes to the Angiogenic Phenotype . FGF-2 and FGF-7 are expressed by CAFs and Repressed by Specific Inhibition of PDGF Receptor Signaling PMID:21098712; PMID:22652804; PMID:25374926 TGFB induces FGF2 expression and secretion in fibroblasts via SMAD3 and MAPK pathways PMID:9242465; PMID:19631971 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="FGF2"/> <bbox w="80.0" h="40.0" x="3580.0" y="4431.0"/> </glyph> <glyph class="macromolecule" id="s4725_sa31" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: hepatocyte growth factor HUGO:HGF hgnc_id:HGNC:4893 HGNC:4893 ENTREZ:3082 UNIPROT:P14210 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:FGF CASCADE:PDGF CASCADE:HGF PMID:9242465; PMID:19631971 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts PMID:27474009 HGF is a activation factor for fibroblasts PMID:23667593 Cancer-Associated Fibroblasts from Hepatocellular Carcinoma Promote Malignant Cell Proliferation by HGF Secretion PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15059978 Proinvasive factors secreted by myofibroblasts are identified as TNC and SF/HGF, each of which is necessary but not sufficient for stimulation of invasion of human colon cancer cells PMID:22763439 HGF is present in the stromal cells of melanoma and correlates with poor response to therapy References_end </body> </html> </notes> <label text="HGF"/> <bbox w="80.0" h="40.0" x="4060.0" y="4431.0"/> </glyph> <glyph class="macromolecule" id="s4726_sa33" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibronectin 1 HUGO:FN1 hgnc_id:HGNC:3778 HGNC:3778 ENTREZ:2335 UNIPROT:P02751 Identifiers_end Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:HH CASCADE:INTEGRIN PMID:21674557 Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype (ACTA2, CNN1,FN (ED-A containing), EDN1, MYL12A, TAGLN2) and inhibition of ACTG2 expression. PMID:18353785 TGFβ1-inducedαvβ3 expression is dependent on integrin-mediated cell adhesion; FN strongly potentiated the effect of TGFβ1. PMID:26519775 fibronectin is a ligand fo a5b1, avb3, avb5 integrins in CAFs References_end </body> </html> </notes> <label text="FN*"/> <bbox w="80.0" h="40.0" x="5490.0" y="4080.0"/> </glyph> <glyph class="macromolecule" id="s4727_sa49" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: serpin family E member 1 HUGO:SERPINE1 hgnc_id:HGNC:8583 HGNC:8583 ENTREZ:5054 UNIPROT:P05121 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:11021826 Fibroblastic expression (immunohistocheemistry) of both uPA and uPAR were positively correlated with tumor size. fibroblastic expression of PAI1 was related to the presence of invasion PMID:25502501 SERPINE1, which encodes PAI-1 and is a target of YAP/TAZ PAI-1 has been definitively linked to both profibrotic functions of cultured fibroblasts (20) and fibrosis in animal models and human disease. PMID:20027185 The proteolytic activities of uPA and plasmin are antagonized by the serine protease inhibitors (serpins) plasminogen activator inhibitor 1 (PAI1; also known as SERPINE1) and PAI2 (also known as SERPINB2) References_end </body> </html> </notes> <label text="SERPINE1"/> <bbox w="80.0" h="40.0" x="2950.0" y="2430.0"/> </glyph> <glyph class="macromolecule" id="s4728_sa63" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 HUGO:IL6 hgnc_id:HGNC:6018 HGNC:6018 ENTREZ:3569 UNIPROT:P05231 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PGE CASCADE:IL1 PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:26268945 Il-6 signaling between ductal carcinoma in situ cells and carcinoma-associated fibroblasts mediates tumor cell growth and migration PMID:24346288 Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. IL-6 enhanced VEGF production by fibroblasts, thereby inducing angiogenesis. PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB PMID:19581928; PMID:24011634 Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells PMID:24011634 Lung-derived fibroblasts were activated by IL-6 and TGF-β IL-6 enhanced TGF-β signaling in A549 cells and lung-derived fibroblasts probably via increased expression of TGF-β receptor type I on the cell surface. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells PMID:25002027 SQSTM1 (p62) p62 is a suppressor of inflammation and the CAF phenotype in the tumor microenvironment p62 controls IL-6 levels by repressing ROS production through metabolic reprogramming References_end </body> </html> </notes> <label text="IL6"/> <clone/> <bbox w="80.0" h="40.0" x="320.0" y="3321.5"/> </glyph> <glyph class="macromolecule" id="s4728_sa367" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interleukin 6 HUGO:IL6 hgnc_id:HGNC:6018 HGNC:6018 ENTREZ:3569 UNIPROT:P05231 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PGE CASCADE:IL1 PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:26268945 Il-6 signaling between ductal carcinoma in situ cells and carcinoma-associated fibroblasts mediates tumor cell growth and migration PMID:24346288 Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. IL-6 enhanced VEGF production by fibroblasts, thereby inducing angiogenesis. PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB PMID:19581928; PMID:24011634 Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells PMID:24011634 Lung-derived fibroblasts were activated by IL-6 and TGF-β IL-6 enhanced TGF-β signaling in A549 cells and lung-derived fibroblasts probably via increased expression of TGF-β receptor type I on the cell surface. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells PMID:25002027 SQSTM1 (p62) p62 is a suppressor of inflammation and the CAF phenotype in the tumor microenvironment p62 controls IL-6 levels by repressing ROS production through metabolic reprogramming References_end </body> </html> </notes> <label text="IL6"/> <clone/> <bbox w="80.0" h="40.0" x="740.0" y="2605.0"/> </glyph> <glyph class="macromolecule" id="s4729_sa67" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: collagen type I alpha 1 chain HUGO:COL1A1 hgnc_id:HGNC:2197 HGNC:2197 ENTREZ:1277 UNIPROT:P02452 collagen type I alpha 2 chain HUGO:COL1A2 hgnc_id:HGNC:2198 HGNC:2198 ENTREZ:1278 UNIPROT:P08123 collagen type II alpha 1 chain HUGO:COL2A1 hgnc_id:HGNC:2200 HGNC:2200 ENTREZ:1280 UNIPROT:P02458 collagen type III alpha 1 chain HUGO:COL3A1 hgnc_id:HGNC:2201 HGNC:2201 ENTREZ:1281 UNIPROT:P02461 collagen type IV alpha 1 chain HUGO:COL4A1 hgnc_id:HGNC:2202 HGNC:2202 ENTREZ:1282 UNIPROT:P02462 collagen type IV alpha 2 chain HUGO:COL4A2 hgnc_id:HGNC:2203 HGNC:2203 ENTREZ:1284 UNIPROT:P08572 collagen type IV alpha 3 chain HUGO:COL4A3 hgnc_id:HGNC:2204 HGNC:2204 ENTREZ:1285 UNIPROT:Q01955 collagen type IV alpha 4 chain HUGO:COL4A4 hgnc_id:HGNC:2206 HGNC:2206 ENTREZ:1286 UNIPROT:P53420 collagen type IV alpha 5 chain HUGO:COL4A5 hgnc_id:HGNC:2207 HGNC:2207 ENTREZ:1287 UNIPROT:P29400 collagen type IV alpha 6 chain HUGO:COL4A6 hgnc_id:HGNC:2208 HGNC:2208 ENTREZ:1288 UNIPROT:Q14031 collagen type V alpha 1 chain HUGO:COL5A1 hgnc_id:HGNC:2209 HGNC:2209 ENTREZ:1289 UNIPROT:P20908 collagen type V alpha 2 chain HUGO:COL5A2 hgnc_id:HGNC:2210 HGNC:2210 ENTREZ:1290 UNIPROT:P05997 collagen type V alpha 3 chain HUGO:COL5A3 hgnc_id:HGNC:14864 HGNC:14864 ENTREZ:50509 UNIPROT:P25940 collagen type VI alpha 1 chain HUGO:COL6A1 hgnc_id:HGNC:2211 HGNC:2211 ENTREZ:1291 UNIPROT:P12109 collagen type VI alpha 2 chain HUGO:COL6A2 hgnc_id:HGNC:2212 HGNC:2212 ENTREZ:1292 UNIPROT:P12110 collagen type VI alpha 3 chain HUGO:COL6A3 hgnc_id:HGNC:2213 HGNC:2213 ENTREZ:1293 UNIPROT:P12111 collagen type VI alpha 4 pseudogene 1 HUGO:COL6A4P1 hgnc_id:HGNC:33484 HGNC:33484 ENTREZ:344875 collagen type VI alpha 4 pseudogene 2 HUGO:COL6A4P2 hgnc_id:HGNC:38501 HGNC:38501 ENTREZ:646300 collagen type VI alpha 5 chain HUGO:COL6A5 hgnc_id:HGNC:26674 HGNC:26674 ENTREZ:256076 UNIPROT:A8TX70 collagen type VI alpha 6 chain HUGO:COL6A6 hgnc_id:HGNC:27023 HGNC:27023 ENTREZ:131873 UNIPROT:A6NMZ7 collagen type VII alpha 1 chain HUGO:COL7A1 hgnc_id:HGNC:2214 HGNC:2214 ENTREZ:1294 UNIPROT:Q02388 collagen type VIII alpha 1 chain HUGO:COL8A1 hgnc_id:HGNC:2215 HGNC:2215 ENTREZ:1295 UNIPROT:P27658 collagen type VIII alpha 2 chain HUGO:COL8A2 hgnc_id:HGNC:2216 HGNC:2216 ENTREZ:1296 UNIPROT:P25067 collagen type IX alpha 1 chain HUGO:COL9A1 hgnc_id:HGNC:2217 HGNC:2217 ENTREZ:1297 UNIPROT:P20849 collagen type IX alpha 2 chain HUGO:COL9A2 hgnc_id:HGNC:2218 HGNC:2218 ENTREZ:1298 UNIPROT:Q14055 collagen type IX alpha 3 chain HUGO:COL9A3 hgnc_id:HGNC:2219 HGNC:2219 ENTREZ:1299 UNIPROT:Q14050 collagen type X alpha 1 chain HUGO:COL10A1 hgnc_id:HGNC:2185 HGNC:2185 ENTREZ:1300 UNIPROT:Q03692 collagen type XI alpha 1 chain HUGO:COL11A1 hgnc_id:HGNC:2186 HGNC:2186 ENTREZ:1301 UNIPROT:P12107 collagen type XI alpha 2 chain HUGO:COL11A2 hgnc_id:HGNC:2187 HGNC:2187 ENTREZ:1302 UNIPROT:P13942 collagen type XII alpha 1 chain HUGO:COL12A1 hgnc_id:HGNC:2188 HGNC:2188 ENTREZ:1303 UNIPROT:Q99715 collagen type XIII alpha 1 chain HUGO:COL13A1 hgnc_id:HGNC:2190 HGNC:2190 ENTREZ:1305 UNIPROT:Q5TAT6 collagen type XIV alpha 1 chain HUGO:COL14A1 hgnc_id:HGNC:2191 HGNC:2191 ENTREZ:7373 UNIPROT:Q05707 collagen type XV alpha 1 chain HUGO:COL15A1 hgnc_id:HGNC:2192 HGNC:2192 ENTREZ:1306 UNIPROT:P39059 collagen type XVI alpha 1 chain HUGO:COL16A1 hgnc_id:HGNC:2193 HGNC:2193 ENTREZ:1307 UNIPROT:Q07092 collagen type XVII alpha 1 chain HUGO:COL17A1 hgnc_id:HGNC:2194 HGNC:2194 ENTREZ:1308 UNIPROT:Q9UMD9 collagen type XVIII alpha 1 chain HUGO:COL18A1 hgnc_id:HGNC:2195 HGNC:2195 ENTREZ:80781 UNIPROT:P39060 collagen type XIX alpha 1 chain HUGO:COL19A1 hgnc_id:HGNC:2196 HGNC:2196 ENTREZ:1310 UNIPROT:Q14993 collagen type XX alpha 1 chain HUGO:COL20A1 hgnc_id:HGNC:14670 HGNC:14670 ENTREZ:57642 UNIPROT:Q9P218 collagen type XXI alpha 1 chain HUGO:COL21A1 hgnc_id:HGNC:17025 HGNC:17025 ENTREZ:81578 UNIPROT:Q96P44 collagen type XXII alpha 1 chain HUGO:COL22A1 hgnc_id:HGNC:22989 HGNC:22989 ENTREZ:169044 UNIPROT:Q8NFW1 collagen type XXIII alpha 1 chain HUGO:COL23A1 hgnc_id:HGNC:22990 HGNC:22990 ENTREZ:91522 UNIPROT:Q86Y22 collagen type XXIV alpha 1 chain HUGO:COL24A1 hgnc_id:HGNC:20821 HGNC:20821 ENTREZ:255631 UNIPROT:Q17RW2 collagen type XXV alpha 1 chain HUGO:COL25A1 hgnc_id:HGNC:18603 HGNC:18603 ENTREZ:84570 UNIPROT:Q9BXS0 collagen type XXVI alpha 1 chain HUGO:COL26A1 hgnc_id:HGNC:18038 HGNC:18038 ENTREZ:136227 UNIPROT:Q96A83 collagen type XXVII alpha 1 chain HUGO:COL27A1 hgnc_id:HGNC:22986 HGNC:22986 ENTREZ:85301 UNIPROT:Q8IZC6 collagen type XXVIII alpha 1 chain HUGO:COL28A1 hgnc_id:HGNC:22442 HGNC:22442 ENTREZ:340267 UNIPROT:Q2UY09 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IFNG CASCADE:INTERGIN CASCADE:IGF1R CASCADE:HH PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. ???? collagen type I, which is known to be secreted by activated fibroblasts, can promote infiltration of immune cells. However it also inhibits the ability of macrophages to kill cancer cells by affecting their polarization into an immunosuppressive phenotype. PMID:11279127 Dominant-Negative Smad3 and Inhibitory Smad7 Expression Block TGF-β-induced ECM Promoter Activation in fibroblasts COL1A2, COL3A1, COL6A1, COL6A3, and TIMP-1 PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells PMID:19397781 collagens are ligands for a1b1, a2b1 and a11b1 integrins in CAFs PMID:24856586 Myofibroblast Depletion Reduced Type I Collagen Content and Altered Extracellular Matrix Organization in PDAC. These results are consistent with the ability of αSMA+ myofibroblasts to produce type I collagen and induce fibrosis in PDAC. References_end </body> </html> </notes> <label text="Collagens*"/> <bbox w="80.0" h="40.0" x="5620.0" y="4380.0"/> </glyph> <glyph class="simple chemical" id="s4730_sa87" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: CASCADE:TGFB CASCADE:PDGF PMID:22101652; PMID:19923890 The M1 or M2 splice isoforms of pyruvate kinase (PK), a mandatory regulatory glycolytic enzyme, shift glucose metabolism towards aerobic glycolysis (PKM2) or oxidative phosphorylation (PKM1) PKM2 and lactate dehydrogenase are highly expressed in the stroma of breast cancer lacking caveolin-1 expression PMID:22874531 Fibroblasts overexpressing the constitutively active TGF-β receptor kinase (RI; T204D) show increased autophagy and oxidative stress-induced aerobic glycolysis ROS production downstream of TGFB induces lactate secretion PMID:25732824 lactate production was increased 2.5-fold in both TGF-β- and PDGF-induced CAFs compared to the control fibroblasts (Figure 1C). Glucose uptake also increased approximately 2-fold in both types of induced CAFs compared to control fibroblasts References_end </body> </html> </notes> <label text="lactate"/> <bbox w="70.0" h="25.0" x="2726.0" y="4787.5"/> </glyph> <glyph class="simple chemical" id="s4734_sa190" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:20823158 CAFs have been identified as a source of hyaluronan, and genetic ablation of the hyaluronan synthase gene (Has2) in fibroblasts strongly diminishes the entry of macrophages into the tumour microenvironment. References_end </body> </html> </notes> <label text="hyaluronan"/> <bbox w="70.0" h="25.0" x="5910.0" y="4658.75"/> </glyph> <glyph class="macromolecule" id="s4735_sa274" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor receptor 1 HUGO:FGFR1 hgnc_id:HGNC:3688 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25467007 FGFRs _rew References_end </body> </html> </notes> <label text="FGFR1"/> <clone/> <bbox w="80.0" h="50.0" x="4750.0" y="1025.0"/> <glyph class="unit of information" id="_b7334a67-9a2f-41af-ac3c-466d496a81d8"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4767.5" y="1020.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4735_sa277" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor receptor 1 HUGO:FGFR1 hgnc_id:HGNC:3688 HGNC:3688 ENTREZ:2260 UNIPROT:P11362 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25467007 FGFRs _rew References_end </body> </html> </notes> <label text="FGFR1"/> <clone/> <bbox w="80.0" h="50.0" x="4750.0" y="1155.0"/> <glyph class="unit of information" id="_1ed9e9ff-8eef-4570-8c2c-40e1162f59bb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4767.5" y="1150.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4736_sa301" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LDOC1, regulator of NFKB signaling HUGO:LDOC1 hgnc_id:HGNC:6548 HGNC:6548 ENTREZ:23641 UNIPROT:O95751 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:20138012 Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent Manner Proinflammatory CAFs from a transgenic mouse model of squamous cell carcinoma mediated immune cell recruitment, angiogenesis, and tumor growth. Inhibition of NF-κB signaling abolished these tumor-promoting effects, demonstrating that NF-κB is critical for tumor-enhancing inflammation mediated by CAFs. Studies using immuno-competent GEM models, demonstrated that normal dermal fibroblasts can be “educated” by carcinoma cells to express pro-inflammatory genes, mainly through activation of the NF-κβ pathway in the activated fibroblasts. Using PDGFRα to select normal and tumour derived fibroblasts, the group of Hanahan identified an NF-κβ dependent pro-inflammatory gene signature in CAFs isolated from different murine models of cancers originating in the skin, the breast and the pancreas. NF-κβ-dependent pro-inflammatory signature included genes such as CXCL1, CXCL2, CXCL5, CCL3 as well as the pro-inflammatory cytokines IL-1β and IL-6, which, as mentioned above, are all potent chemo-attractants for several immune cell types including, neutrophils, macrophages and other leukocyte populations PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:20855962 Hypoxia induces NfkB activation. pharmacological inactivation of NFκB--another inducer of autophagy-prevents Cav-1 degradation References_end </body> </html> </notes> <label text="NFkB*"/> <clone/> <bbox w="80.0" h="40.0" x="2160.0" y="3490.0"/> </glyph> <glyph class="macromolecule" id="s4736_sa302" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LDOC1, regulator of NFKB signaling HUGO:LDOC1 hgnc_id:HGNC:6548 HGNC:6548 ENTREZ:23641 UNIPROT:O95751 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:IL1 CASCADE:TNF PMID:20138012 Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent Manner Proinflammatory CAFs from a transgenic mouse model of squamous cell carcinoma mediated immune cell recruitment, angiogenesis, and tumor growth. Inhibition of NF-κB signaling abolished these tumor-promoting effects, demonstrating that NF-κB is critical for tumor-enhancing inflammation mediated by CAFs. Studies using immuno-competent GEM models, demonstrated that normal dermal fibroblasts can be “educated” by carcinoma cells to express pro-inflammatory genes, mainly through activation of the NF-κβ pathway in the activated fibroblasts. Using PDGFRα to select normal and tumour derived fibroblasts, the group of Hanahan identified an NF-κβ dependent pro-inflammatory gene signature in CAFs isolated from different murine models of cancers originating in the skin, the breast and the pancreas. NF-κβ-dependent pro-inflammatory signature included genes such as CXCL1, CXCL2, CXCL5, CCL3 as well as the pro-inflammatory cytokines IL-1β and IL-6, which, as mentioned above, are all potent chemo-attractants for several immune cell types including, neutrophils, macrophages and other leukocyte populations PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:20855962 Hypoxia induces NfkB activation. pharmacological inactivation of NFκB--another inducer of autophagy-prevents Cav-1 degradation References_end </body> </html> </notes> <label text="NFkB*"/> <clone/> <bbox w="80.0" h="40.0" x="2160.0" y="3570.0"/> </glyph> <glyph class="macromolecule" id="s4737_sa443" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha HUGO:PIK3CA hgnc_id:HGNC:8975 HGNC:8975 ENTREZ:5290 UNIPROT:P42336 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta HUGO:PIK3CB hgnc_id:HGNC:8976 HGNC:8976 ENTREZ:5291 UNIPROT:P42338 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta HUGO:PIK3CD hgnc_id:HGNC:8977 HGNC:8977 ENTREZ:5293 UNIPROT:O00329 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma HUGO:PIK3CG hgnc_id:HGNC:8978 HGNC:8978 ENTREZ:5294 UNIPROT:P48736 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG CASCADE:PDGF CASCADE:FGF CASCADE:GAST PMID:23523669 Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. PMID:11447289 PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast References_end </body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="3850.0" y="2320.0"/> </glyph> <glyph class="macromolecule" id="s4737_sa446" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha HUGO:PIK3CA hgnc_id:HGNC:8975 HGNC:8975 ENTREZ:5290 UNIPROT:P42336 DSN1 homolog, MIS12 kinetochore complex component HUGO:DSN1 hgnc_id:HGNC:16165 HGNC:16165 ENTREZ:79980 UNIPROT:Q9H410 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta HUGO:PIK3CB hgnc_id:HGNC:8976 HGNC:8976 ENTREZ:5291 UNIPROT:P42338 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta HUGO:PIK3CD hgnc_id:HGNC:8977 HGNC:8977 ENTREZ:5293 UNIPROT:O00329 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma HUGO:PIK3CG hgnc_id:HGNC:8978 HGNC:8978 ENTREZ:5294 UNIPROT:P48736 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: REACTOME:61074 KEGG:5290 ATLASONC:PIK3CAID415ch3q26 WIKI:PIK3CA phosphoinositide-3-kinase, catalytic, beta polypeptide REACTOME:61076 KEGG:5291 ATLASONC:GC_PIK3CB WIKI:PIK3CB phosphoinositide-3-kinase, catalytic, delta polypeptide REACTOME:61078 KEGG:5293 ATLASONC:PIK3CDID46261ch1p36 WIKI:PIK3CD phosphoinositide-3-kinase, catalytic, gamma polypeptide REACTOME:61080 KEGG:5294 ATLASONC:GC_PIK3CG WIKI:PIK3CG CASCADE:PDGF CASCADE:FGF CASCADE:GAST PMID:23523669 Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. PMID:11447289 PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast References_end </body> </html> </notes> <label text="p110*"/> <clone/> <bbox w="80.0" h="40.0" x="3850.0" y="2465.0"/> </glyph> <glyph class="macromolecule" id="s4738_sa444" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: phosphoinositide-3-kinase regulatory subunit 1 HUGO:PIK3R1 hgnc_id:HGNC:8979 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 phosphoinositide-3-kinase regulatory subunit 2 HUGO:PIK3R2 hgnc_id:HGNC:8980 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:FGF CASCADE:GAST PMID:23523669 Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. PMID:24751819 PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling PMID:11447289 FGF-induced stimulation of PI-3 kinase activity in Gab1 immunoprecipitates from wild-type fibroblasts. By contrast, PI-3 kinase activity was not detected in Gab1 immunoprecipitates from FGF-stimulated FRS2α-deficient fibroblasts. However, stimulation of PI-3 kinase was completely restored by ectopic expression of FRS2α cDNA in FRS2α-deficient fibroblasts (Fig. (Fig.33C). These experiments demonstrate that FRS2α functions as a site of assembly of an additional docking protein that brings to the complex its own effectors in addition to the effectors that bind directly to FRS2α. References_end </body> </html> </notes> <label text="PI3KR(p85)*"/> <clone/> <bbox w="80.0" h="40.0" x="3995.0" y="2295.0"/> </glyph> <glyph class="macromolecule" id="s4738_sa445" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: phosphoinositide-3-kinase regulatory subunit 1 HUGO:PIK3R1 hgnc_id:HGNC:8979 HGNC:8979 ENTREZ:5295 UNIPROT:P27986 phosphoinositide-3-kinase regulatory subunit 2 HUGO:PIK3R2 hgnc_id:HGNC:8980 HGNC:8980 ENTREZ:5296 UNIPROT:O00459 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:PDGF CASCADE:FGF CASCADE:GAST PMID:23523669 Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. PMID:24751819 PMID:11687500 The class IA PI3Ks, which transmit signals from tyrosine kinase-coupled receptors, are heterodimeric proteins having a p110 catalytic subunit associated with a p85, p55, or p50 regulatory subunit. PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling PMID:11447289 FGF-induced stimulation of PI-3 kinase activity in Gab1 immunoprecipitates from wild-type fibroblasts. By contrast, PI-3 kinase activity was not detected in Gab1 immunoprecipitates from FGF-stimulated FRS2α-deficient fibroblasts. However, stimulation of PI-3 kinase was completely restored by ectopic expression of FRS2α cDNA in FRS2α-deficient fibroblasts (Fig. (Fig.33C). These experiments demonstrate that FRS2α functions as a site of assembly of an additional docking protein that brings to the complex its own effectors in addition to the effectors that bind directly to FRS2α. References_end </body> </html> </notes> <label text="PI3KR(p85)*"/> <clone/> <bbox w="80.0" h="40.0" x="3995.0" y="2395.0"/> </glyph> <glyph class="macromolecule" id="s4739_sa519" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: early growth response 1 HUGO:EGR1 hgnc_id:HGNC:3238 HGNC:3238 ENTREZ:1958 UNIPROT:P18146 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:TGFB PMID:17559085 The human p300 gene has been recently cloned. The regulatory region is highly GC-rich, and contains six early growth response 1 (Egr-1) binding sites, along with serum response elements and Sp1 binding sites (Yu et al., 2004). Ectopic expression of Egr-1 in skin fibroblasts by itself stimulated basal p300 gene expression, and further enhanced the stimulation induced by TGF-β. Furthermore, reporter constructs driven by p300 promoter fragments harboring mutations in the Egr-1 binding sites failed to respond to TGF-β in transient transfection assays (Ghosh et al., unpublished data). These observations establish a critical role for Egr-1 in the regulation of p300 gene expression by TGF-β in normal fibroblasts. References_end </body> </html> </notes> <label text="EGR1"/> <clone/> <bbox w="80.0" h="40.0" x="5180.0" y="3700.0"/> </glyph> <glyph class="macromolecule" id="s4739_sa520" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: early growth response 1 HUGO:EGR1 hgnc_id:HGNC:3238 HGNC:3238 ENTREZ:1958 UNIPROT:P18146 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:TGFB PMID:17559085 The human p300 gene has been recently cloned. The regulatory region is highly GC-rich, and contains six early growth response 1 (Egr-1) binding sites, along with serum response elements and Sp1 binding sites (Yu et al., 2004). Ectopic expression of Egr-1 in skin fibroblasts by itself stimulated basal p300 gene expression, and further enhanced the stimulation induced by TGF-β. Furthermore, reporter constructs driven by p300 promoter fragments harboring mutations in the Egr-1 binding sites failed to respond to TGF-β in transient transfection assays (Ghosh et al., unpublished data). These observations establish a critical role for Egr-1 in the regulation of p300 gene expression by TGF-β in normal fibroblasts. References_end </body> </html> </notes> <label text="EGR1"/> <clone/> <bbox w="80.0" h="40.0" x="5180.0" y="3600.0"/> </glyph> <glyph class="macromolecule" id="s4740_sa561" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: matrix metallopeptidase 2 HUGO:MMP2 hgnc_id:HGNC:7166 HGNC:7166 ENTREZ:4313 UNIPROT:P08253 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:INTEGRIN PMID:11112697 TNF-α upregulates MT1-MMP (MMP14) mRNA in organ-cultured human skin and dermal fibroblasts in a collagen environment NF-κB inhibitor, SN50, blocks TNF-α and collagen mediated MT1-MMP expression and pro-MMP-2 activation. PMID:1323219 MMP2 and TIMP2 are axpressed by CAFS References_end </body> </html> </notes> <label text="MMP2"/> <clone/> <bbox w="80.0" h="40.0" x="5030.0" y="4690.0"/> </glyph> <glyph class="macromolecule" id="s4740_sa562" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: matrix metallopeptidase 2 HUGO:MMP2 hgnc_id:HGNC:7166 HGNC:7166 ENTREZ:4313 UNIPROT:P08253 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:TNF CASCADE:INTEGRIN PMID:11112697 TNF-α upregulates MT1-MMP (MMP14) mRNA in organ-cultured human skin and dermal fibroblasts in a collagen environment NF-κB inhibitor, SN50, blocks TNF-α and collagen mediated MT1-MMP expression and pro-MMP-2 activation. PMID:1323219 MMP2 and TIMP2 are axpressed by CAFS References_end </body> </html> </notes> <label text="MMP2"/> <clone/> <bbox w="80.0" h="40.0" x="5030.0" y="4790.0"/> </glyph> <glyph class="macromolecule" id="s4741_sa572" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin linked kinase HUGO:ILK hgnc_id:HGNC:6040 HGNC:6040 ENTREZ:3611 UNIPROT:Q13418 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:11696562 Integrin-linked kinase (ILK) is a binding partner of the integrin 1 and 3 subunits and is involved in the signal transduction from integrin receptors The activity is stimulated in a phosphatidylinositol (PI) 3-kinase–dependent manner and likely involves binding of the phosphoinositide phospholipid product of PI 3-kinase, PI 3,4,5-triphosphate, to the PH-like domain of ILK ILK has been shown recently to directly phosphorylate proteins such as PKB (PKB/Akt) on ser 473. PMID:15905178 Knock-down of ILK by small, interfering RNA (siRNA) attenuated Akt phosphorylation in response to ligation of beta1 integrin by collagen or activating antibody and enhanced fibroblast apoptosis in response to collagen contraction. PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast PMID:25100717 Probably colagen signaling activates NFkB via ILK ILK is involved in an alternative activation of NF-κB signaling by modulating the phosphorylation of p65 at Ser-536 (Cre-mediated ILK deletion in ilkfl/fl MEFs demonstrates that LPS-induced p65 Ser-536 phosphorylation was inhibited by ILK deficiency). PMID:24527345 Integrins are Modulators of Transforming Growth Factor Beta Signaling in Fibroblasts; integrin-linked kinase-deficient dermal fibroblasts isolated from newborn mice fail to express alpha–smooth muscle actin and to show Smad2 and Smad3 phosphorylation upon stimulation by exogenous TGF-β1. PMID:25268583 Cross-talk processes between TGF-b and ILK are crucial for myoﬁbroblast formation, as ILK-deﬁcient dermal ﬁbroblasts exhibit impaired responses to TGF-b receptor stimulation. ILK prevents TGFBR2 ubiquitination and degradation. References_end </body> </html> </notes> <label text="ILK"/> <clone/> <bbox w="80.0" h="40.0" x="6280.0" y="2290.0"/> </glyph> <glyph class="macromolecule" id="s4741_sa573" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin linked kinase HUGO:ILK hgnc_id:HGNC:6040 HGNC:6040 ENTREZ:3611 UNIPROT:Q13418 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:11696562 Integrin-linked kinase (ILK) is a binding partner of the integrin 1 and 3 subunits and is involved in the signal transduction from integrin receptors The activity is stimulated in a phosphatidylinositol (PI) 3-kinase–dependent manner and likely involves binding of the phosphoinositide phospholipid product of PI 3-kinase, PI 3,4,5-triphosphate, to the PH-like domain of ILK ILK has been shown recently to directly phosphorylate proteins such as PKB (PKB/Akt) on ser 473. PMID:15905178 Knock-down of ILK by small, interfering RNA (siRNA) attenuated Akt phosphorylation in response to ligation of beta1 integrin by collagen or activating antibody and enhanced fibroblast apoptosis in response to collagen contraction. PMID:27111285 ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast PMID:25100717 Probably colagen signaling activates NFkB via ILK ILK is involved in an alternative activation of NF-κB signaling by modulating the phosphorylation of p65 at Ser-536 (Cre-mediated ILK deletion in ilkfl/fl MEFs demonstrates that LPS-induced p65 Ser-536 phosphorylation was inhibited by ILK deficiency). PMID:24527345 Integrins are Modulators of Transforming Growth Factor Beta Signaling in Fibroblasts; integrin-linked kinase-deficient dermal fibroblasts isolated from newborn mice fail to express alpha–smooth muscle actin and to show Smad2 and Smad3 phosphorylation upon stimulation by exogenous TGF-β1. PMID:25268583 Cross-talk processes between TGF-b and ILK are crucial for myoﬁbroblast formation, as ILK-deﬁcient dermal ﬁbroblasts exhibit impaired responses to TGF-b receptor stimulation. ILK prevents TGFBR2 ubiquitination and degradation. References_end </body> </html> </notes> <label text="ILK"/> <clone/> <bbox w="80.0" h="40.0" x="6280.0" y="2420.0"/> </glyph> <glyph class="macromolecule" id="s4742_sa592" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ETS proto-oncogene 1, transcription factor HUGO:ETS1 hgnc_id:HGNC:3488 HGNC:3488 ENTREZ:2113 UNIPROT:P14921 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:15001984 Tenascin-C upregulation by transforming growth factor-β in human dermal fibroblasts involves Smad3, Sp1, and Ets1 Smad3 complex interact with SP1 and ETS1 and induces activity of TN-C promoter. References_end </body> </html> </notes> <label text="ETS1"/> <clone/> <bbox w="80.0" h="40.0" x="1930.0" y="4160.0"/> </glyph> <glyph class="macromolecule" id="s4742_sa594" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: ETS proto-oncogene 1, transcription factor HUGO:ETS1 hgnc_id:HGNC:3488 HGNC:3488 ENTREZ:2113 UNIPROT:P14921 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: CASCADE:TGFB PMID:15001984 Tenascin-C upregulation by transforming growth factor-β in human dermal fibroblasts involves Smad3, Sp1, and Ets1 Smad3 complex interact with SP1 and ETS1 and induces activity of TN-C promoter. References_end </body> </html> </notes> <label text="ETS1"/> <clone/> <bbox w="80.0" h="40.0" x="1930.0" y="4070.0"/> </glyph> <glyph class="macromolecule" id="s4743_sa633" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Rho associated coiled-coil containing protein kinase 1 HUGO:ROCK1 hgnc_id:HGNC:10251 HGNC:10251 ENTREZ:6093 UNIPROT:Q13464 Rho associated coiled-coil containing protein kinase 2 HUGO:ROCK2 hgnc_id:HGNC:10252 HGNC:10252 ENTREZ:9475 UNIPROT:O75116 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:LIF CASCADE:TGFB PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1 Actomyosin contractility in CAFs, as in many other cell types, results from phosphorylation of MLC2 in myosin II downstream of the Rho kinases ROCK I and II PMID:21840487 ROCK acts together with JAK1, in regulation of actomyosin contractility treatment with ROCK inhibitors reduced phosphorylation of STAT3 in CAFs ROCK-induced STAT3 phosphorylation required JAK kinase activity PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). At the cell periphery, on the other hand, MLCK but not ROCK appears to be the kinase responsible for phosphorylating MLC. These results suggest that ROCK and MLCK play distinct roles in spatial regulation of MLC phosphorylation. PMID:24857661 Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-β1 stimulation Rho–ROCK function is required only in stromal fibroblasts for collective SCC invasion References_end </body> </html> </notes> <label text="ROCK*"/> <clone/> <bbox w="80.0" h="40.0" x="6930.0" y="3360.0"/> </glyph> <glyph class="macromolecule" id="s4743_sa635" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Rho associated coiled-coil containing protein kinase 1 HUGO:ROCK1 hgnc_id:HGNC:10251 HGNC:10251 ENTREZ:6093 UNIPROT:Q13464 Rho associated coiled-coil containing protein kinase 2 HUGO:ROCK2 hgnc_id:HGNC:10252 HGNC:10252 ENTREZ:9475 UNIPROT:O75116 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MOTILITY Maps_Modules_end References_begin: CASCADE:LIF CASCADE:TGFB PMID:18037882 Rho–ROCK function is required in leading fibroblasts probably downstream of integrins a5b1 and a3b1 Actomyosin contractility in CAFs, as in many other cell types, results from phosphorylation of MLC2 in myosin II downstream of the Rho kinases ROCK I and II PMID:21840487 ROCK acts together with JAK1, in regulation of actomyosin contractility treatment with ROCK inhibitors reduced phosphorylation of STAT3 in CAFs ROCK-induced STAT3 phosphorylation required JAK kinase activity PMID:10953004 ROCK not only inhibits myosin phosphatase but also phosphorylates MLC directly in the center of cells (fibroblasts). At the cell periphery, on the other hand, MLCK but not ROCK appears to be the kinase responsible for phosphorylating MLC. These results suggest that ROCK and MLCK play distinct roles in spatial regulation of MLC phosphorylation. PMID:24857661 Long-term stimulation of both TGF-β and LIF cytokines also upregulated RhoA small GTPase and myosin light chain 2 (MLC2) proteins, leading to an increase in MLC2 phosphorylation at ser19, which attests for an increased activity (Figure S2D). Finally, forced expression of an active form of ROCK (ROCK-ER) (Croft and Olson, 2006) following 4-hydroxytamoxifen (4OHT) treatment was sufficient to induce hDF contractility (Figure S2E), proinvasive capacity (Figures S2Fa and b), and MLC2 phosphorylation (Figure S2G) and also rescued the inhibitory effect of P6 or anti-LIF antibody treatments under TGF-β1 stimulation Rho–ROCK function is required only in stromal fibroblasts for collective SCC invasion References_end </body> </html> </notes> <label text="ROCK*"/> <clone/> <bbox w="80.0" h="40.0" x="6930.0" y="3460.0"/> </glyph> <glyph class="simple chemical" id="s4744_sa634" compartmentRef="c5_ca5"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="6678.75" y="3166.875"/> </glyph> <glyph class="simple chemical" id="s4744_sa686" compartmentRef="c5_ca5"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="6278.75" y="3156.875"/> </glyph> <glyph class="simple chemical" id="s4744_sa762" compartmentRef="c5_ca5"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="5938.75" y="3166.875"/> </glyph> <glyph class="simple chemical" id="s4744_sa854" compartmentRef="c5_ca5"> <label text="GDP"/> <clone/> <bbox w="62.5" h="26.25" x="5008.75" y="2581.875"/> </glyph> <glyph class="simple chemical" id="s4745_sa636" compartmentRef="c5_ca5"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="6765.0" y="3167.5"/> </glyph> <glyph class="simple chemical" id="s4745_sa685" compartmentRef="c5_ca5"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="6345.0" y="3157.5"/> </glyph> <glyph class="simple chemical" id="s4745_sa761" compartmentRef="c5_ca5"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="5835.0" y="3167.5"/> </glyph> <glyph class="simple chemical" id="s4745_sa853" compartmentRef="c5_ca5"> <label text="GTP"/> <clone/> <bbox w="70.0" h="25.0" x="4855.0" y="2577.5"/> </glyph> <glyph class="macromolecule" id="s4746_sa660" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta 1 HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137 transforming growth factor beta 2 HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812 transforming growth factor beta 3 HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF PMID:21098712 Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:23784029, PMID:16572188, PMID:8515656 TGF-β1 treatment successfully transformed primary resting fibroblasts into CAFs PMID:19038247 TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3. Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1–3 and ERK inhibition reduces TGFβ-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGFβ [9]. Similarly, p38 MAPK has been shown to be central to TGFβ mediated-collagen and fibronectin expression in SSc fibroblasts [10]. PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:18423981 Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. PMID:23034983 Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects PMID:21041659 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts PMID:17768418 TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). ??? both TGF-β1 and TGF-β2 are up-regulated in CAFs PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, PMID:17979848 TGF-β promotes the generation and function of Treg cells TGF-β is able to convert CD4+CD25− non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="3510.0" y="4640.0"/> </glyph> <glyph class="macromolecule" id="s4747_sa661" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1 hgnc_id:HGNC:6714 HGNC:6714 ENTREZ:4052 UNIPROT:Q14766 latent transforming growth factor beta binding protein 2 HUGO:LTBP2 hgnc_id:HGNC:6715 HGNC:6715 ENTREZ:4053 UNIPROT:Q14767 latent transforming growth factor beta binding protein 3 HUGO:LTBP3 hgnc_id:HGNC:6716 HGNC:6716 ENTREZ:4054 UNIPROT:Q9NS15 latent transforming growth factor beta binding protein 4 HUGO:LTBP4 hgnc_id:HGNC:6717 HGNC:6717 ENTREZ:8425 UNIPROT:Q8N2S1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LTBP*"/> <bbox w="80.0" h="40.0" x="3510.0" y="4710.0"/> </glyph> <glyph class="macromolecule" id="s4748_sa662" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGFB induced factor homeobox 1 HUGO:TGIF1 hgnc_id:HGNC:11776 HGNC:11776 ENTREZ:7050 UNIPROT:Q15583 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LAP"/> <bbox w="80.0" h="40.0" x="3510.0" y="4770.0"/> <glyph class="unit of information" id="_012e7330-d03f-47fc-8efc-a1343fb9c19e"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="3525.0" y="4765.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4749_sa21" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 2 HUGO:IGF2 hgnc_id:HGNC:5466 HGNC:5466 ENTREZ:3481 UNIPROT:P01344 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:17600088 IIntegrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. PMID:24668028 IGF2 expressed by CAFs promotes tumor growth PMID:11237532 In breast cancers, both IGF-I and IGF-II are expressed in the stromal ﬁbroblasts and expression of IGF-II in particular correlates with tumor progression PMID:15003992 TGF-β induced the myofibroblast phenotype via a CTGF-dependent pathway, CTGF mediates EGF-stimulated proliferation and IGF-2-induced differentiation of fibroblasts References_end </body> </html> </notes> <label text="IGF2"/> <bbox w="80.0" h="40.0" x="3970.0" y="4431.0"/> </glyph> <glyph class="macromolecule" id="s4750_sa691" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: CDC42 binding protein kinase alpha HUGO:CDC42BPA hgnc_id:HGNC:1737 HGNC:1737 ENTREZ:8476 UNIPROT:Q5VT25 CDC42 binding protein kinase beta HUGO:CDC42BPB hgnc_id:HGNC:1738 HGNC:1738 ENTREZ:9578 UNIPROT:Q9Y5S2 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: PMID:15723050 Cdc42–MRCK signal mediates myosin-dependent cell motility (non fibroblast data) PMID:15882626 Cdc42 and MRCK Activate Nuclear Movement to Reorient the MTOC (The microtubule-organizing center )in fibroblasts References_end </body> </html> </notes> <label text="MRCK*"/> <clone/> <bbox w="80.0" h="40.0" x="5900.0" y="3240.0"/> </glyph> <glyph class="macromolecule" id="s4750_sa699" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: CDC42 binding protein kinase alpha HUGO:CDC42BPA hgnc_id:HGNC:1737 HGNC:1737 ENTREZ:8476 UNIPROT:Q5VT25 CDC42 binding protein kinase beta HUGO:CDC42BPB hgnc_id:HGNC:1738 HGNC:1738 ENTREZ:9578 UNIPROT:Q9Y5S2 Identifiers_end Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: PMID:15723050 Cdc42–MRCK signal mediates myosin-dependent cell motility (non fibroblast data) PMID:15882626 Cdc42 and MRCK Activate Nuclear Movement to Reorient the MTOC (The microtubule-organizing center )in fibroblasts References_end </body> </html> </notes> <label text="MRCK*"/> <clone/> <bbox w="80.0" h="40.0" x="5900.0" y="3340.0"/> </glyph> <glyph class="macromolecule" id="s4751_sa698" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: LIF, interleukin 6 family cytokine HUGO:LIF hgnc_id:HGNC:6596 HGNC:6596 ENTREZ:3976 UNIPROT:P15018 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:TNF CASCADE:LIF PMID:24857661 LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, LIF as the major cytokine mediating STAT3 phosphorylation upon TGF-β1 stimulation. TGF-β1 relies on a LIF/GP130-IL6ST/JAK1 signaling cascade to induce STAT3 activation. LIF signaling mediates onset of a proinvasive microenvironment by proinvasive fibroblast activation and actomyosin contractility regulation independent of α-SMA expression. References_end </body> </html> </notes> <label text="LIF"/> <bbox w="80.0" h="40.0" x="470.0" y="3321.5"/> </glyph> <glyph class="macromolecule" id="s4753_sa744" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: platelet derived growth factor subunit A HUGO:PDGFA hgnc_id:HGNC:8799 HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet derived growth factor subunit B HUGO:PDGFB hgnc_id:HGNC:8800 HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC hgnc_id:HGNC:8801 HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:23123598 paracrine PDGF stimulation of CAFs induces production of the prototypical pro-angiogenic inducer fibroblast growth factor (FGF)-2 in both cervical carcinomas and melanoma [11] and [85]. Interestingly, CAFs activated by PDGF-CC in melanomas also secrete the extracellular matrix protein osteopontin, the action of which is known to synergistically stimulate angiogenesis together with FGF-2 and promote autocrine VEGF-A signaling in endothelial cells PMID:15207817; PMID:19118022 PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Tumor fibroblasts a recruted by PDGF PMID:18232728 Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. PMID:19111878 PDGF-C is upregulated in TAFs derived from refractory tumors and that PDGF-C, together with VEGF-A, mediates the angiogenesis induced by such TAFs in vivo. This study also demonstrates that inhibition of PDGF-C may reduce tumor angiogenesis and growth in vivo. PMID:26921338 TGFB induces expression of PDGFB and PDGFR in CAFs and indirectly suppresses PEDF expression via PDGFB signaling References_end </body> </html> </notes> <label text="PDGF*"/> <bbox w="80.0" h="40.0" x="4200.0" y="4746.0"/> </glyph> <glyph class="nucleic acid feature" id="s4754_sa776" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR320A Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:22179046 MiR-320 is a Pten target in fibroblasts that suppresses tumor growth Ets2 is a direct target of miR-320 in fibroblasts Mmp9 and Emilin2 are directly regulated by miR-320 via their 3′ UTR target sequences References_end </body> </html> </notes> <label text="MIR320A"/> <bbox w="90.0" h="25.0" x="2745.0" y="2807.5"/> <glyph class="unit of information" id="_63d44722-d1f9-48aa-bf8b-cdd9a77fb778"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2775.0" y="2802.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4755_sa792" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: insulin like growth factor 1 HUGO:IGF1 hgnc_id:HGNC:5464 HGNC:5464 ENTREZ:3479 UNIPROT:P05019 Identifiers_end References_begin: CASCADE:TGFB PMID:11237532 ; PMID:19631971 In breast cancers, both IGF-I and IGF-II are expressed in the stromal ﬁbroblasts and expression of IGF-II in particular correlates with tumor progression PMID:12181198 IGF-I potently stimulated proliferation of TGF-β1-activated myofibroblasts without reversing activated fibrogenic phenotype. We conclude that TGF-β1 and IGF-I both stimulate type I collagen synthesis but have differential effects on activated phenotype and proliferation. TGF-β1 induces IGF-I expression in CCD-18Co fibroblast cells. References_end </body> </html> </notes> <label text="IGF1"/> <bbox w="80.0" h="40.0" x="3850.0" y="4431.0"/> </glyph> <glyph class="macromolecule" id="s4756_sa798" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: amphiregulin HUGO:AREG hgnc_id:HGNC:651 HGNC:651 ENTREZ:374 UNIPROT:P15514 Identifiers_end References_begin: MODULE:GROWTH_FACTORS_PRODUCTION PMID:23010081 Celecoxib (specific COX-2 inhibitor)increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation and increase colon TAFs proliferation in the presence of EGF. Also it induces neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist; EGF signaling induces AREG release. References_end </body> </html> </notes> <label text="AREG"/> <bbox w="80.0" h="40.0" x="3470.0" y="4430.0"/> </glyph> <glyph class="macromolecule" id="s4757_sa469" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: caveolin 1 HUGO:CAV1 hgnc_id:HGNC:1527 HGNC:1527 ENTREZ:857 UNIPROT:Q03135 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:20855962 Cav-1 behaves as a tumor suppressor in fibroblasts PMID:21729786 Stroma of human breast, kidney and colon carcinoma and melanoma metastases are enriched in Cav1-expressing fibroblasts caveolin-1 (Cav1) favors cell elongation in three-dimensional cultures and promotes Rho- and force-dependent contraction, matrix alignment, and microenvironment stiffening through regulation of p190RhoGAP. In turn, microenvironment remodeling by Cav1 fibroblasts forces cell elongation. Cav1 expression in breast CAFs correlates with low survival PMID:18458534; PMID:19411448 Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy. PMID:26828520 CAV1 and Podoplanin are markers of fibroblast activation PMID:17517963 Caveolin-1-deficient cells lose normal cell polarity, exhibit impaired wound healing, and have decreased Rho and increased Rac and Cdc42 GTPase activities. Directional persistency of migration is lost, and the cells show an impaired response to external directional stimuli. Both Src inactivation and p190RhoGAP knockdown restore the wild-type phenotype to caveolin-1-deficient cells, suggesting that caveolin-1 stimulates normal Rho GTP loading through inactivation of the Src-p190RhoGAP pathway. These findings highlight the importance of caveolin-1 in the establishment of cell polarity during directional migration through coordination of the signaling of Src kinase and Rho GTPases. caveolin-1 deficiency has been implicated in the aggressiveness of breast cancer stromal fibroblasts PMID:21051947 bone marrow-derived stromal cells from Cav-1(-/-) mice had elevated levels of miR-31 hypoxia-induced degradation of Cav-1 via HIF1 and NFKB , a loss of stromal fibroblast Cav-1 is a biomarker for chronic hypoxia, oxidative stress and autophagy in the tumor microenvironment. PMID:25364523; PMID:22411312; PMID:11102446 CAV1 could inhibit growth factor signaling (EGFR and TGFB) and decrease prolifiration of fibroblasts. Cav-1 interacts with the Type I TGF-beta receptor. Additionally, Cav-1 is able to suppress TGF-beta-mediated phosphorylation of Smad-2 and subsequent downstream events. PMID:21150282 A loss of stromal Cav-1 is sufficient to dramatically increase tumor growth. Proteomic analysis of Cav-1 deficient fibroblasts provides evidence for the onset of a myofibroblast phenotype and mitochondrial oxidative stress. PMID:23907124 Loss of Cav-1 in the stroma and gain of monocarboxylate transporter 4 (MCT4) expression in the stroma have been found to be involved in the progression of DCIS to IDC PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="CAV1"/> <bbox w="80.0" h="40.0" x="3130.0" y="3170.0"/> </glyph> <glyph class="macromolecule" id="s4758_sa830" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 3 HUGO:FGF3 hgnc_id:HGNC:3681 HGNC:3681 ENTREZ:2248 UNIPROT:P11487 MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Identifiers_end References_begin: PMID:26183471 CAFs secrete more FGF-1/-3 than normal fibroblasts References_end </body> </html> </notes> <label text="FGF3"/> <bbox w="80.0" h="40.0" x="3870.0" y="4630.0"/> </glyph> <glyph class="macromolecule" id="s4759_sa831" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: fibroblast growth factor 1 HUGO:FGF1 hgnc_id:HGNC:3665 HGNC:3665 ENTREZ:2246 UNIPROT:P05230 Identifiers_end References_begin: PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts PMID:26183471 CAFs secrete more FGF-1/-3 than normal fibroblasts References_end </body> </html> </notes> <label text="FGF1"/> <bbox w="80.0" h="40.0" x="3490.0" y="4520.0"/> </glyph> <glyph class="macromolecule" id="s4760_sa834" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SOS Ras/Rac guanine nucleotide exchange factor 1 HUGO:SOS1 hgnc_id:HGNC:11187 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 SOS Ras/Rho guanine nucleotide exchange factor 2 HUGO:SOS2 hgnc_id:HGNC:11188 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:15863030 GRB2 forms a complex with SOS protein and activate it downstream of FGF signaling PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="SOS*"/> <clone/> <bbox w="80.0" h="40.0" x="5410.0" y="2480.0"/> </glyph> <glyph class="macromolecule" id="s4760_sa849" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: SOS Ras/Rac guanine nucleotide exchange factor 1 HUGO:SOS1 hgnc_id:HGNC:11187 HGNC:11187 ENTREZ:6654 UNIPROT:Q07889 SOS Ras/Rho guanine nucleotide exchange factor 2 HUGO:SOS2 hgnc_id:HGNC:11188 HGNC:11188 ENTREZ:6655 UNIPROT:Q07890 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:15863030 GRB2 forms a complex with SOS protein and activate it downstream of FGF signaling PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="SOS*"/> <clone/> <bbox w="80.0" h="40.0" x="5190.0" y="2580.0"/> </glyph> <glyph class="macromolecule" id="s4761_sa440" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: growth factor receptor bound protein 2 HUGO:GRB2 hgnc_id:HGNC:4566 HGNC:4566 ENTREZ:2885 UNIPROT:P62993 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:15567848 Canonicaly growth factor pathways activates ERK sigvaling via GRB2/SOS/RAS/RAF/MAPK pathway, probably in fibroblast too. PMID:11447289 Grb2 forms a complex with tyrosine-phosphorylated Shc in FGF-stimulated fibroblasts in an FRS2α-independent manner PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway EGFR induces SHC phosphorylation, directly interacts with GRB2 and induces formation of SHC:GRB2:SOS activated complex. PMID:12175651; PMID:10086337 Upon IGF-IR autophosphorylation the protein Shc is recruited to the receptor and becomes phosphorylated on tyrosine residues.36 Activated Shc then binds the adaptor Grb2 in an IRS-1-independent manner, leading to activation of the Ras-ERK pathway.36 This pathway of IGF-IR signaling has been most closely associated with cell differentiation and migration, but in some cases also can regulate the machinery of apoptosis, for example, in detachment-induced death, or anoikis, in fibroblasts. References_end </body> </html> </notes> <label text="GRB2"/> <clone/> <bbox w="80.0" h="40.0" x="5290.0" y="2210.0"/> </glyph> <glyph class="macromolecule" id="s4761_sa847" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: growth factor receptor bound protein 2 HUGO:GRB2 hgnc_id:HGNC:4566 HGNC:4566 ENTREZ:2885 UNIPROT:P62993 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:15567848 Canonicaly growth factor pathways activates ERK sigvaling via GRB2/SOS/RAS/RAF/MAPK pathway, probably in fibroblast too. PMID:11447289 Grb2 forms a complex with tyrosine-phosphorylated Shc in FGF-stimulated fibroblasts in an FRS2α-independent manner PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway EGFR induces SHC phosphorylation, directly interacts with GRB2 and induces formation of SHC:GRB2:SOS activated complex. PMID:12175651; PMID:10086337 Upon IGF-IR autophosphorylation the protein Shc is recruited to the receptor and becomes phosphorylated on tyrosine residues.36 Activated Shc then binds the adaptor Grb2 in an IRS-1-independent manner, leading to activation of the Ras-ERK pathway.36 This pathway of IGF-IR signaling has been most closely associated with cell differentiation and migration, but in some cases also can regulate the machinery of apoptosis, for example, in detachment-induced death, or anoikis, in fibroblasts. References_end </body> </html> </notes> <label text="GRB2"/> <clone/> <bbox w="80.0" h="40.0" x="5260.0" y="2430.0"/> </glyph> <glyph class="macromolecule" id="s4762_sa858" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Raf-1 proto-oncogene, serine/threonine kinase HUGO:RAF1 hgnc_id:HGNC:9829 HGNC:9829 ENTREZ:5894 UNIPROT:P04049 A-Raf proto-oncogene, serine/threonine kinase HUGO:ARAF hgnc_id:HGNC:646 HGNC:646 ENTREZ:369 UNIPROT:P10398 B-Raf proto-oncogene, serine/threonine kinase HUGO:BRAF hgnc_id:HGNC:1097 HGNC:1097 ENTREZ:673 UNIPROT:P15056 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:16227978 Ras GTPases comprise a large family of mostly membrane-resident proteins that shuttle between an inactive GDP-bound and active GTP-bound conformation105. The best-characterized family members are K-Ras, H-Ras and N-Ras. RasGTP can bind to a number of effector molecules, including the serine/threonine kinase Raf, phosphatidylinositol 3-kinase, RalGDS and others106. RasGTP recruits these proteins to the membrane compartment, which is crucial for their activation and signalling function. All three Raf family members, A-Raf, B-Raf and Raf-1, bind RasGTP as the first step in their activation process. Whereas RasGTP association might suffice to activate B-Raf, both Raf-1 and A-Raf undergo a complex series of activation steps that have not been entirely elucidated and involve changes in phosphorylation levels and protein interactions. For recent reviews on Raf isoforms and their activation mechanisms see Refs 1–3. All Raf isoforms can activate MAPK and ERK kinase (MEK) by phosphorylating two serines in the MEK ACTIVATION LOOP, PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="RAF*"/> <clone/> <bbox w="80.0" h="40.0" x="4920.0" y="2830.0"/> </glyph> <glyph class="macromolecule" id="s4762_sa859" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Raf-1 proto-oncogene, serine/threonine kinase HUGO:RAF1 hgnc_id:HGNC:9829 HGNC:9829 ENTREZ:5894 UNIPROT:P04049 A-Raf proto-oncogene, serine/threonine kinase HUGO:ARAF hgnc_id:HGNC:646 HGNC:646 ENTREZ:369 UNIPROT:P10398 B-Raf proto-oncogene, serine/threonine kinase HUGO:BRAF hgnc_id:HGNC:1097 HGNC:1097 ENTREZ:673 UNIPROT:P15056 Identifiers_end Maps_Modules_begin: MODULE:CORE MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGFR GASCADE:IGF1R PMID:16227978 Ras GTPases comprise a large family of mostly membrane-resident proteins that shuttle between an inactive GDP-bound and active GTP-bound conformation105. The best-characterized family members are K-Ras, H-Ras and N-Ras. RasGTP can bind to a number of effector molecules, including the serine/threonine kinase Raf, phosphatidylinositol 3-kinase, RalGDS and others106. RasGTP recruits these proteins to the membrane compartment, which is crucial for their activation and signalling function. All three Raf family members, A-Raf, B-Raf and Raf-1, bind RasGTP as the first step in their activation process. Whereas RasGTP association might suffice to activate B-Raf, both Raf-1 and A-Raf undergo a complex series of activation steps that have not been entirely elucidated and involve changes in phosphorylation levels and protein interactions. For recent reviews on Raf isoforms and their activation mechanisms see Refs 1–3. All Raf isoforms can activate MAPK and ERK kinase (MEK) by phosphorylating two serines in the MEK ACTIVATION LOOP, PMID:10567412; PMID:15567848 EGFR activates ERK via GRB2/SOS/RAS/RAF pathway References_end </body> </html> </notes> <label text="RAF*"/> <clone/> <bbox w="80.0" h="40.0" x="5140.0" y="2940.0"/> </glyph> <glyph class="macromolecule" id="s4763_sa942" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: plasminogen activator, urokinase HUGO:PLAU hgnc_id:HGNC:9052 HGNC:9052 ENTREZ:5328 UNIPROT:P00749 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: CASCADE:FGF CASCADE:EGF PMID:11021826 Fibroblastic expression (immunohistocheemistry) of both uPA and uPAR were positively correlated with tumor size. fibroblastic expression of PAI1 was related to the presence of invasion PMID:19631971 co-culturing fibroblasts with ovarian cancer cells (ES-2) led to induction of uPA in fibroblasts; the same effect was observed when the fibroblasts were grown in ES-2 cell-conditioned medium. The basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) were the cancer cell-derived paracrine factors inducing uPA transcription in the fibroblasts. References_end </body> </html> </notes> <label text="proPLAU*"/> <bbox w="80.0" h="40.0" x="850.0" y="3321.5"/> </glyph> <glyph class="macromolecule" id="s4764_sa945" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SERPINF1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26921338 (PEDF, SERPINF1) normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. PEDF treatment strongly elevated cytoplasmic PEDF levels in the activated fibroblasts, suggesting a positive feedback loop. References_end </body> </html> </notes> <label text="SERPINF1"/> <bbox w="80.0" h="40.0" x="2850.0" y="2430.0"/> </glyph> <glyph class="macromolecule" id="s4768_sa138" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-C motif chemokine ligand 7 HUGO:CCL7 hgnc_id:HGNC:10634 HGNC:10634 ENTREZ:6354 UNIPROT:P80098 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:19937793 Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. References_end </body> </html> </notes> <label text="CCL7"/> <bbox w="80.0" h="40.0" x="920.0" y="4080.0"/> </glyph> <glyph class="macromolecule" id="s4770_sa349" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 6 HUGO:TRAF6 hgnc_id:HGNC:12036 HGNC:12036 ENTREZ:7189 UNIPROT:Q9Y4K3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL1 Maps_Modules_end References_begin: PMID:19161412 , PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="1770.0" y="1740.0"/> </glyph> <glyph class="macromolecule" id="s4770_sa350" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TNF receptor associated factor 6 HUGO:TRAF6 hgnc_id:HGNC:12036 HGNC:12036 ENTREZ:7189 UNIPROT:Q9Y4K3 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS CASCADE:IL1 Maps_Modules_end References_begin: PMID:19161412 , PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1 and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. References_end </body> </html> </notes> <label text="TRAF6"/> <clone/> <bbox w="80.0" h="40.0" x="1950.0" y="1740.0"/> </glyph> <glyph class="macromolecule" id="s4771_sa697" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 2 HUGO:JAK2 hgnc_id:HGNC:6192 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:PLAU CASCADE:IFNG Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="JAK2"/> <clone/> <bbox w="80.0" h="40.0" x="400.0" y="2100.0"/> <glyph class="state variable" id="_764fa147-375a-4e27-93f2-b013c2822807"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="392.5" y="2115.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4771_sa725" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 2 HUGO:JAK2 hgnc_id:HGNC:6192 HGNC:6192 ENTREZ:3717 UNIPROT:O60674 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:PLAU CASCADE:IFNG Maps_Modules_end References_begin: PMID:14610620 JAK2 is a member of the Janus kinase family. JAK2 associated with IL13RA1 participates in signal transduction. PMID:19833085 IFNG receptor is assosiated with kinases JAK1 and JAK2 PMID:20406969, PMID:24091328, PMID:11867689 GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation, probably downstream of JAK2. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. PMID:27216177 FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. References_end </body> </html> </notes> <label text="JAK2"/> <clone/> <bbox w="80.0" h="40.0" x="940.0" y="2540.0"/> <glyph class="state variable" id="_a4b715a8-ade2-4d29-a940-d633b2091687"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="932.5" y="2555.0"/> </glyph> </glyph> <glyph class="complex" id="s4773_csa65" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:15187087 αvβ3 Integrin Interacts with the Transforming Growth Factor β (TGFβ) Type II Receptor to Potentiate the Proliferative Effects of TGFβ1 in Living Human Lung Fibroblasts PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="s4311"/> <clone/> <bbox w="100.0" h="120.0" x="7450.0" y="2770.0"/> <glyph class="macromolecule" id="s4774_sa601"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 3 HUGO:ITGB3 hgnc_id:HGNC:6156 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 TGFβ1-induced β3 Integrin Expression Is Dependent on αvβ3 Activation References_end </body> </html> </notes> <label text="ITGB3"/> <clone/> <bbox w="80.0" h="50.0" x="7460.0" y="2825.0"/> <glyph class="unit of information" id="_6fe13b7e-94f1-4727-8c9d-3ee8c19266f5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7477.5" y="2820.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4775_sa602"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <clone/> <bbox w="80.0" h="50.0" x="7460.0" y="2775.0"/> <glyph class="unit of information" id="_954b817f-22ef-4e66-ad32-79023ddaa9d4"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7477.5" y="2770.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4773_csa63" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB3 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:15187087 αvβ3 Integrin Interacts with the Transforming Growth Factor β (TGFβ) Type II Receptor to Potentiate the Proliferative Effects of TGFβ1 in Living Human Lung Fibroblasts PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="s4311"/> <clone/> <bbox w="100.0" h="120.0" x="7640.0" y="2560.0"/> <glyph class="macromolecule" id="s4774_sa582"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 3 HUGO:ITGB3 hgnc_id:HGNC:6156 HGNC:6156 ENTREZ:3690 UNIPROT:P05106 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 TGFβ1-induced β3 Integrin Expression Is Dependent on αvβ3 Activation References_end </body> </html> </notes> <label text="ITGB3"/> <clone/> <bbox w="80.0" h="50.0" x="7650.0" y="2625.0"/> <glyph class="unit of information" id="_49c8f838-8f35-459f-8c2a-8cf09179ddd5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7667.5" y="2620.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4775_sa583"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <clone/> <bbox w="80.0" h="50.0" x="7650.0" y="2565.0"/> <glyph class="unit of information" id="_3bd629dc-7fc2-44bd-a9a0-82e5f6cbaaf2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7667.5" y="2560.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4776_csa66" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:24309651;PMID:24639195 It has to be the αv: myofibroblast integrins activate latent TGF-β1. Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction PMID:22470492 treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="s4314"/> <clone/> <bbox w="100.0" h="120.0" x="7550.0" y="2940.0"/> <glyph class="macromolecule" id="s4777_sa603"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <clone/> <bbox w="80.0" h="50.0" x="7560.0" y="2945.0"/> <glyph class="unit of information" id="_5b210352-a1ab-4078-9d8b-770e852e5c15"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7577.5" y="2940.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4778_sa604"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 5 HUGO:ITGB5 hgnc_id:HGNC:6160 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. uPA (PLAU) signaling has a negative influence on myofibroblast differentiation; References_end </body> </html> </notes> <label text="ITGB5"/> <clone/> <bbox w="80.0" h="50.0" x="7560.0" y="2985.0"/> <glyph class="state variable" id="_3cac1d76-e473-44f5-a642-92480a14c84e"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7555.0" y="3004.9602"/> </glyph> <glyph class="unit of information" id="_c0c614f2-3835-4dbd-8c3d-e7acec621aff"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7577.5" y="2980.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4776_csa64" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB5 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:24309651;PMID:24639195 It has to be the αv: myofibroblast integrins activate latent TGF-β1. Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction PMID:22470492 treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="s4314"/> <clone/> <bbox w="100.0" h="120.0" x="7750.0" y="2750.0"/> <glyph class="macromolecule" id="s4777_sa584"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <clone/> <bbox w="80.0" h="50.0" x="7760.0" y="2755.0"/> <glyph class="unit of information" id="_96a5789e-7c30-491a-898e-aceb36584be9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7777.5" y="2750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4778_sa585"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 5 HUGO:ITGB5 hgnc_id:HGNC:6160 HGNC:6160 ENTREZ:3693 UNIPROT:P18084 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:22470492 Degradation of internalized αvβ5 integrin is controlled by uPAR bound uPA: effect on β1 integrin activity and α-SMA stress fiber assembly. uPA (PLAU) signaling has a negative influence on myofibroblast differentiation; References_end </body> </html> </notes> <label text="ITGB5"/> <clone/> <bbox w="80.0" h="50.0" x="7760.0" y="2805.0"/> <glyph class="state variable" id="_bfc061af-777f-4212-90e8-47447df5da90"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="7755.0" y="2824.9602"/> </glyph> <glyph class="unit of information" id="_3ab2267a-d865-4b24-a22a-c38bf4cf46b5"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7777.5" y="2800.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4779_csa67" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB6 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:20075988 the integrins α3β1, αvβ5 and—most notably—αvβ6 control TGF‐β activity or signalling in fibrosis. PMID:23673986 Expression of fibronectin receptro αvβ6 in CAFs is a negative factor for patient survival. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ6 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="s4329"/> <clone/> <bbox w="100.0" h="120.0" x="7870.0" y="2940.0"/> <glyph class="macromolecule" id="s4780_sa606"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 6 HUGO:ITGB6 hgnc_id:HGNC:6161 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:23673986 Expression of fibronectin receptro αvβ6 in CAFs is a negative factor for patient survival. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ6 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="ITGB6"/> <clone/> <bbox w="80.0" h="50.0" x="7880.0" y="2995.0"/> <glyph class="unit of information" id="_586a8e12-c05a-4312-899c-7427d4a519fa"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7897.5" y="2990.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4781_sa607"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <clone/> <bbox w="80.0" h="50.0" x="7880.0" y="2945.0"/> <glyph class="unit of information" id="_38f32d92-beda-4306-ab1b-64d92cc90b0d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7897.5" y="2940.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4779_csa77" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGAV:ITGB6 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:20075988 the integrins α3β1, αvβ5 and—most notably—αvβ6 control TGF‐β activity or signalling in fibrosis. PMID:23673986 Expression of fibronectin receptro αvβ6 in CAFs is a negative factor for patient survival. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ6 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="s4329"/> <clone/> <bbox w="100.0" h="120.0" x="7670.0" y="3120.0"/> <glyph class="macromolecule" id="s4780_sa649"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 6 HUGO:ITGB6 hgnc_id:HGNC:6161 HGNC:6161 ENTREZ:3694 UNIPROT:P18564 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:23673986 Expression of fibronectin receptro αvβ6 in CAFs is a negative factor for patient survival. PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ6 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC References_end </body> </html> </notes> <label text="ITGB6"/> <clone/> <bbox w="80.0" h="50.0" x="7680.0" y="3165.0"/> <glyph class="unit of information" id="_2c662583-9f08-4c6e-9f61-b8d7ccb2ef1b"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7697.5" y="3160.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4781_sa650"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha V HUGO:ITGAV hgnc_id:HGNC:6150 HGNC:6150 ENTREZ:3685 UNIPROT:P06756 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:18353785 Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway* References_end </body> </html> </notes> <label text="ITGAV"/> <clone/> <bbox w="80.0" h="50.0" x="7680.0" y="3125.0"/> <glyph class="unit of information" id="_3b1e7be5-d7c9-4efe-8396-d802677751f2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7697.5" y="3120.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4784_csa75" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA3:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN References_end </body> </html> </notes> <label text="s4358"/> <clone/> <bbox w="100.0" h="120.0" x="7310.0" y="2610.0"/> <glyph class="macromolecule" id="s4785_sa643"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="7320.0" y="2620.0"/> <glyph class="unit of information" id="_244e1dec-7e61-4a22-9de6-9fdadfc041a6"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7337.5" y="2615.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4786_sa644"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 3 HUGO:ITGA3 hgnc_id:HGNC:6139 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:21666923 Integrin α3 blockade enhances microtopographical down-regulation of α-smooth muscle actin: role of microtopography in ECM regulation. PMID:18037882 Integrin a3 and a5 are important in leading fibroblasts in SCC. siRNA against integrin 3 or integrin 5 in stromal fibroblasts would prevent the invasion of SCC cells and Figure 4C shows that siRNA-mediated depletion of either integrin 3 or integrin 5 in stromal fibroblasts, but not in SCC cells, reduced the collective invasion of SCC cells. References_end </body> </html> </notes> <label text="ITGA3"/> <clone/> <bbox w="80.0" h="50.0" x="7320.0" y="2655.0"/> <glyph class="unit of information" id="_608db784-29e1-425f-9099-4043ff82d284"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7337.5" y="2650.0"/> </glyph> </glyph> </glyph> <glyph class="complex" id="s4784_csa71" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:ITGA3:ITGB1 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN References_end </body> </html> </notes> <label text="s4358"/> <clone/> <bbox w="100.0" h="120.0" x="7510.0" y="2380.0"/> <glyph class="macromolecule" id="s4785_sa630"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit beta 1 HUGO:ITGB1 hgnc_id:HGNC:6153 HGNC:6153 ENTREZ:3688 UNIPROT:P05556 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:PLAU PMID:9456329;PMID:11112697 Integrin α2β1 is a heterodimeric adhesive protein receptor belonging to the β1 subfamily. It serves as a collagen receptor on fibroblasts and platelets and additionally as a laminin receptor on epithelial and endothelial cells Collagen signaling nduces NF-κB Activity in fibroblasts probably via this receptor. PMID:22470492 Treatment with αvβ5 blocking antibody reduces integrin β1/matrix binding. increase in β5 cell-surface levels after uPA-silencing promotes β1-mediated cell attachment that correlates with a decrease in integrin β1 activity. References_end </body> </html> </notes> <label text="ITGB1"/> <clone/> <bbox w="80.0" h="40.0" x="7520.0" y="2380.0"/> <glyph class="unit of information" id="_d8165332-973a-4e0f-904b-cadce6d340fc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7537.5" y="2375.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4786_sa632"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 3 HUGO:ITGA3 hgnc_id:HGNC:6139 HGNC:6139 ENTREZ:3675 UNIPROT:P26006 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:21666923 Integrin α3 blockade enhances microtopographical down-regulation of α-smooth muscle actin: role of microtopography in ECM regulation. PMID:18037882 Integrin a3 and a5 are important in leading fibroblasts in SCC. siRNA against integrin 3 or integrin 5 in stromal fibroblasts would prevent the invasion of SCC cells and Figure 4C shows that siRNA-mediated depletion of either integrin 3 or integrin 5 in stromal fibroblasts, but not in SCC cells, reduced the collective invasion of SCC cells. References_end </body> </html> </notes> <label text="ITGA3"/> <clone/> <bbox w="80.0" h="50.0" x="7520.0" y="2415.0"/> <glyph class="unit of information" id="_0ce4e706-f8d6-4e05-bf19-36546896982f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="7537.5" y="2410.0"/> </glyph> </glyph> </glyph> <glyph class="macromolecule" id="s4790_sa615" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: integrin subunit alpha 1 HUGO:ITGA1 hgnc_id:HGNC:6134 HGNC:6134 ENTREZ:3672 UNIPROT:P56199 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26148229 Fibroblasts express the α1β1, α2β1 and α11β1 collagen-binding integrins PMID:19397781 alpha(1)beta(1) integrin is of importance not only for the differentiation of mesenchymal cells into myofibroblasts but also for the neovascularization and connective tissue organization and emphasize the importance of myofibroblasts in the pathophysiology of tissue repair, inflammation and tumour growth. References_end </body> </html> </notes> <label text="ITGA1"/> <bbox w="80.0" h="40.0" x="6800.0" y="1650.0"/> <glyph class="unit of information" id="_6543a976-2702-47aa-a700-b448062f18a9"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="6817.5" y="1645.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4791_sa538" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL1B Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:IL1 PMID:20138012 Tumor-enhancing activity of skin CAFs is NF-κB dependent and activatable by IL-1β PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:9242465 IL1B, FGF2, FGF1, FGF4, PDGF induce HGF expression and production in fibroblasts References_end </body> </html> </notes> <label text="trIL1B"/> <bbox w="80.0" h="40.0" x="590.0" y="3450.0"/> <glyph class="unit of information" id="_7d90751a-df49-4d8e-8562-17fdd14fa779"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="605.0" y="3445.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4792_sa139"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-C motif chemokine ligand 7 HUGO:CCL7 hgnc_id:HGNC:10634 HGNC:10634 ENTREZ:6354 UNIPROT:P80098 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:19937793 Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. References_end </body> </html> </notes> <label text="CCL7"/> <bbox w="80.0" h="40.0" x="920.0" y="4230.0"/> </glyph> <glyph class="simple chemical" id="s4793_sa85"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:20818174 L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ∼10-fold. References_end </body> </html> </notes> <label text="lactate"/> <bbox w="70.0" h="25.0" x="2725.0" y="4957.5"/> </glyph> <glyph class="simple chemical" id="s4794_sa99"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:25732824 CAFs have a higher capacity for glucose uptake than do fibroblasts References_end </body> </html> </notes> <label text="glucose"/> <bbox w="70.0" h="25.0" x="2965.0" y="4967.5"/> </glyph> <glyph class="simple chemical" id="s4806_sa131"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:23873014, PMID:19934056,PMID:22182446 Probably CAFS inhibit NK cells via PGE2 signaling. addition of the PGE2 inhibitor NS398 to cocultures restored the expression of NKp44 and NKp30. There is a correlation between PGE2 release and inhibitory functions in tumor fibroblasts. PMID:22182446 Increased levels of PGE2 were found in cocultured supernatants from HCC-derived fibroblasts, and up-regulated expression of IDO and COX-2 were detected in these cells. The expression of NKP30, NKG2D, granzyme B and perforin were partly restored by PGE2 inhibitor and IDO inhibitor and the production of TNF-α and IFN-γ were fully restored by them. References_end </body> </html> </notes> <label text="PGE2"/> <clone/> <bbox w="70.0" h="25.0" x="1075.0" y="4367.5"/> </glyph> <glyph class="simple chemical" id="s4806_sa387"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:23873014, PMID:19934056,PMID:22182446 Probably CAFS inhibit NK cells via PGE2 signaling. addition of the PGE2 inhibitor NS398 to cocultures restored the expression of NKp44 and NKp30. There is a correlation between PGE2 release and inhibitory functions in tumor fibroblasts. PMID:22182446 Increased levels of PGE2 were found in cocultured supernatants from HCC-derived fibroblasts, and up-regulated expression of IDO and COX-2 were detected in these cells. The expression of NKP30, NKG2D, granzyme B and perforin were partly restored by PGE2 inhibitor and IDO inhibitor and the production of TNF-α and IFN-γ were fully restored by them. References_end </body> </html> </notes> <label text="PGE2"/> <clone/> <bbox w="70.0" h="25.0" x="845.0" y="1367.5"/> </glyph> <glyph class="simple chemical" id="s4811_sa189"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:20823158 CAFs have been identified as a source of hyaluronan, and genetic ablation of the hyaluronan synthase gene (Has2) in fibroblasts strongly diminishes the entry of macrophages into the tumour microenvironment. References_end </body> </html> </notes> <label text="hyaluronan"/> <bbox w="70.0" h="25.0" x="5925.0" y="4957.5"/> </glyph> <glyph class="simple chemical" id="s4812_sa129" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:23873014, PMID:19934056,PMID:22182446 Probably CAFS inhibit NK cells via PGE2 signaling. addition of the PGE2 inhibitor NS398 to cocultures restored the expression of NKp44 and NKp30. There is a correlation between PGE2 release and inhibitory functions in tumor fibroblasts. PMID:22182446 Increased levels of PGE2 were found in cocultured supernatants from HCC-derived fibroblasts, and up-regulated expression of IDO and COX-2 were detected in these cells. The expression of NKP30, NKG2D, granzyme B and perforin were partly restored by PGE2 inhibitor and IDO inhibitor and the production of TNF-α and IFN-γ were fully restored by them. References_end </body> </html> </notes> <label text="PGE2"/> <bbox w="70.0" h="25.0" x="1075.0" y="4207.5"/> </glyph> <glyph class="nucleic acid feature" id="s4813_sa959" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTGER2 Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. PMID:21209948 PGE2 can induce IL-6 expression in fibroblasts through EP2 References_end </body> </html> </notes> <label text="PTGER2"/> <bbox w="70.0" h="25.0" x="1005.0" y="1997.5"/> </glyph> <glyph class="nucleic acid feature" id="s4814_sa960" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTGER2 Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. PMID:21209948 PGE2 can induce IL-6 expression in fibroblasts through EP2 References_end </body> </html> </notes> <label text="PTGER2"/> <bbox w="90.0" h="25.0" x="995.0" y="1857.5"/> <glyph class="unit of information" id="_c4d692fd-f6eb-43fb-97f9-23c372b28c5b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1030.0" y="1852.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4815_sa961" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR149 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs miR-149 mimics significantly suppressed the stimulatory effect of CAFs on GC cell proliferation, colony forming ability, migration and invasion; conversely, miR-149 inhibitors conferred NFs the enhancing effects. PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. References_end </body> </html> </notes> <label text="MIR149"/> <bbox w="90.0" h="25.0" x="2715.0" y="2562.25"/> <glyph class="unit of information" id="_4c146e5a-a00e-4292-9428-bdf6fa5fda51"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2745.0" y="2557.25"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4816_sa962" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR149 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: CASCADE:PGE PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. References_end </body> </html> </notes> <label text="MIR149"/> <bbox w="70.0" h="25.0" x="2565.0" y="2547.5"/> </glyph> <glyph class="complex" id="s4817_csa106" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:MIR149:PTGER2 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4817"/> <bbox w="100.0" h="120.0" x="1070.0" y="2080.0"/> <glyph class="nucleic acid feature" id="s4818_sa963"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR149 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs miR-149 mimics significantly suppressed the stimulatory effect of CAFs on GC cell proliferation, colony forming ability, migration and invasion; conversely, miR-149 inhibitors conferred NFs the enhancing effects. PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. References_end </body> </html> </notes> <label text="MIR149"/> <bbox w="90.0" h="25.0" x="1075.0" y="2137.5"/> <glyph class="unit of information" id="_0950a55a-fa05-42b6-aaf3-232e1b88dd59"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="1105.0" y="2132.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4824_sa964"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PTGER2 Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF Maps_Modules_end References_begin: PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. PMID:21209948 PGE2 can induce IL-6 expression in fibroblasts through EP2 References_end </body> </html> </notes> <label text="PTGER2"/> <bbox w="90.0" h="25.0" x="1075.0" y="2107.5"/> <glyph class="unit of information" id="_35aa50c9-8242-48c7-9c54-e068766f2492"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="1110.0" y="2102.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s4819_sa965" compartmentRef="c5_ca5"> <label text="csa106_degraded"/> <bbox w="30.0" h="30.0" x="1115.0" y="2255.0"/> </glyph> <glyph class="complex" id="s4820_csa107" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IL6:MIR149 Identifiers_end </body> </html> </notes> <label text="s4820"/> <bbox w="100.0" h="120.0" x="180.0" y="3140.0"/> <glyph class="nucleic acid feature" id="s4821_sa968"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR149 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: CASCADE:PGE PMID:25916550 miR-149 targets IL-6 mRNA and is downregulated in GC CAFs miR-149 mimics significantly suppressed the stimulatory effect of CAFs on GC cell proliferation, colony forming ability, migration and invasion; conversely, miR-149 inhibitors conferred NFs the enhancing effects. PGE2 receptor, PTGER2 and IL6, are potential targets of miR-149 PGE2 binds to EP2 and induces the hypermethylation and suppression of miR-149, reversing the downregulation of IL-6 and EP2 expression. References_end </body> </html> </notes> <label text="MIR149"/> <bbox w="90.0" h="25.0" x="185.0" y="3167.5"/> <glyph class="unit of information" id="_63529cff-2151-480a-8f82-3b2727d5718f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="215.0" y="3162.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4822_sa969"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL6 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:IL1 CASCADE:PGE PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:20138012 PTGS2, CXCL1, and CXCL2; the proinflammatory cytokines IL-1β and IL-6, CYR61 and OPN are upregulated in CAFs, probably downstream of IL1B via NFkB References_end </body> </html> </notes> <label text="IL6"/> <bbox w="90.0" h="25.0" x="185.0" y="3197.5"/> <glyph class="unit of information" id="_89ff98a3-4c23-48c6-ad2b-63e55d7dccc2"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="220.0" y="3192.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s4823_sa970" compartmentRef="c5_ca5"> <label text="csa107_degraded"/> <bbox w="30.0" h="30.0" x="215.0" y="3075.0"/> </glyph> <glyph class="macromolecule" id="s4636_sa948"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SERPINF1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26921338 (PEDF, SERPINF1) normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. PEDF treatment strongly elevated cytoplasmic PEDF levels in the activated fibroblasts, suggesting a positive feedback loop. References_end </body> </html> </notes> <label text="SERPINF1"/> <bbox w="80.0" h="40.0" x="2300.0" y="640.0"/> </glyph> <glyph class="source and sink" id="s4502_sa795" compartmentRef="c5_ca5"> <label text="sa275_degraded"/> <bbox w="30.0" h="30.0" x="5125.0" y="1075.0"/> </glyph> <glyph class="macromolecule" id="s4827_sa971" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MMP10 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:19509166 FGFR2, WNT2, WNT5A, WISP1, MMP1, MMP10, IGFBP2, IL8, FZD9, CD14, IL32, CXCL14, PKP2 are upregulated in CAFs, ISL1, HIST1H4K, BRCA2, BRCA1, CCNA2, CCNB2, and CDC2 are downregulated References_end </body> </html> </notes> <label text="MMP10"/> <bbox w="80.0" h="40.0" x="5340.0" y="4590.0"/> </glyph> <glyph class="source and sink" id="s4591_sa904" compartmentRef="c5_ca5"> <label text="csa101_degraded"/> <bbox w="30.0" h="30.0" x="2245.0" y="4045.0"/> </glyph> <glyph class="macromolecule" id="s4828_sa972" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL22 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:21339327 The Th2 chemoattractants thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) were secreted as expected by TSLP-treated DCs and, importantly, by DCs conditioned with the supernatant of activated CAFs PMID:18514095; PMID:18514095 MDC/CCL22 expression in the stroma was not attributable to fibroblasts PMID:24127572 CCL17 and CCL22 have common receptor ccr4 Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. References_end </body> </html> </notes> <label text="CCL22"/> <bbox w="80.0" h="40.0" x="407.5" y="4595.0"/> </glyph> <glyph class="macromolecule" id="s4829_sa973" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL28 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:21753853 The ability of hypoxic medium to recruit preferentially CD4+CD25+FOXP3+ cells was abrogated by antibody that neutralized human CCL28 (no data that they are produced by fibroblasts) References_end </body> </html> </notes> <label text="CCL28"/> <bbox w="80.0" h="40.0" x="402.5" y="4674.0"/> </glyph> <glyph class="macromolecule" id="s4830_sa974" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL9 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:18514095 CXCL10 and CXCL11 ligands fo CXCR3 receptor are expressed in fibroblasts after TNF stimulation, and CXCL9 after IFNG stimulation PMID:22798340 3-CXCR3 ligands (such as CXCL9, 10, and 11), also reportedly contribute to Treg-cell infiltration PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) References_end </body> </html> </notes> <label text="CXCL9"/> <bbox w="80.0" h="40.0" x="872.5" y="4595.0"/> </glyph> <glyph class="macromolecule" id="s4832_sa976" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL11 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:18514095 CXCL10 and CXCL11 ligands fo CXCR3 receptor are expressed in fibroblasts after TNF stimulation, and CXCL9 after IFNG stimulation PMID:22798340 3-CXCR3 ligands (such as CXCL9, 10, and 11), also reportedly contribute to Treg-cell infiltration References_end </body> </html> </notes> <label text="CXCL11"/> <bbox w="80.0" h="40.0" x="872.5" y="4755.0"/> </glyph> <glyph class="macromolecule" id="s4833_sa977" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL17 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:12642832 Some subpopulations of fibroblasts could express IL17 after IL4/IL13 + TNF stimulation The combination of TNF-alpha with either IL-4 or IL-13, however, markedly increased both TARC release and the abundance of TARC mRNA in corneal and dermal fibroblasts, but not in lung fibroblasts. PMID:24127572 CCL17 and CCL22 have common receptor ccr4 Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. References_end </body> </html> </notes> <label text="CCL17"/> <bbox w="80.0" h="40.0" x="972.5" y="4595.0"/> </glyph> <glyph class="macromolecule" id="s4838_sa982" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: indoleamine 2,3-dioxygenase 1 HUGO:IDO1 hgnc_id:HGNC:6059 HGNC:6059 ENTREZ:3620 UNIPROT:P14902 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:22182446 Increased levels of PGE2 were found in cocultured supernatants from HCC-derived fibroblasts, and up-regulated expression of IDO and COX-2 were detected in these cells. The expression of NKP30, NKG2D, granzyme B and perforin were partly restored by PGE2 inhibitor and IDO inhibitor and the production of TNF-α and IFN-γ were fully restored by them. PMID:23891282 IDO expressing fibroblasts promote the expansion of antigen specific regulatory T cells References_end </body> </html> </notes> <label text="IDO1"/> <bbox w="80.0" h="40.0" x="562.5" y="4605.0"/> </glyph> <glyph class="macromolecule" id="s4839_sa983" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL2 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:22224781 L-2 is also required for TGF-β-mediated induction of Foxp3 in peripheral T cells in vitro ( but there are no data that it is expressed by fibroblast) References_end </body> </html> </notes> <label text="IL2"/> <bbox w="80.0" h="40.0" x="402.5" y="4755.0"/> </glyph> <glyph class="macromolecule" id="s4840_sa984" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL15 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:20007590 IL15 is important cytokine for tregs. Fibroblast could modulate Tregs by IL15 production. References_end </body> </html> </notes> <label text="IL15"/> <bbox w="80.0" h="40.0" x="1182.5" y="4595.0"/> </glyph> <glyph class="macromolecule" id="s4841_sa985" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-C motif chemokine ligand 5 HUGO:CCL5 hgnc_id:HGNC:10632 HGNC:10632 ENTREZ:6352 UNIPROT:P13501 Identifiers_end Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:23171795 Downregulation of miR-31 and miR-214 and upregulation of miR-155 was confirmed in all CAF and induced CAF samples; CCL5 is a Target of miR-214 . The CCL5 secreted by CAFs is a key tumor-promoting factor. PMID:21326202 CAFs may be the stromal source of the T cell attracting chemokine CCL5/RANTES, recruiting Treg cells into primary mammary tumors, which in turn stimulate metastatic progression CCL5 neutralization also inhibited recruitment of tumor-associated CD25+ cells in vivo Expression of CCR1, one of the cognate CCL5 receptors22, was strongly elevated in tumor CD4+ T cells relative to splenic CD4+ T cells of tumor-bearing or naïve mice. Notably, CD4+CD25+ tumor T cells expressed more Ccr1 mRNA than CD4+CD25− tumor T cells PMID:23567181 CCL5/RANTES and CCL2 secreted by CAFs isolated from human melanoma, breast and colon cancers mediated recruitment of Th17 cells from peripheral blood References_end </body> </html> </notes> <label text="CCL5"/> <bbox w="80.0" h="40.0" x="1082.5" y="4595.0"/> </glyph> <glyph class="complex" id="s4842_csa108" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LAP:LTBP*:TGFB* Identifiers_end References_begin: PMID:26519775; PMID:18086923; PMID:24309651 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text=" Large_Latent_Complex "/> <bbox w="105.0" h="165.0" x="1070.0" y="4692.0"/> <glyph class="macromolecule" id="s4719_sa986"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: latent transforming growth factor beta binding protein 1 HUGO:LTBP1 hgnc_id:HGNC:6714 HGNC:6714 ENTREZ:4052 UNIPROT:Q14766 latent transforming growth factor beta binding protein 2 HUGO:LTBP2 hgnc_id:HGNC:6715 HGNC:6715 ENTREZ:4053 UNIPROT:Q14767 latent transforming growth factor beta binding protein 3 HUGO:LTBP3 hgnc_id:HGNC:6716 HGNC:6716 ENTREZ:4054 UNIPROT:Q9NS15 latent transforming growth factor beta binding protein 4 HUGO:LTBP4 hgnc_id:HGNC:6717 HGNC:6717 ENTREZ:8425 UNIPROT:Q8N2S1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LTBP*"/> <bbox w="80.0" h="40.0" x="1085.0" y="4702.0"/> </glyph> <glyph class="macromolecule" id="s4720_sa987"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: TGFB induced factor homeobox 1 HUGO:TGIF1 hgnc_id:HGNC:11776 HGNC:11776 ENTREZ:7050 UNIPROT:Q15583 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:26519775 The αv-containing integrins αvβ1, αvβ3, αvβ5, and αvβ8 in a variety of fibroblasts and pericytes are reported to activate latent TGF-β by binding to the RGD motif of the latency-associated protein (LAP) that is bound to TGF-β and the latent TGF-β binding protein (LTBP) forming the large latent complex (LLC) References_end </body> </html> </notes> <label text="LAP"/> <bbox w="80.0" h="40.0" x="1085.0" y="4742.0"/> <glyph class="unit of information" id="_4218be29-3a8b-489f-bc55-704b63cc7f72"> <label text="truncated"/> <bbox w="50.0" h="10.0" x="1100.0" y="4737.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4721_sa988"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: transforming growth factor beta 1 HUGO:TGFB1 hgnc_id:HGNC:11766 HGNC:11766 ENTREZ:7040 UNIPROT:P01137 transforming growth factor beta 2 HUGO:TGFB2 hgnc_id:HGNC:11768 HGNC:11768 ENTREZ:7042 UNIPROT:P61812 transforming growth factor beta 3 HUGO:TGFB3 hgnc_id:HGNC:11769 HGNC:11769 ENTREZ:7043 UNIPROT:P10600 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: CASCADE:TNF PMID:21098712 Cancer TGFB exosomes trigger fibroblast to myofibroblast differentiation PMID:15653932 Treatment of fibroblasts with TNF-α resulted in a significant increase in TGF-β1 protein as measured by ELISA. The increase in protein was preceded by a 200–400% increase in TGF-β1 mRNA detected by quantitative, real-time, reverse transcriptase–polymerase chain reaction. Western blot analysis showed that TNF-α activated the extracellular signal–regulated kinase (ERK), and inhibitors of the ERK-specific mitogen-activated protein kinase pathway (PD98059 or U0126) blocked TNF-α induction of TGF-β1 PMID:23784029, PMID:16572188, PMID:8515656 TGF-β1 treatment successfully transformed primary resting fibroblasts into CAFs PMID:19038247 TGFbeta induces fibroblast collagen biosynthesis downstream of CCL7 and via SMAD3. Thus, ERK, a MAPK family member, phosphorylates serine residues in the linker regions of Smad1–3 and ERK inhibition reduces TGFβ-stimulated Smad phosphorylation as well as collagen biosynthesis, suggesting that ERK activation is necessary for an optimal response to TGFβ [9]. Similarly, p38 MAPK has been shown to be central to TGFβ mediated-collagen and fibronectin expression in SSc fibroblasts [10]. PMID:19747910 Through paracrine signaling molecules, TGF-beta and IL-1beta, cancer cells activate stromal fibroblasts and induce the expression of fibroblast activation protein (FAP). FAP, in turn, affects the proliferation, invasion and migration of the cancer cells. We report that TGF-beta and IL-1beta are important factors in inducing differentiation of myofibroblasts and expression of functional markers, notably alpha-SMA. PMID:18423981 Differential impact of TGF-beta and EGF on fibroblast differentiation and invasion reciprocally promotes colon cancer cell invasion. PMID:23034983 Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects PMID:21041659 Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts PMID:17768418 TGFbeta is responsible for skin tumour infiltration by macrophages enabling the tumours to escape immune destruction. TGFbeta-mediated tumour progression was accompanied by an increase in tumour-associated macrophages (TAM) and a decrease in tumour-infiltrating dendritic cells (DCs). ??? both TGF-β1 and TGF-β2 are up-regulated in CAFs PMID:15265520 , PMID:11279127 TGF/SMAD pathway regulates genes involved in extracellular matrix remodeling PMID:15003992 TGF-β-mediated myofibroblast differentiation and proliferation of the NRK fibroblasts are mutually exclusive responses to TGF-β. Differentiation into myofibroblasts appears to be the default pathway whereas proliferation becomes the dominant and sole response when both TGF-β and EGF are present. TGF-β induced a strong activation of RhoA and stress fiber formation in fibroblasts, PMID:17979848 TGF-β promotes the generation and function of Treg cells TGF-β is able to convert CD4+CD25− non-Treg cells into CD4+CD25+ Treg cells, and this conversion was accompanied with increased Foxp3 expression PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:22874531 TGFB treatment induces the autophagy-mediated downregulation of Cav-1 in fibroblasts. References_end </body> </html> </notes> <label text="TGFB*"/> <bbox w="80.0" h="40.0" x="1085.0" y="4782.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4846_sa989" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: thymic stromal lymphopoietin HUGO:TSLP hgnc_id:HGNC:30743 HGNC:30743 ENTREZ:85480 UNIPROT:Q969D9 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:TNF CASCADE:IL1 PMID:21339327 TSLP is produced by cancer-associated fibroblasts (CAFs) after activation by tumor-derived TNF and IL-1β TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. PMID:22270071 Probably IL1 and TNF regulate TSLP expression via NFkB References_end </body> </html> </notes> <label text="TSLP"/> <bbox w="80.0" h="40.0" x="662.5" y="4605.0"/> </glyph> <glyph class="macromolecule" id="s4848_sa991" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL7 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:22224781 IL2, IL7, IL15 are the key ligands of Treg differentiation (no fibroblast data fot IL7) References_end </body> </html> </notes> <label text="IL7"/> <bbox w="80.0" h="40.0" x="399.0" y="4830.0"/> </glyph> <glyph class="macromolecule" id="s4849_sa992" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL10 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:18514095 CXCL10 and CXCL11 ligands fo CXCR3 receptor are expressed in fibroblasts after TNF stimulation, and CXCL9 after IFNG stimulation PMID:22798340 3-CXCR3 ligands (such as CXCL9, 10, and 11), also reportedly contribute to Treg-cell infiltration PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="80.0" h="40.0" x="1380.0" y="4320.0"/> </glyph> <glyph class="macromolecule" id="s4850_sa993" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL11 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:18514095 CXCL10 and CXCL11 ligands fo CXCR3 receptor are expressed in fibroblasts after TNF stimulation, and CXCL9 after IFNG stimulation PMID:22798340 3-CXCR3 ligands (such as CXCL9, 10, and 11), also reportedly contribute to Treg-cell infiltration References_end </body> </html> </notes> <label text="CXCL11"/> <bbox w="80.0" h="40.0" x="1480.0" y="4320.0"/> </glyph> <glyph class="macromolecule" id="s4851_sa994" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL9 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:18514095 CXCL10 and CXCL11 ligands fo CXCR3 receptor are expressed in fibroblasts after TNF stimulation, and CXCL9 after IFNG stimulation PMID:22798340 3-CXCR3 ligands (such as CXCL9, 10, and 11), also reportedly contribute to Treg-cell infiltration PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) References_end </body> </html> </notes> <label text="CXCL9"/> <bbox w="80.0" h="40.0" x="1350.0" y="4240.0"/> </glyph> <glyph class="macromolecule" id="s4852_sa995" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL15 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:20007590 IL15 is important cytokine for tregs. Fibroblast could modulate Tregs by IL15 production. References_end </body> </html> </notes> <label text="IL15"/> <bbox w="80.0" h="40.0" x="1400.0" y="4390.0"/> </glyph> <glyph class="macromolecule" id="s4853_sa996" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CCL17 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:12642832 Some subpopulations of fibroblasts could express IL17 after IL4/IL13 + TNF stimulation The combination of TNF-alpha with either IL-4 or IL-13, however, markedly increased both TARC release and the abundance of TARC mRNA in corneal and dermal fibroblasts, but not in lung fibroblasts. PMID:24127572 CCL17 and CCL22 have common receptor ccr4 Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. References_end </body> </html> </notes> <label text="CCL17"/> <bbox w="80.0" h="40.0" x="1270.0" y="4320.0"/> </glyph> <glyph class="macromolecule" id="s4831_sa975" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCL10 Maps_Modules_begin: MODULE:TREG_MODULATORS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:18514095 CXCL10 and CXCL11 ligands fo CXCR3 receptor are expressed in fibroblasts after TNF stimulation, and CXCL9 after IFNG stimulation PMID:22798340 3-CXCR3 ligands (such as CXCL9, 10, and 11), also reportedly contribute to Treg-cell infiltration PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) References_end </body> </html> </notes> <label text="CXCL10"/> <bbox w="80.0" h="40.0" x="872.5" y="4675.0"/> </glyph> <glyph class="macromolecule" id="s4857_sa1000" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:JUND Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:20535745 junD−/− fibroblasts exhibit features of carcinoma-associated myofibroblasts. The expression of the chemokine CXCL12 was increased in junD−/− fibroblasts HIF-1α protein accumulates in junD−/− fibroblasts and mice (Gerald et al, 2004; Laurent et al, 2008), the up-regulation of CXCL12 in junD−/− fibroblasts could be mediated, at least partly, through HIF. Specific inhibition of HIF-1α by siRNA strongly reduced HIF-1α mRNA levels (Fig S3A) and decreased the expression of its target gene, CXCL12 References_end </body> </html> </notes> <label text="JUND"/> <bbox w="80.0" h="40.0" x="3230.0" y="2880.0"/> </glyph> <glyph class="macromolecule" id="s4858_sa1001" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCR4 Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:CXCL12 PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation and promotes RhoA-activation aand actin polymerisation. References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="80.0" h="50.0" x="1120.0" y="1515.0"/> <glyph class="unit of information" id="_fd294c80-4a21-4717-ab76-9a536263cfbc"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1137.5" y="1510.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4859_sa1002"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 12 HUGO:CXCL12 hgnc_id:HGNC:10672 HGNC:10672 ENTREZ:6387 UNIPROT:P48061 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:CXCL12 CASCADE:TGFB CASCADE:HGF PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:15882617 CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15261139 The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. PMID:24277834 Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) PMID:21521526 Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response. References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="980.0" y="1260.0"/> </glyph> <glyph class="complex" id="s4861_csa109" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CXCL12:CXCR4 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4861"/> <bbox w="100.0" h="120.0" x="1100.0" y="1620.0"/> <glyph class="macromolecule" id="s4862_sa1003"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CXCR4 Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:CXCL12 PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation and promotes RhoA-activation aand actin polymerisation. References_end </body> </html> </notes> <label text="CXCR4"/> <bbox w="80.0" h="50.0" x="1110.0" y="1675.0"/> <glyph class="unit of information" id="_bad66153-042e-4b76-87ea-3fca7a4f19ca"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="1127.5" y="1670.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4863_sa1004"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 12 HUGO:CXCL12 hgnc_id:HGNC:10672 HGNC:10672 ENTREZ:6387 UNIPROT:P48061 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:CXCL12 CASCADE:TGFB CASCADE:HGF PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:15882617 CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15261139 The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. PMID:24277834 Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) PMID:21521526 Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response. References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="1110.0" y="1630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4864_sa1005" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CD274 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:26201938 CAFs expressed the co-regulatory molecules, B7H1 (PDL1) and B7DC (PDL2), whereas NFs (normal fibroblasts) did not. References_end </body> </html> </notes> <label text="PDL1*"/> <bbox w="80.0" h="50.0" x="490.0" y="3685.0"/> <glyph class="unit of information" id="_dec573ff-5414-4865-86b6-221221061dc0"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="507.5" y="3680.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4865_sa1006" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PDCD1LG2 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:CAF Maps_Modules_end References_begin: PMID:26201938 CAFs expressed the co-regulatory molecules, B7H1 (PDL1) and B7DC (PDL2), whereas NFs (normal fibroblasts) did not References_end </body> </html> </notes> <label text="PDL2*"/> <bbox w="80.0" h="50.0" x="570.0" y="3755.0"/> <glyph class="unit of information" id="_9b0e7966-9c99-45ef-a570-9894447e929d"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="587.5" y="3750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4867_sa1007" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor necrosis factor HUGO:TNF hgnc_id:HGNC:11892 HGNC:11892 ENTREZ:7124 UNIPROT:P01375 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CYTOKINES_CHEMOKINES_PRODUCTION CASCADE:TNF Maps_Modules_end References_begin: PMID:23769623 TNF is one of key CAF activating agents PMID:17916596 In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNFA). The effect of TNFA on CAFs is inhibited by the nuclear factor-kB inhibitor parthenolide. PMID:8910423 both TNFR1 and TNFR2 receptors play role in TNF signal transduction in mouse fibroblasts Tnfr1 is essential in mediating proliferative signals Tnfr1 Exclusively Activates Transcription Factor NF-κB in Mouse Fibroblasts Ap-1 was independently activated through both Tnf receptors, probably via prolonged activation of the c-Jun kinase Tnfr1 and Tnfr2 Control Erk1 and Erk2 Kinase Activity Tnfr1 and Tnfr2 Control activation of RPS6KA1 Raf-1, Mek-1, and Mekk responded with enhanced kinase activity to Tnf treatment in all wt, tnfr1o, and tnfr2o fibroblasts, supporting again that both Tnf receptors individually are signaling-competent. The activation factors were about 1.5-4 for Raf-1, Mekk, and Mek-1 in wt, tnfr1o, and tnfr2o fibroblasts (Table II). Interestingly, Raf-B, an isoform of c-Raf-1 reported to be mainly localized to the brain (64, 65, 66), also responded to Tnf treatment of the fibroblasts. PMID:11112697 TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:20184663 PMID:23567181 Tumor necrosis factor (TNF) and IL6 were shown to be a potent mast cell chemoattractant. TNF induced a strong, dose-dependent migratory response of peritoneal mast cells References_end </body> </html> </notes> <label text="TNF"/> <bbox w="80.0" h="40.0" x="980.0" y="3320.0"/> </glyph> <glyph class="macromolecule" id="s4869_sa1009" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: CASCADE:GAST PMID:10477091, PMID:24584707 CCKRB is a gastrin receptor. References_end </body> </html> </notes> <label text="CCKBR"/> <bbox w="80.0" h="50.0" x="5930.0" y="1105.0"/> <glyph class="unit of information" id="_10d1c857-bfe0-431b-bd70-77f2adc45c33"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5947.5" y="1100.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s396_sa1013" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PLCG1 Maps_Modules_begin: MODULE:CORE Maps_Modules_end References_begin: CASCADE:GAST CASCADE:PDGF PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling PMID:23523669; PMID:24584707 Prorastin induces fibroblast activation via PKC and PI3K pathways; probably PKC is activated downstream of PLCG. PMID:24584707 A dominant and early event triggered by gastrin binding to its receptors on target cells is activation of the PLC signaling pathway. The involvement of the PLC pathway in promoting gastrin’s effects has been defined in NIH3T3 fibroblasts expressing the CCKB/gastrin receptor [130], Rat1 fibroblasts transfected with the CCKB/gastrin receptor (Rat1CCKBR1) [108], Receptor activation of PLC induces the breakdown of membrane phosphatidylinositol4,5-bisphosphate (PIP2), leading to the formation of two second messengers, IP3 and 1,2-diacylglycerol (DG) [6] and [88]. IP3 induces Ca2+ release from the internal storage pool [6], or probably affects membrane ion channels [57], and DG activates the protein kinase C (PKC) enzyme system References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="5581.0" y="2000.0"/> <glyph class="state variable" id="_4331a80e-12e9-41a5-bde5-7861caeb2275"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="5576.0" y="2015.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4873_sa1015" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PLCG1 Maps_Modules_begin: MODULE:CORE Maps_Modules_end References_begin: CASCADE:GAST CASCADE:PDGF PMID:7682895; PMID:17397400 PDGF -receptor directly binds and activates PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts downstream of PDGF signaling PMID:23523669; PMID:24584707 Prorastin induces fibroblast activation via PKC and PI3K pathways; probably PKC is activated downstream of PLCG. PMID:24584707 A dominant and early event triggered by gastrin binding to its receptors on target cells is activation of the PLC signaling pathway. The involvement of the PLC pathway in promoting gastrin’s effects has been defined in NIH3T3 fibroblasts expressing the CCKB/gastrin receptor [130], Rat1 fibroblasts transfected with the CCKB/gastrin receptor (Rat1CCKBR1) [108], Receptor activation of PLC induces the breakdown of membrane phosphatidylinositol4,5-bisphosphate (PIP2), leading to the formation of two second messengers, IP3 and 1,2-diacylglycerol (DG) [6] and [88]. IP3 induces Ca2+ release from the internal storage pool [6], or probably affects membrane ion channels [57], and DG activates the protein kinase C (PKC) enzyme system References_end </body> </html> </notes> <label text="PLCG1"/> <bbox w="80.0" h="40.0" x="5580.0" y="2130.0"/> <glyph class="state variable" id="_cd531cfc-b90e-4a62-9388-59b86439ec46"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="5572.5" y="2145.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s405_sa1017" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="PI4,5-P2"/> <bbox w="70.0" h="25.0" x="5395.0" y="1937.5"/> </glyph> <glyph class="simple chemical" id="s406_sa1018" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 References_end </body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="5175.0" y="2027.5"/> </glyph> <glyph class="simple chemical" id="s397_sa1019" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:18287025 PLCG is upstream of JNK in the pathway of NKG2D-mediated cytotoxicity PMID:20189481 PLCG inhibitor completely abrogated synergistic Erk phosphorylation downstream of NKG2D and 2B4. These data suggest that PLCG, rather than PI3K, is a critical upstream regulator of Erk activation in this pathway. References_end </body> </html> </notes> <label text="IP3"/> <bbox w="70.0" h="25.0" x="5255.0" y="2147.5"/> </glyph> <glyph class="complex" id="s4874_csa110" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CCKBR:GAST Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="s4874"/> <bbox w="100.0" h="120.0" x="5940.0" y="1210.0"/> <glyph class="macromolecule" id="s4875_sa1011"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> References_begin: CASCADE:GAST PMID:10477091, PMID:24584707 CCKRB is a gastrin receptor. References_end </body> </html> </notes> <label text="CCKBR"/> <bbox w="80.0" h="50.0" x="5950.0" y="1265.0"/> <glyph class="unit of information" id="_c03073a8-5a11-403c-ae1c-92881eec64c3"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="5967.5" y="1260.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4872_sa1012"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GAST References_begin: CASCADE:GAST PMID:23523669 Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. http://cancerres.aacrjournals.org/content/75/1_Supplement/B16.short Progastrin activates colon fibroblasts and participates to the dialogue between tumor epithelial cells and stromal fibroblasts in colorectal cancer PMID:24584707 A network map of the gastrin signaling pathway. References_end </body> </html> </notes> <label text="GAST"/> <bbox w="80.0" h="40.0" x="5950.0" y="1220.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4876_sa1008"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GAST References_begin: CASCADE:GAST PMID:23523669 Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. http://cancerres.aacrjournals.org/content/75/1_Supplement/B16.short Progastrin activates colon fibroblasts and participates to the dialogue between tumor epithelial cells and stromal fibroblasts in colorectal cancer PMID:24584707 A network map of the gastrin signaling pathway. References_end </body> </html> </notes> <label text="GAST"/> <bbox w="80.0" h="40.0" x="6110.0" y="780.0"/> </glyph> <glyph class="macromolecule" id="s4878_sa1021" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PRKCA_B_E_G* protein kinase C, alpha PRKCA REACTOME:58197 KEGG:5578 ATLASONC:GC_PRKCA WIKI:PRKCA protein kinase C, beta PRKCB REACTOME:58199 KEGG:5579 ATLASONC:GC_PRKCB WIKI:PRKCB protein kinase C, epsilon PRKCE REACTOME:58203 KEGG:5581 ATLASONC:GC_PRKCE WIKI:PRKCE protein kinase C, gamma PRKCG REACTOME:58205 KEGG:5582 ATLASONC:GC_PRKCG WIKI:PRKCG protein kinase C, zeta PRKCZ REACTOME:58219 KEGG:5590 ATLASONC:GC_PRKCZ WIKI:PRKCZ protein kinase C, delta PRKCD REACTOME:58201 KEGG:5580 ATLASONC:PRKCDID42901ch3p21 WIKI:PRKCD protein kinase C, eta PRKCH REACTOME:58209 KEGG:5583 ATLASONC:GC_PRKCH WIKI:PRKCH protein kinase C, theta PRKCQ REACTOME:58217 KEGG:5588 ATLASONC:GC_PRKCQ WIKI:PRKCQ protein kinase C, iota PRKCI REACTOME:58207 KEGG:5584 ATLASONC:PRKCIID41857ch3q26 WIKI:PRKCI PKCA PKCB PRKCB1 PRKCB2 “protein kinase C beta 1″ PKCG SCA14 CASCADE:GAST PMID:24584707 Receptor activation of PLC induces the breakdown of membrane phosphatidylinositol4,5-bisphosphate (PIP2), leading to the formation of two second messengers, IP3 and 1,2-diacylglycerol (DG) [6] and [88]. IP3 induces Ca2+ release from the internal storage pool [6], or probably affects membrane ion channels [57], and DG activates the protein kinase C (PKC) enzyme system References_end </body> </html> </notes> <label text="PKC*"/> <bbox w="80.0" h="40.0" x="5040.0" y="1970.0"/> </glyph> <glyph class="complex" id="s4879_csa111" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DAG:PKC* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end </body> </html> </notes> <label text="s4879"/> <bbox w="100.0" h="120.0" x="5030.0" y="2100.0"/> <glyph class="macromolecule" id="s4880_sa1022"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PRKCA_B_E_G* protein kinase C, alpha PRKCA REACTOME:58197 KEGG:5578 ATLASONC:GC_PRKCA WIKI:PRKCA protein kinase C, beta PRKCB REACTOME:58199 KEGG:5579 ATLASONC:GC_PRKCB WIKI:PRKCB protein kinase C, epsilon PRKCE REACTOME:58203 KEGG:5581 ATLASONC:GC_PRKCE WIKI:PRKCE protein kinase C, gamma PRKCG REACTOME:58205 KEGG:5582 ATLASONC:GC_PRKCG WIKI:PRKCG protein kinase C, zeta PRKCZ REACTOME:58219 KEGG:5590 ATLASONC:GC_PRKCZ WIKI:PRKCZ protein kinase C, delta PRKCD REACTOME:58201 KEGG:5580 ATLASONC:PRKCDID42901ch3p21 WIKI:PRKCD protein kinase C, eta PRKCH REACTOME:58209 KEGG:5583 ATLASONC:GC_PRKCH WIKI:PRKCH protein kinase C, theta PRKCQ REACTOME:58217 KEGG:5588 ATLASONC:GC_PRKCQ WIKI:PRKCQ protein kinase C, iota PRKCI REACTOME:58207 KEGG:5584 ATLASONC:PRKCIID41857ch3q26 WIKI:PRKCI PKCA PKCB PRKCB1 PRKCB2 “protein kinase C beta 1″ PKCG SCA14 CASCADE:GAST PMID:24584707 Receptor activation of PLC induces the breakdown of membrane phosphatidylinositol4,5-bisphosphate (PIP2), leading to the formation of two second messengers, IP3 and 1,2-diacylglycerol (DG) [6] and [88]. IP3 induces Ca2+ release from the internal storage pool [6], or probably affects membrane ion channels [57], and DG activates the protein kinase C (PKC) enzyme system References_end </body> </html> </notes> <label text="PKC*"/> <bbox w="80.0" h="40.0" x="5040.0" y="2110.0"/> </glyph> <glyph class="simple chemical" id="s4881_sa1023"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CASCADE:IFNAB PMID:18784374, PMID:23077238 PKC-theta requires DAG for activation. DAG is generated by PLCG through enzymatic cleavage of PIP2 </body> </html> </notes> <label text="DAG"/> <bbox w="70.0" h="25.0" x="5045.0" y="2167.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4883_sa1024" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NOTCH3 Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: PMID:27124156 NOTCH3 Is Induced in Cancer-Associated Fibroblasts and Promotes Angiogenesis in Oral Squamous Cell Carcinoma. References_end </body> </html> </notes> <label text="NOTCH3"/> <bbox w="80.0" h="40.0" x="4100.0" y="4840.0"/> </glyph> <glyph class="macromolecule" id="s4885_sa1026" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IQGAP1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:23454766 IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. TGF-β1 stimulation increases IQGAP1/TβRII binding. References_end </body> </html> </notes> <label text="IQGAP1 "/> <bbox w="80.0" h="40.0" x="3320.0" y="2650.0"/> </glyph> <glyph class="complex" id="s4886_csa112" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IQGAP1 :TGFBR2 Identifiers_end Maps_Modules_begin: MODULE:CAF Maps_Modules_end </body> </html> </notes> <label text="s4886"/> <bbox w="100.0" h="120.0" x="3990.0" y="1290.0"/> <glyph class="macromolecule" id="s4887_sa1028"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IQGAP1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:23454766 IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. TGF-β1 stimulation increases IQGAP1/TβRII binding. References_end </body> </html> </notes> <label text="IQGAP1 "/> <bbox w="80.0" h="40.0" x="4000.0" y="1300.0"/> </glyph> <glyph class="macromolecule" id="s4888_sa1029"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Identifiers_end Maps_Modules_begin: Maps_Modules_end References_begin: References_end ----- content merged by Celldesigner to SBGN-ML translation ------ Identifiers_begin: transforming growth factor beta receptor 2 HUGO:TGFBR2 hgnc_id:HGNC:11773 HGNC:11773 ENTREZ:7048 UNIPROT:P37173 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:CAF CASCADE:TGFB Maps_Modules_end References_begin: PMID:24132110,PMID:15265520 TGFB1, TGFB2, TGFB3 ligands bind to the type 2 TGFβ receptor (TGFBR2), which causes recruitment and phosphorylation of TGFBR1, resulting in downstream signalling activation. PMID:24336330 TGFBR2 in CAFs References_end </body> </html> </notes> <label text="TGFBR2"/> <bbox w="80.0" h="50.0" x="4000.0" y="1345.0"/> <glyph class="state variable" id="_75df1ac2-d4b6-4af3-b426-8e462a384951"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3995.0" y="1365.0"/> </glyph> <glyph class="unit of information" id="_13b4d414-07ea-4c16-addb-91b572fa0acb"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="4017.5" y="1340.0"/> </glyph> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4889_sa1031" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EGF Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:21098712; TGFB induces EGF expression and secretion in fibroblasts References_end </body> </html> </notes> <label text="EGF"/> <bbox w="70.0" h="25.0" x="4075.0" y="4593.5"/> </glyph> <glyph class="nucleic acid feature" id="s4890_sa1032" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EGF Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB PMID:21098712; TGFB induces EGF expression and secretion in fibroblasts References_end </body> </html> </notes> <label text="EGF"/> <bbox w="90.0" h="25.0" x="4065.0" y="4673.5"/> <glyph class="unit of information" id="_a94c58e2-ef62-440f-8bbc-bd15c0819fbb"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4100.0" y="4668.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4891_sa1033" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:LOXL2 Maps_Modules_begin: MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: PMID:26206869 LOXL2 Is Highly Expressed in Cancer-Associated Fibroblasts and Associates to Poor Colon Cancer Survival. PMID:25128648 Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer References_end </body> </html> </notes> <label text="LOXL2"/> <bbox w="80.0" h="40.0" x="5500.0" y="4750.0"/> </glyph> <glyph class="macromolecule" id="s4892_sa1034" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STC1 Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PDGF PMID:23243022 Quantitative real-time PCR (qRT-PCR) analyses of STC1 expression confirmed a 15-fold STC1-induction upon PDGF stimulation of fibroblasts STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. References_end </body> </html> </notes> <label text="STC1"/> <bbox w="80.0" h="40.0" x="4430.0" y="4746.0"/> </glyph> <glyph class="nucleic acid feature" id="s4893_sa1035" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STC1 Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PDGF PMID:23243022 Quantitative real-time PCR (qRT-PCR) analyses of STC1 expression confirmed a 15-fold STC1-induction upon PDGF stimulation of fibroblasts STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. References_end </body> </html> </notes> <label text="STC1"/> <bbox w="70.0" h="25.0" x="4435.0" y="4593.5"/> </glyph> <glyph class="nucleic acid feature" id="s4894_sa1036" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:STC1 Maps_Modules_begin: MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:PDGF PMID:23243022 Quantitative real-time PCR (qRT-PCR) analyses of STC1 expression confirmed a 15-fold STC1-induction upon PDGF stimulation of fibroblasts STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. References_end </body> </html> </notes> <label text="STC1"/> <bbox w="90.0" h="25.0" x="4425.0" y="4673.5"/> <glyph class="unit of information" id="_646dc89b-3cbf-4839-9273-a6b46c0b0da5"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="4460.0" y="4668.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s14_sa14"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: platelet derived growth factor subunit A HUGO:PDGFA hgnc_id:HGNC:8799 HGNC:8799 ENTREZ:5154 UNIPROT:P04085 platelet derived growth factor subunit B HUGO:PDGFB hgnc_id:HGNC:8800 HGNC:8800 ENTREZ:5155 UNIPROT:P01127 platelet derived growth factor C HUGO:PDGFC hgnc_id:HGNC:8801 HGNC:8801 ENTREZ:56034 UNIPROT:Q9NRA1 Identifiers_end Maps_Modules_begin: MODULE:GROWTH_FACTORS_SIGNALING_PATHWAYS MODULE:GROWTH_FACTORS_PRODUCTION Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:23123598 paracrine PDGF stimulation of CAFs induces production of the prototypical pro-angiogenic inducer fibroblast growth factor (FGF)-2 in both cervical carcinomas and melanoma [11] and [85]. Interestingly, CAFs activated by PDGF-CC in melanomas also secrete the extracellular matrix protein osteopontin, the action of which is known to synergistically stimulate angiogenesis together with FGF-2 and promote autocrine VEGF-A signaling in endothelial cells PMID:15207817; PMID:19118022 PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Tumor fibroblasts a recruted by PDGF PMID:18232728 Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. PMID:19111878 PDGF-C is upregulated in TAFs derived from refractory tumors and that PDGF-C, together with VEGF-A, mediates the angiogenesis induced by such TAFs in vivo. This study also demonstrates that inhibition of PDGF-C may reduce tumor angiogenesis and growth in vivo. PMID:26921338 TGFB induces expression of PDGFB and PDGFR in CAFs and indirectly suppresses PEDF expression via PDGFB signaling References_end </body> </html> </notes> <label text="PDGF*"/> <bbox w="80.0" h="40.0" x="4270.0" y="490.0"/> </glyph> <glyph class="macromolecule" id="s4896_sa1038" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:POSTN Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN CASCADE:TGFB PMID:20096135 Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker. PN promotes proliferation and invasion of CCA cells Knockdown of ITGα5 attenuates PN-induced proliferation and invasion PMID:22158103 Postn expression in fibroblast is activated by TGFB signaling, probably via SMAD. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. References_end </body> </html> </notes> <label text="POSTN"/> <bbox w="80.0" h="40.0" x="5900.0" y="4481.625"/> </glyph> <glyph class="nucleic acid feature" id="s4897_sa1039" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:POSTN Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:22158103 Postn expression in fibroblast is activated by TGFB signaling, probably via SMAD. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. References_end </body> </html> </notes> <label text="POSTN"/> <bbox w="70.0" h="25.0" x="5905.0" y="4349.125"/> </glyph> <glyph class="nucleic acid feature" id="s4898_sa1040" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:POSTN Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:22158103 Postn expression in fibroblast is activated by TGFB signaling, probably via SMAD. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. References_end </body> </html> </notes> <label text="POSTN"/> <bbox w="90.0" h="25.0" x="5895.0" y="4407.5"/> <glyph class="unit of information" id="_37a74bae-eb12-4c2e-83b7-a4c2312adee8"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="5930.0" y="4402.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4899_sa1042" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HSF1 Maps_Modules_begin: MODULE:FIBROBLAST_ACTIVATION_MARKERS Maps_Modules_end References_begin: PMID:25083868 The transcriptional regulator Heat-Shock Factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs) The effects of stromal HSF1 activation on cancer cells are mediated by TGFβ and SDF1 signaling, expression levels of Sdf1, Tgfβ1 and Tgfβ2 were significantly lower in Hsf1 null MEFs than in WT MEFs, even without co-culture with cancer cells References_end </body> </html> </notes> <label text="HSF1"/> <bbox w="80.0" h="40.0" x="2210.0" y="4120.0"/> </glyph> <glyph class="macromolecule" id="s4900_sa1043" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:RBPJ Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26302407 CSL (RBPJ) as a common repressor of fibroblast senescence and CAF activation CSL may affect p53 activity through physical interaction. Levels of CSL, p53 and CDKN1A expression were all significantly decreased in lesion-adjacent stroma versus distant unaffected skin References_end </body> </html> </notes> <label text="RBPJ"/> <bbox w="80.0" h="40.0" x="2520.0" y="2620.0"/> </glyph> <glyph class="complex" id="s4901_csa113" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:RBPJ:TP53 Identifiers_end </body> </html> </notes> <label text="s4901"/> <bbox w="100.0" h="120.0" x="2610.0" y="2690.0"/> <glyph class="macromolecule" id="s4902_sa1044"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:RBPJ Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26302407 CSL (RBPJ) as a common repressor of fibroblast senescence and CAF activation CSL may affect p53 activity through physical interaction. Levels of CSL, p53 and CDKN1A expression were all significantly decreased in lesion-adjacent stroma versus distant unaffected skin References_end </body> </html> </notes> <label text="RBPJ"/> <bbox w="80.0" h="40.0" x="2620.0" y="2700.0"/> </glyph> <glyph class="macromolecule" id="s4903_sa1045"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: tumor protein p53 HUGO:TP53 hgnc_id:HGNC:11998 HGNC:11998 ENTREZ:7157 UNIPROT:P04637 Identifiers_end Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26302407 Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation Levels of CSL, p53 and CDKN1A expression were all significantly decreased in lesion-adjacent stroma versus distant unaffected skin PMID:24254977 Mouse models have validated the tumour-promoting effects of deleting Rb, Pten or p53 in fibroblasts that converts them from normal fibroblasts to carcinoma associated fibroblasts (CAFs). PMID:19836055 P53 expression in tumor-stromal fibroblasts is closely associated with the nodal metastasis and outcome of patients with invasive ductal carcinoma who received neoadjuvant therapy References_end </body> </html> </notes> <label text="TP53"/> <bbox w="80.0" h="40.0" x="2620.0" y="2750.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4905_sa1047" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SQSTM1 Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:25002027 SQSTM1 (p62) p62 is a suppressor of inflammation and the CAF phenotype in the tumor microenvironment p62 controls IL-6 levels by repressing ROS production through metabolic reprogramming We found significantly reduced levels of c-Myc in p62 KO fibroblasts as well as in WT fibroblasts in which p62 has been knocked down by shRNA reduction in GLUT1 levels in p62-deficient fibroblasts. We also observed a decrease in the direct conversion of [U-13C5] glutamine to glutamate in p62 KO fibroblasts, with a relative increase in the fraction of glutamate derived from [1,2-13C2]glucose and reduced levels of the glutamine transporters SLC7A5 and SLC1A5, as well as glutaminase-1 (GLS1) (Figure 4O), a critical enzyme in the pathway that catalyzes the conversion of glutamine into glutamate p62 KO cells exhibited decreased glucose uptake and lactate secretion p62 KO cells displayed reduced mTORC1 activity mTORC1 activity in p62 KO fibroblasts accounts for the low levels of c-Myc and the subsequent increase in IL-6 production in these mutant cells. Treatment of WT fibroblasts with rapamycin or Torin, two different inhibitors of mTORC1, effectively reduced c-Myc levels We found significantly reduced levels of c-Myc in p62 KO fibroblasts as well as in WT fibroblasts in which p62 has been knocked down by shRNA (Figures 5A and 5B), and a reduction in the levels of the key glutamine transporters SLC7A5 and SLC1A5, and GLS1 (Figure 4O), which are targets of c-Myc (Dang, 2012). Interestingly, ectopic expression of c-Myc in p62 KO fibroblasts (Figure 5C) reverted the p62-deficient phenotype in terms of IL-6 production PMID:21981924 p62 is a key regulator of nutrient sensing in the mTORC1 pathway (data is not from fibroblasts). References_end </body> </html> </notes> <label text="SQSTM1"/> <bbox w="80.0" h="40.0" x="3260.0" y="3300.0"/> </glyph> <glyph class="macromolecule" id="s4906_sa1048" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: HUGO:MYC MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:25002027 We found significantly reduced levels of c-Myc in p62 KO fibroblasts as well as in WT fibroblasts in which p62 has been knocked down by shRNA References_end </body> </html> </notes> <label text="MYC"/> <bbox w="80.0" h="40.0" x="3360.0" y="3470.0"/> </glyph> <glyph class="macromolecule" id="s1052_sa1050" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBA Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation. References_end </body> </html> </notes> <label text="CYBA"/> <bbox w="80.0" h="40.0" x="2822.9688" y="3997.5"/> </glyph> <glyph class="simple chemical" id="s1056_sa1054" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: CHEBI:30413 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end </body> </html> </notes> <label text="heme"/> <bbox w="70.0" h="25.0" x="2827.9688" y="4075.0"/> </glyph> <glyph class="simple chemical" id="s3446_sa1056" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation References_end </body> </html> </notes> <label text="O2"/> <bbox w="70.0" h="25.0" x="3085.0" y="4337.5"/> </glyph> <glyph class="simple chemical" id="s2811_sa1057" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation References_end </body> </html> </notes> <label text="hydroxyl"/> <bbox w="70.0" h="25.0" x="3335.0" y="4417.5"/> </glyph> <glyph class="simple chemical" id="s2810_sa1058" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation References_end </body> </html> </notes> <label text="O2-"/> <bbox w="70.0" h="25.0" x="3082.0" y="4416.5"/> </glyph> <glyph class="simple chemical" id="s2809_sa1059" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation References_end </body> </html> </notes> <label text="H2O2"/> <bbox w="70.0" h="25.0" x="3211.0" y="4418.5"/> </glyph> <glyph class="macromolecule" id="s4908_sa1071" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HLA-DMA HUGO:HLA-DMB HUGO:HLA-DOA HUGO:HLA-DOB HUGO:HLA-DPA1 HUGO:HLA-DPB1 HUGO:HLA-DQA1 HUGO:HLA-DQA2 HUGO:HLA-DQB1 HUGO:HLA-DQB2 HUGO:HLA-DRA HUGO:HLA-DRB1 HUGO:HLA-DRB3 HUGO:HLA-DRB4 HUGO:HLA-DRB5 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:26405600 CAFs express MHC class II but do not provide costimulation through CD80 as normal fibroblasts References_end </body> </html> </notes> <label text="MHC_class_II*"/> <bbox w="80.0" h="50.0" x="270.0" y="3439.0"/> <glyph class="state variable" id="_117e5f17-2491-4000-89d6-4751c0bda3ba"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="265.0" y="3459.0"/> </glyph> <glyph class="unit of information" id="_10746329-eec6-4a41-9bf8-4550a24dc24a"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="287.5" y="3434.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s3449_sa1072" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CD80 Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: PMID:26405600 CAFs express MHC class II but do not provide costimulation through CD80 as normal fibroblasts References_end </body> </html> </notes> <label text="CD80"/> <bbox w="80.0" h="40.0" x="2610.0" y="2860.0"/> <glyph class="unit of information" id="_0992a56d-e1dd-403c-ae8e-7c3b27f86a4f"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2627.5" y="2855.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4909_sa1073" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TNFSF4 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:27298374 Fibroblast could express OX40L PMID:17641007 OX40L prevents Treg transformation of naive T cells by inhibition of Foxp3 expression "we established a two-step T cell culture system with IEk+ fibroblast APC expressing only OX40L. Naive T cells were cultured as before with low-dose Ag for 18 h. These activated cells were then repurified for secondary culture with OX40L-expressing APC in the presence or absence of TGF-β. At 18 h before restimulation, wild-type and OX40−/− T cells expressed equivalent CD25 and TGF-βRII and no Foxp3 (Fig. 4⇓A). After restimulation with Ag and OX40L, wild-type T cells did not develop into Foxp3+ cells without the addition of TGF-β (Fig. 4⇓, B and C). Moreover, even when TGF-β was added only a small fraction of T cells became Foxp3+, implying that OX40L specifically suppressed the induction of Foxp3". References_end </body> </html> </notes> <label text="OX40L*"/> <bbox w="80.0" h="40.0" x="340.0" y="3526.0"/> </glyph> <glyph class="macromolecule" id="s4911_sa1075" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CD276 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: http://www.fasebj.org/content/23/1_Supplement/894.7.short FIZZ1 binds to B7-H3 on fibroblasts and activates myofibroblast differentiation This FIZZ1-B7-H3 interaction was confirmed by co-immunoprecipitation and FRET assays. B7-H3 expression by fibroblasts was confirmed by immunostaining and real time PCR. Further studies indicated that FIZZ1 induced the phosphorylation of B7-H3. In contrast to wild type fibroblasts, B7-H3 deficient cells from knockout mice failed to undergo myofibroblast differentiation in response to FIZZ1 treatment. PMID: 19544488 B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction https://link.springer.com/chapter/10.1007%2F978-4-431-99644-6_60 The cell line named H1C1 had abilities to differentiate into adipocytes, osteocytes, and chondrocytes; therefore, we termed H1C1 as the human mesenchymal stem cells. RT-PCR showed that H1C1 constantly expressed mRNA of costimulatory molecules B7-H1, B7-H2, and B7-H3, which are known as immunosuppressive molecules. When human PBMC were cocultured with H1C1, the population of Tregs was increased compared with monoculture of PBMC, and neutralization of B7-H3 suppressed this induction. These results suggest that the human oral mesenchymal stem cells such as H1C1 have the abilities to suppress immunoreactions by costimulatory molecules and increasing Tregs. References_end </body> </html> </notes> <label text="B7H3*"/> <bbox w="80.0" h="50.0" x="400.0" y="3635.0"/> <glyph class="unit of information" id="_972a75d9-d43b-4443-a96c-3f120c8c8176"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="417.5" y="3630.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4912_sa1076" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NT5E References_begin: PMID:1989648 Among 102 unselected breast carcinoma primary lesions, only 9 contained CD73-positive tumour cells, whereas in 95 cases, stromal fibroblasts and fibrocytes showed variable degrees of CD73 expression. PMID:26363007 CD73 (NT5E) expression in fibroblasts promotes tumor immune escape and thereby tumor growth. CD73 expression in HGS ovarian tumors contributes to suppress the function of tumor-infiltrating CD8+ T cells. References_end </body> </html> </notes> <label text="NT5E"/> <bbox w="80.0" h="40.0" x="210.0" y="3321.5"/> </glyph> <glyph class="macromolecule" id="s4913_sa1077" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:DPP4 Maps_Modules_begin: MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: PMID:1345821; PMID:10569731 DPP4 is expressed in breast fibroblasts PMID:17981655 CD26/DPPIV can associate with several proteins, among them fibroblast activating protein-alpha (FAP-alpha), plasminogen, adenosine deaminase (ADA), the tyrosine phosphatase CD45, and the chemokine receptor CXCR4. It can also bind to the extracellular matrix (ECM) and depending on the presence of other ligands, this process can either lead to increased or decreased invasive activity of the cells on which it is expressed. As a result of these characteristics, CD26/DPPIV plays an important role in tumor biology, and is useful as a marker for various cancers References_end </body> </html> </notes> <label text="DPP4"/> <bbox w="80.0" h="40.0" x="6050.0" y="4580.0"/> </glyph> <glyph class="macromolecule" id="s4914_sa1078" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TNFSF4 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: PMID:27298374 Fibroblast could express OX40L PMID:17641007 OX40L prevents Treg transformation of naive T cells by inhibition of Foxp3 expression "we established a two-step T cell culture system with IEk+ fibroblast APC expressing only OX40L. Naive T cells were cultured as before with low-dose Ag for 18 h. These activated cells were then repurified for secondary culture with OX40L-expressing APC in the presence or absence of TGF-β. At 18 h before restimulation, wild-type and OX40−/− T cells expressed equivalent CD25 and TGF-βRII and no Foxp3 (Fig. 4⇓A). After restimulation with Ag and OX40L, wild-type T cells did not develop into Foxp3+ cells without the addition of TGF-β (Fig. 4⇓, B and C). Moreover, even when TGF-β was added only a small fraction of T cells became Foxp3+, implying that OX40L specifically suppressed the induction of Foxp3". References_end </body> </html> </notes> <label text="OX40L*"/> <bbox w="80.0" h="40.0" x="520.0" y="4679.0"/> </glyph> <glyph class="macromolecule" id="s4915_sa1079" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CD276 Maps_Modules_begin: MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:TREG_MODULATORS MODULE:CAF Maps_Modules_end References_begin: http://www.fasebj.org/content/23/1_Supplement/894.7.short FIZZ1 binds to B7-H3 on fibroblasts and activates myofibroblast differentiation This FIZZ1-B7-H3 interaction was confirmed by co-immunoprecipitation and FRET assays. B7-H3 expression by fibroblasts was confirmed by immunostaining and real time PCR. Further studies indicated that FIZZ1 induced the phosphorylation of B7-H3. In contrast to wild type fibroblasts, B7-H3 deficient cells from knockout mice failed to undergo myofibroblast differentiation in response to FIZZ1 treatment. PMID: 19544488 B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction https://link.springer.com/chapter/10.1007%2F978-4-431-99644-6_60 The cell line named H1C1 had abilities to differentiate into adipocytes, osteocytes, and chondrocytes; therefore, we termed H1C1 as the human mesenchymal stem cells. RT-PCR showed that H1C1 constantly expressed mRNA of costimulatory molecules B7-H1, B7-H2, and B7-H3, which are known as immunosuppressive molecules. When human PBMC were cocultured with H1C1, the population of Tregs was increased compared with monoculture of PBMC, and neutralization of B7-H3 suppressed this induction. These results suggest that the human oral mesenchymal stem cells such as H1C1 have the abilities to suppress immunoreactions by costimulatory molecules and increasing Tregs. References_end </body> </html> </notes> <label text="B7H3*"/> <bbox w="80.0" h="50.0" x="580.0" y="4785.0"/> <glyph class="unit of information" id="_73b04636-ed29-44c3-91e9-717d87fcd7d2"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="597.5" y="4780.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4917_sa1081" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SOD2 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:22850421; PMID:21358671 SIRT3 is involved in the control of HIF1 expression, and redox signaling. A decrease in SIRT3 expression leads to increased superoxide dismutase 2 (SOD2) acetylation/inhibition, thereby causing ROS increase and HIF1 stabilization. SIRT3 is upregulated in normal fibroblasts and downregulated in CAFs. PMID:21150282 the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. I References_end </body> </html> </notes> <label text="SOD2"/> <bbox w="80.0" h="40.0" x="3140.0" y="4510.0"/> <glyph class="state variable" id="_a29d6bb8-4875-4a11-ba76-cdc2c65ae507"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3135.0" y="4525.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4918_sa1080" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SOD2 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF_INHIBITION_ANTITUMOR MODULE:CAF Maps_Modules_end References_begin: PMID:22850421; PMID:21358671 SIRT3 is involved in the control of HIF1 expression, and redox signaling. A decrease in SIRT3 expression leads to increased superoxide dismutase 2 (SOD2) acetylation/inhibition, thereby causing ROS increase and HIF1 stabilization. SIRT3 is upregulated in normal fibroblasts and downregulated in CAFs. PMID:21150282 the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. I References_end </body> </html> </notes> <label text="SOD2"/> <bbox w="80.0" h="40.0" x="3290.0" y="4510.0"/> <glyph class="state variable" id="_00c40d31-dd40-485a-8c44-2229a8af05df"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="3280.0" y="4525.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4919_sa1082" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NOX4 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation Nox4 mediates TGFB1–induced SMalpha actin in human cardiac fibroblasts. PMID:21273445 ROS signaling by NOX4 drives fibroblast-to-myofibroblast transdifferentiation in the diseased prostatic stroma downstream of TGFB References_end </body> </html> </notes> <label text="NOX4"/> <bbox w="80.0" h="40.0" x="2822.9688" y="3937.5"/> </glyph> <glyph class="macromolecule" id="s4921_sa1083" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:POLDIP2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:19644055 Poldip2 co-localizes with p22phox at sites of Nox4 in SMCs and, when present, increases Nox4 activity by three-fold. In addition, Nox4-Poldip2-derived ROS activate RhoA to strengthen focal adhesions and increase stress fiber formation. References_end </body> </html> </notes> <label text="POLDIP2"/> <bbox w="80.0" h="40.0" x="2930.0" y="3940.0"/> </glyph> <glyph class="nucleic acid feature" id="s4924_sa1086" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NOX4 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation Nox4 mediates TGFB1–induced SMalpha actin in human cardiac fibroblasts. PMID:21273445 ROS signaling by NOX4 drives fibroblast-to-myofibroblast transdifferentiation in the diseased prostatic stroma downstream of TGFB References_end </body> </html> </notes> <label text="NOX4"/> <bbox w="70.0" h="25.0" x="2827.9688" y="3805.0"/> </glyph> <glyph class="nucleic acid feature" id="s4925_sa1087" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NOX4 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation Nox4 mediates TGFB1–induced SMalpha actin in human cardiac fibroblasts. PMID:21273445 ROS signaling by NOX4 drives fibroblast-to-myofibroblast transdifferentiation in the diseased prostatic stroma downstream of TGFB References_end </body> </html> </notes> <label text="NOX4"/> <bbox w="90.0" h="25.0" x="2817.9688" y="3865.0"/> <glyph class="unit of information" id="_974dc058-e804-447d-942e-71ae655e5f9c"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2852.9688" y="3860.0"/> </glyph> </glyph> <glyph class="complex" id="s4920_csa115" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:CYBA:NOX4:POLDIP2:heme Identifiers_end References_begin: CASCADE:TGFB 19995913 16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation Nox4 mediates TGFB1–induced SMalpha actin in human cardiac fibroblasts. 21273445 ROS signaling by NOX4 drives fibroblast-to-myofibroblast transdifferentiation in the diseased prostatic stroma downstream of TGFB References_end </body> </html> </notes> <label text="NADPH oxidase_4"/> <bbox w="182.96875" h="157.5" x="2927.0" y="4052.0"/> <glyph class="macromolecule" id="s4922_sa1085"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:POLDIP2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:19644055 Poldip2 co-localizes with p22phox at sites of Nox4 in SMCs and, when present, increases Nox4 activity by three-fold. In addition, Nox4-Poldip2-derived ROS activate RhoA to strengthen focal adhesions and increase stress fiber formation. References_end </body> </html> </notes> <label text="POLDIP2"/> <bbox w="80.0" h="40.0" x="3022.9375" y="4107.0"/> </glyph> <glyph class="macromolecule" id="s4923_sa1084"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NOX4 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:15927447; PMID:19995913 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation PMID:16179589 NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. On stimulation with TGF-beta1, Nox4 mRNA is dramatically upregulated. Depletion of Nox4 but not Nox5 inhibits baseline and TGF-beta1 stimulation of Smad 2/3 phosphorylation Nox4 mediates TGFB1–induced SMalpha actin in human cardiac fibroblasts. PMID:21273445 ROS signaling by NOX4 drives fibroblast-to-myofibroblast transdifferentiation in the diseased prostatic stroma downstream of TGFB References_end </body> </html> </notes> <label text="NOX4"/> <bbox w="80.0" h="40.0" x="2938.875" y="4062.0"/> </glyph> <glyph class="macromolecule" id="s1039_sa1069"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CYBA Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:15927447 Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22phox on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22phox for ROS generation. References_end </body> </html> </notes> <label text="CYBA"/> <bbox w="80.0" h="40.0" x="2942.9375" y="4107.0"/> </glyph> <glyph class="simple chemical" id="s1046_sa1063"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> CHEBI:30413 MODULE:CAF MODULE:METABOLIC </body> </html> </notes> <label text="heme"/> <bbox w="70.0" h="25.0" x="2944.9688" y="4157.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4926_sa1089" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:PKM Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:22101652; PMID:19923890 The M1 or M2 splice isoforms of pyruvate kinase (PK), a mandatory regulatory glycolytic enzyme, shift glucose metabolism towards aerobic glycolysis (PKM2) or oxidative phosphorylation (PKM1) PKM2 and lactate dehydrogenase are highly expressed in the stroma of breast cancer lacking caveolin-1 expression References_end </body> </html> </notes> <label text="PKM2*"/> <bbox w="80.0" h="40.0" x="2620.0" y="4570.0"/> </glyph> <glyph class="simple chemical" id="s4927_sa1091" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:22101652; PMID:19923890 The M1 or M2 splice isoforms of pyruvate kinase (PK), a mandatory regulatory glycolytic enzyme, shift glucose metabolism towards aerobic glycolysis (PKM2) or oxidative phosphorylation (PKM1) PKM2 and lactate dehydrogenase are highly expressed in the stroma of breast cancer lacking caveolin-1 expression References_end </body> </html> </notes> <label text="Phosphoenolpyruvate"/> <bbox w="70.0" h="25.0" x="2715.0" y="4527.5"/> </glyph> <glyph class="phenotype" id="s4928_sa1092" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:TGFB Maps_Modules_end References_begin: PMID:22874531 Fibroblasts overexpressing the constitutively active TGF-β receptor kinase (RI; T204D) show increased autophagy and oxidative stress-induced aerobic glycolysis. We n References_end </body> </html> </notes> <label text="Glycolysis"/> <bbox w="80.0" h="30.0" x="2830.0" y="4535.0"/> </glyph> <glyph class="macromolecule" id="s4931_sa1095" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:TFAM Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:22129993 TFAM is mitochondrial transcription factor A, which is important in functionally maintaining the mitochondrial respiratory chain. Interestingly, TFAM-deficient fibroblasts showed evidence of mitochondrial dysfunction and oxidative stress, with the loss of certain mitochondrial respiratory chain components, and the over-production of hydrogen peroxide and L-lactate. TFAM-deficient fibroblasts also showed a loss of caveolin-1 (Cav-1), a known breast cancer stromal biomarker. References_end </body> </html> </notes> <label text="TFAM"/> <bbox w="80.0" h="40.0" x="3020.0" y="3059.0"/> </glyph> <glyph class="macromolecule" id="s4932_sa1096" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IDH3A Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: CASCADE:TGFB MUDULE:METABOLIC PMID:25732824 CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. DH3A downregulation occurred mainly through transcriptional regulation downstream of TGFB IDH3A converts isocitrate into alpha-KG The activity of PHD requires oxygen and alpha-KG References_end </body> </html> </notes> <label text="IDH3A"/> <bbox w="80.0" h="40.0" x="2780.0" y="3500.0"/> </glyph> <glyph class="phenotype" id="s4933_sa1097" compartmentRef="c5_ca5"> <label text="TCA_CYCLE"/> <bbox w="80.0" h="30.0" x="2830.0" y="4635.0"/> </glyph> <glyph class="macromolecule" id="s4934_sa1098" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EGLN1 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 Proline hydroxylase (PHD), a member of the dioxygenase family, hydroxylated HIF-1A at prolines 402 and 564. This hydroxylation led to the binding of E3 ligase VHL and consequent ubiquitination and degradation of HIF-1A. The activity of PHD requires oxygen and alpha-KG, TGFB signaling regulates PDH activity downstream of TGFB References_end </body> </html> </notes> <label text="EGLN1"/> <clone/> <bbox w="80.0" h="40.0" x="3180.0" y="3750.0"/> </glyph> <glyph class="macromolecule" id="s4934_sa1114" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:EGLN1 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 Proline hydroxylase (PHD), a member of the dioxygenase family, hydroxylated HIF-1A at prolines 402 and 564. This hydroxylation led to the binding of E3 ligase VHL and consequent ubiquitination and degradation of HIF-1A. The activity of PHD requires oxygen and alpha-KG, TGFB signaling regulates PDH activity downstream of TGFB References_end </body> </html> </notes> <label text="EGLN1"/> <clone/> <bbox w="80.0" h="40.0" x="3180.0" y="3680.0"/> </glyph> <glyph class="source and sink" id="s4935_sa1099" compartmentRef="c5_ca5"> <label text="sa94_degraded"/> <bbox w="30.0" h="30.0" x="3115.0" y="3775.0"/> </glyph> <glyph class="nucleic acid feature" id="s4936_sa1100" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SLC2A1 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:11120745 Glut1 promoter has HIF1 binding site PMID:25732824 HIF1 upregulates GLUT1 protein level SLC2A1 (GLUT1) is upregulated in CAFs. It provides enhanced glucose uptake by CAFs. References_end </body> </html> </notes> <label text="SLC2A1"/> <bbox w="70.0" h="25.0" x="3055.0" y="4637.5"/> </glyph> <glyph class="nucleic acid feature" id="s4937_sa1101" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SLC2A1 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:11120745 Glut1 promoter has HIF1 binding site PMID:25732824 HIF1 upregulates GLUT1 protein level SLC2A1 (GLUT1) is upregulated in CAFs. It provides enhanced glucose uptake by CAFs. PMID:25002027 SQSTM1 (p62) reduction in GLUT1 levels in p62-deficient fibroblasts References_end </body> </html> </notes> <label text="SLC2A1"/> <bbox w="90.0" h="25.0" x="3045.0" y="4697.5"/> <glyph class="unit of information" id="_384ccd02-ffbe-468a-b82f-1629625ba948"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3080.0" y="4692.5"/> </glyph> </glyph> <glyph class="macromolecule" id="s4938_sa1102" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HK2 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:25732824 Hexokinase 2 is upregulated in CAFs downstream of HIF1A PMID:9436976 HK2 is a dicrect target of HIF1A References_end </body> </html> </notes> <label text="HK2"/> <bbox w="80.0" h="40.0" x="2910.0" y="4450.0"/> </glyph> <glyph class="nucleic acid feature" id="s4939_sa1103" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HK2 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:25732824 Hexokinase 2 is upregulated in CAFs downstream of HIF1A PMID:9436976 HK2 id e dicrect target of HIF1A References_end </body> </html> </notes> <label text="HK2"/> <bbox w="90.0" h="25.0" x="2905.0" y="4387.5"/> <glyph class="unit of information" id="_df665475-d9e5-4a2d-b92d-eeab7ae0f4c1"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2940.0" y="4382.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4940_sa1104" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HK2 Maps_Modules_begin: MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: PMID:25732824 Hexokinase 2 is upregulated in CAFs downstream of HIF1A PMID:9436976 HK2 id e dicrect target of HIF1A References_end </body> </html> </notes> <label text="HK2"/> <bbox w="70.0" h="25.0" x="2915.0" y="4317.5"/> </glyph> <glyph class="macromolecule" id="s4941_sa1105" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NDUFA4L2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2), a negative regulator of mitochondrial complex 1, was upregulated in CAFs The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2 downstream of TGFB. References_end </body> </html> </notes> <label text="NDUFA4L2 "/> <bbox w="80.0" h="40.0" x="3200.0" y="4080.0"/> </glyph> <glyph class="nucleic acid feature" id="s4942_sa1106" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NDUFA4L2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2), a negative regulator of mitochondrial complex 1, was upregulated in CAFs The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2 downstream of TGFB References_end </body> </html> </notes> <label text="NDUFA4L2 "/> <bbox w="70.0" h="25.0" x="3195.0" y="3956.5"/> </glyph> <glyph class="nucleic acid feature" id="s4943_sa1107" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:NDUFA4L2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2), a negative regulator of mitochondrial complex 1, was upregulated in CAFs The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2 downstream of TGFB References_end </body> </html> </notes> <label text="NDUFA4L2 "/> <bbox w="90.0" h="25.0" x="3185.0" y="4017.5"/> <glyph class="unit of information" id="_fdbbd7c1-3c2f-4f71-b40f-e4750d42066e"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3220.0" y="4012.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4944_sa1108" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR424 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 miR-424 Regulates IDH3A Expression downstream of TGFB the miR-424 level was increased in fibroblasts after 12 hr of TGF-beta treatment miR-424 promotes glycolysis in CAFs by downregulating IDH3A References_end </body> </html> </notes> <label text="MIR424"/> <bbox w="90.0" h="25.0" x="2675.0" y="3377.5"/> <glyph class="unit of information" id="_360e09bc-9a26-4522-9ca7-fa7e837d48a1"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2705.0" y="3372.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s4945_sa1109" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end </body> </html> </notes> <label text="Alpha_ketoglutarate"/> <bbox w="70.0" h="25.0" x="3045.0" y="3727.5"/> </glyph> <glyph class="simple chemical" id="s4946_sa1110" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end </body> </html> </notes> <label text="Glutamate"/> <bbox w="70.0" h="25.0" x="3045.0" y="3567.5"/> </glyph> <glyph class="macromolecule" id="s4947_sa1111" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GPT2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:25732824 the expression of ALT2 (GPT2) was significantly increased in induced CAFs (Figure 4C), suggesting that the slight elevation of alpha-KG is likely through the glutamate pathway by feedback upregulation of ALT2 in CAFs and fibroblasts with IDH3α knockdown. ALT2 is upregulated downstream of TGFB and PDGF. References_end </body> </html> </notes> <label text="GPT2"/> <bbox w="80.0" h="40.0" x="3170.0" y="3510.0"/> </glyph> <glyph class="nucleic acid feature" id="s4948_sa1112" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GPT2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:25732824 the expression of ALT2 (GPT2) was significantly increased in induced CAFs (Figure 4C), suggesting that the slight elevation of α-KG is likely through the glutamate pathway by feedback upregulation of ALT2 in CAFs and fibroblasts with IDH3α knockdown. ALT2 is upregulated downstream of TGFB and PDGF. References_end </body> </html> </notes> <label text="GPT2"/> <bbox w="70.0" h="25.0" x="3175.0" y="3397.5"/> </glyph> <glyph class="nucleic acid feature" id="s4949_sa1113" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GPT2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB CASCADE:PDGF PMID:25732824 the expression of ALT2 (GPT2) was significantly increased in induced CAFs (Figure 4C), suggesting that the slight elevation of α-KG is likely through the glutamate pathway by feedback upregulation of ALT2 in CAFs and fibroblasts with IDH3α knockdown. ALT2 is upregulated downstream of TGFB and PDGF. References_end </body> </html> </notes> <label text="GPT2"/> <bbox w="90.0" h="25.0" x="3165.0" y="3457.5"/> <glyph class="unit of information" id="_ef7a07f9-ea34-4a14-a408-419698e91ca0"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3200.0" y="3452.5"/> </glyph> </glyph> <glyph class="simple chemical" id="s4950_sa1115" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end </body> </html> </notes> <label text="isocitrate"/> <bbox w="70.0" h="25.0" x="2905.0" y="3727.5"/> </glyph> <glyph class="nucleic acid feature" id="s4951_sa1116" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IDH3A Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. DH3α downregulation occurred mainly through transcriptional regulation downstream of TGFB References_end </body> </html> </notes> <label text="IDH3A"/> <bbox w="70.0" h="25.0" x="2785.0" y="3347.5"/> </glyph> <glyph class="nucleic acid feature" id="s4952_sa1117" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IDH3A Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. DH3α downregulation occurred mainly through transcriptional regulation downstream of TGFB References_end </body> </html> </notes> <label text="IDH3A"/> <bbox w="90.0" h="25.0" x="2775.0" y="3427.5"/> <glyph class="unit of information" id="_36346beb-a7c6-47f4-8ff4-03203a334d2b"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2810.0" y="3422.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4953_sa1118" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR424 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 miR-424 Regulates IDH3A Expression downstream of TGFB the miR-424 level was increased in fibroblasts after 12 hr of TGF-β treatment References_end </body> </html> </notes> <label text="MIR424"/> <bbox w="70.0" h="25.0" x="2685.0" y="3317.5"/> </glyph> <glyph class="complex" id="s4954_csa116" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IDH3A:MIR424 Identifiers_end </body> </html> </notes> <label text="s4954"/> <bbox w="100.0" h="120.0" x="2610.0" y="3450.0"/> <glyph class="nucleic acid feature" id="s4956_sa1120"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MIR424 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 miR-424 Regulates IDH3A Expression downstream of TGFB the miR-424 level was increased in fibroblasts after 12 hr of TGF-beta treatment miR-424 promotes glycolysis in CAFs by downregulating IDH3A References_end </body> </html> </notes> <label text="MIR424"/> <bbox w="90.0" h="25.0" x="2615.0" y="3467.5"/> <glyph class="unit of information" id="_3fe91efd-4edf-4a6c-a2a3-20bec672606f"> <label text="asRNA"/> <bbox w="30.0" h="10.0" x="2645.0" y="3462.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4955_sa1121"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IDH3A Maps_Modules_begin: MODULE:CAF_INHIBITION_ANTITUMOR MODULE:METABOLIC MODULE:CAF Maps_Modules_end References_begin: CASCADE:TGFB PMID:25732824 CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. DH3α downregulation occurred mainly through transcriptional regulation downstream of TGFB References_end </body> </html> </notes> <label text="IDH3A"/> <bbox w="90.0" h="25.0" x="2615.0" y="3507.5"/> <glyph class="unit of information" id="_f5858bc9-8af6-4c47-973c-28bc1fbcfcd3"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2650.0" y="3502.5"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s4957_sa1122" compartmentRef="c5_ca5"> <label text="csa116_degraded"/> <bbox w="30.0" h="30.0" x="2655.0" y="3625.0"/> </glyph> <glyph class="macromolecule" id="s4958_sa1123" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HMGCS2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:27833036 CAFs secrete large amounts of ketone bodies which are then re-utilized by tumor cells for anabolic metabolism or OXPHOS like lactat PMID:23082722 Coculture with fibroblasts overexpressing BDH1 or HMGCS2 increases the cancer cell population. Probably via keton bodies production. PMID:21109197 SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production (in vitro data) References_end </body> </html> </notes> <label text="HMGCS2"/> <bbox w="80.0" h="40.0" x="3210.0" y="4770.0"/> <glyph class="state variable" id="_72d1aab7-27cd-493d-a99c-2b64f5d3e90f"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3205.0" y="4785.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4959_sa1124" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:BDH1 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:27833036 CAFs secrete large amounts of ketone bodies which are then re-utilized by tumor cells for anabolic metabolism or OXPHOS like lactat PMID:23082722 Coculture with fibroblasts overexpressing BDH1 or HMGCS2 increases the cancer cell population. Probably via keton bodies production. References_end </body> </html> </notes> <label text="BDH1"/> <bbox w="80.0" h="40.0" x="3340.0" y="4770.0"/> </glyph> <glyph class="phenotype" id="s4960_sa1125"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:20818174 administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ~2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. References_end </body> </html> </notes> <label text="Keton_body_production"/> <bbox w="150.0" h="35.0" x="3225.0" y="5022.5"/> </glyph> <glyph class="macromolecule" id="s4961_sa1128" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:HMGCS2 Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:27833036 CAFs secrete large amounts of ketone bodies which are then re-utilized by tumor cells for anabolic metabolism or OXPHOS like lactat PMID:23082722 Coculture with fibroblasts overexpressing BDH1 or HMGCS2 increases the cancer cell population. Probably via keton bodies production. PMID:21109197 SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production (in vitro data) References_end </body> </html> </notes> <label text="HMGCS2"/> <bbox w="80.0" h="40.0" x="3210.0" y="4690.0"/> <glyph class="state variable" id="_14efd151-d41b-4d8c-9ff1-e9cf25982c37"> <state value="Ac" variable=""/> <bbox w="20.0" h="10.0" x="3200.0" y="4705.0"/> </glyph> </glyph> <glyph class="simple chemical" id="s4962_sa1129" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:20861672 CAF pdoduce a lot of glutamines for cancer cells. References_end </body> </html> </notes> <label text="glutamine"/> <bbox w="70.0" h="25.0" x="2905.0" y="3567.5"/> </glyph> <glyph class="simple chemical" id="s4963_sa1130"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:20861672 CAF pdoduce a lot of glutamine for cancer cells. References_end </body> </html> </notes> <label text="glutamine"/> <bbox w="70.0" h="25.0" x="2905.0" y="5007.5"/> </glyph> <glyph class="macromolecule" id="s4964_sa1131" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC Maps_Modules_end References_begin: PMID:27833036 GLUL, Glutamate ammonia ligase, the key enzyme in glutamine synthesis, is upregulated in CAFs PMID:20861672 CAF pdoduce a lot of glutamine for cancer cells. References_end </body> </html> </notes> <label text="GLUL"/> <bbox w="80.0" h="40.0" x="2970.0" y="3480.0"/> </glyph> <glyph class="macromolecule" id="s4965_sa1132" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL4 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:20184663 CAFs may also directly influence the polarization of macrophages toward an M2 phenotype: IL-4, one of the key cytokines driving M2-like polarization of macrophages, was shown to be secreted by CAFs References_end </body> </html> </notes> <label text="IL4"/> <bbox w="80.0" h="40.0" x="740.0" y="3526.0"/> </glyph> <glyph class="macromolecule" id="s4966_sa1133" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL10 References_begin: PMID:20184663 Production of cytokines, chemokines and growth factors showed a significant increase in TAFs for vascular endothelial growth factor, transforming growth factor-beta1, interleukins (IL-4, IL-10) and tumour necrosis factor alpha. References_end </body> </html> </notes> <label text="IL10"/> <bbox w="80.0" h="40.0" x="620.0" y="3526.0"/> </glyph> <glyph class="macromolecule" id="s4967_sa1134" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:IL13 Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION Maps_Modules_end References_begin: PMID:20184663 CAFs may also directly influence the polarization of macrophages toward an M2 phenotype: IL-13, one of the key cytokines driving M2-like polarization of macrophages, was shown to be secreted by CAFs References_end </body> </html> </notes> <label text="IL13"/> <bbox w="80.0" h="40.0" x="620.0" y="3690.0"/> </glyph> <glyph class="macromolecule" id="s4968_sa1137" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: vascular endothelial growth factor A HUGO:VEGFA hgnc_id:HGNC:12680 HGNC:12680 ENTREZ:7422 UNIPROT:P15692 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:GROWTH_FACTORS_PRODUCTION MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:IL6 PMID:24346288 IL-6 promoted VEGF expression by fibroblasts but not by cancer cell lines PMID:12629515; PMID:11960372 Probably IL6 induces VEGF expression in fibroblasts via STAT3 pathway (data from non fibroblasts only) PMID:16572188; PMID:9753319 Vascular endothelial growth factor (VEGF, also known as vascular permeability factor (VPF)) has a central role in the emergence of the reactive stroma27. VEGF can be released by cancer cells themselves, but fibroblasts and inflammatory cells are the principal source of host-derived VEGF28. VEGF induces microvascular permeability, which leads to the extravasation of plasma proteins such as fibrin, which in turn attract an influx of fibroblasts, inflammatory cells and endothelial cells27, 29, 30. These cells produce ECM that is rich in fibronectin and type I collagen, both of which are conducive to initiating tumour angiogenesis PMID:26201938 The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. PMID:19414323 overexpression of VEGF activity in tumours can lead to increased infiltration of TReg cells and MDSCs, which as discussed above are key cell types that trigger immunosuppression. References_end </body> </html> </notes> <label text="VEGFA"/> <bbox w="80.0" h="40.0" x="1200.0" y="4680.0"/> </glyph> <glyph class="macromolecule" id="s528_sa414" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: interferon gamma receptor 1 HUGO:IFNGR1 hgnc_id:HGNC:5439 HGNC:5439 ENTREZ:3459 UNIPROT:P15260 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IFNG Maps_Modules_end References_begin: PMID:17683974 IFNG dimer binds to receptor contained two IFNGR1 and two IFNGR2 subunits. References_end </body> </html> </notes> <label text="IFNGR1"/> <bbox w="80.0" h="50.0" x="2450.0" y="1205.0"/> <glyph class="state variable" id="_19ccc770-6f98-4a41-a856-1f537edbe981"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2445.0" y="1224.9602"/> </glyph> <glyph class="unit of information" id="_b552c35b-f906-4b6d-bc5c-4d8b4ee5fbdd"> <label text="receptor"/> <bbox w="45.0" h="10.0" x="2467.5" y="1200.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4444_sa58"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: serpin family E member 1 HUGO:SERPINE1 hgnc_id:HGNC:8583 HGNC:8583 ENTREZ:5054 UNIPROT:P05121 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF MODULE:CAF_INHIBITION_ANTITUMOR Maps_Modules_end References_begin: _INHIBITION_ANTITUMOR PMID:11021826 Fibroblastic expression (immunohistocheemistry) of both uPA and uPAR were positively correlated with tumor size. fibroblastic expression of PAI1 was related to the presence of invasion PMID:25502501 SERPINE1, which encodes PAI-1 and is a target of YAP/TAZ PAI-1 has been definitively linked to both profibrotic functions of cultured fibroblasts (20) and fibrosis in animal models and human disease. PMID:20027185 The proteolytic activities of uPA and plasmin are antagonized by the serine protease inhibitors (serpins) plasminogen activator inhibitor 1 (PAI1; also known as SERPINE1) and PAI2 (also known as SERPINB2) References_end </body> </html> </notes> <label text="SERPINE1"/> <bbox w="80.0" h="40.0" x="570.0" y="1440.0"/> </glyph> <glyph class="complex" id="s3589_csa20" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:IKBKG:IKK_alpha_*:IKK_beta_* Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: complex PMID‭:15145317, PMID:15573129 The activated IKK complex, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKK complex"/> <bbox w="100.0" h="164.0" x="2160.0" y="2288.0"/> <glyph class="macromolecule" id="s58_sa314"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: conserved helix-loop-helix ubiquitous kinase HUGO:CHUK hgnc_id:HGNC:1974 HGNC:1974 ENTREZ:1147 UNIPROT:O15111 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKKα*"/> <bbox w="80.0" h="40.0" x="2170.0" y="2390.0"/> <glyph class="state variable" id="_a46ca7ab-db22-49f2-9e41-722a2c0cfba0"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="2165.0" y="2405.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s649_sa313"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: inhibitor of nuclear factor kappa B kinase subunit gamma HUGO:IKBKG hgnc_id:HGNC:5961 HGNC:5961 ENTREZ:8517 UNIPROT:Q9Y6K9 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKBKG"/> <bbox w="80.0" h="40.0" x="2168.0" y="2295.0"/> <glyph class="state variable" id="_ef270ed0-7055-42ed-80fb-20286e4a568a"> <state value="Ub" variable=""/> <bbox w="20.0" h="10.0" x="2238.0" y="2310.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s650_sa312"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: inhibitor of nuclear factor kappa B kinase subunit beta HUGO:IKBKB hgnc_id:HGNC:5960 HGNC:5960 ENTREZ:3551 UNIPROT:O14920 Identifiers_end Maps_Modules_begin: MODULE:CAF CASCADE:IL1 MODULE:CORE Maps_Modules_end References_begin: PMID:20138012 To determine whether the tumor-promoting activity of the fibroblasts was dependent on NF-κB, we knocked down Ikkβ in CAFs using shRNA (Figure 5C). Knockdown of IKKβ did not have an effect in vitro on CAF survival (data not shown). IKKβ-shRNA CAFs were then coinjected orthotopically with PDSC5 cells. Tumors coinjected with shRNA IKKβ fibroblasts grew significantly slower than did tumors coinjected with control fibroblasts References_end </body> </html> </notes> <label text="IKKβ*"/> <bbox w="80.0" h="40.0" x="2170.0" y="2340.0"/> <glyph class="state variable" id="_16875806-2b47-48d5-96ad-7e5b0e50faba"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="2162.5" y="2355.0"/> </glyph> </glyph> </glyph> <glyph class="source and sink" id="s3586_sa299" compartmentRef="c5_ca5"> <label text="sa122_degraded"/> <bbox w="30.0" h="30.0" x="1705.0" y="3125.0"/> </glyph> <glyph class="source and sink" id="s4969_sa1140" compartmentRef="c5_ca5"> <label text="sa295_degraded"/> <bbox w="30.0" h="30.0" x="1705.0" y="2635.0"/> </glyph> <glyph class="complex" id="s4077_csa117" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DEPTOR:MLST8:MTOR:PRAS40*:RPTOR Identifiers_end Maps_Modules_begin: MODULE:DC MODULE:NK MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION Maps_Modules_end References_begin: CASCADE:IL15 CASCADE:CSF2 PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR PMID:21981924 p62 is a key regulator of nutrient sensing in the mTORC1 pathway (data is not from fibroblasts). PMID:25002027 SQSTM1 (p62) p62 is a suppressor of inflammation and the CAF phenotype in the tumor microenvironment p62 KO cells displayed reduced mTORC1 activity References_end </body> </html> </notes> <label text="mTORC1*"/> <bbox w="210.0" h="210.0" x="3560.0" y="2990.0"/> <glyph class="macromolecule" id="s4082_sa1141"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MTOR Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR PMID:21981924 p62 is a key regulator of nutrient sensing in the mTORC1 pathway (data is not from fibroblasts). PMID:25002027 SQSTM1 (p62) p62 is a suppressor of inflammation and the CAF phenotype in the tumor microenvironment p62 KO cells displayed reduced mTORC1 activity. p62 regulates Myc expression via mTOR activation. References_end </body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="3575.0" y="3125.0"/> <glyph class="state variable" id="_1ef4e701-f753-4e79-9a3a-be00efff9f9b"> <state value="P" variable=""/> <bbox w="15.0" h="10.0" x="3567.5" y="3140.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4078_sa1142"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:RPTOR Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="RPTOR"/> <bbox w="80.0" h="40.0" x="3575.0" y="3065.0"/> </glyph> <glyph class="macromolecule" id="s4079_sa1143"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MLST8 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="3665.0" y="3065.0"/> </glyph> <glyph class="macromolecule" id="s4080_sa1144"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:DEPTOR Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="DEPTOR"/> <bbox w="80.0" h="40.0" x="3665.0" y="3115.0"/> </glyph> <glyph class="macromolecule" id="s4081_sa1145"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:AKT1S1 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="PRAS40*"/> <bbox w="80.0" h="40.0" x="3665.0" y="3005.0"/> </glyph> </glyph> <glyph class="complex" id="s4068_csa118" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:DEPTOR:MLST8:MTOR:PRAS40*:RPTOR Identifiers_end Maps_Modules_begin: MODULE:CORE_SIGNALING MODULE:CORE_ACTIVATION MODULE:DC MODULE:NK Maps_Modules_end References_begin: 16469695, 26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR 22504639, 20805416 Impaired mTORC1 signal resulted in the suppression of IL-10 production in DC. IL-10 expression was impaired at both protein and mRNA levels in RaptorDC−/− mice. 19143636 The signalling function of mTOR complex 1 is activated by Rheb-GTP. 20805416 mTOR pathway plays divergent roles during activation and differentiation of myeloid DCs (mDCs) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in mDCs activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on mDCs and significantly increased the T cell allostimulatory potential of mDCs. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. References_end </body> </html> </notes> <label text="mTORC1*"/> <bbox w="210.0" h="210.0" x="3905.0" y="2995.0"/> <glyph class="macromolecule" id="s2257_sa1146"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MTOR Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR PMID:21981924 p62 is a key regulator of nutrient sensing in the mTORC1 pathway (data is not from fibroblasts). PMID:25002027 SQSTM1 (p62) p62 is a suppressor of inflammation and the CAF phenotype in the tumor microenvironment p62 KO cells displayed reduced mTORC1 activity. p62 regulates Myc expression via mTOR activation. References_end </body> </html> </notes> <label text="MTOR"/> <bbox w="80.0" h="40.0" x="3920.0" y="3130.0"/> <glyph class="state variable" id="_69fd5aaf-5a3b-4f2d-ab90-ccb00f261f81"> <state value="" variable=""/> <bbox w="10.0" h="10.0" x="3915.0" y="3145.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s2258_sa1147"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:RPTOR Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="RPTOR"/> <bbox w="80.0" h="40.0" x="3920.0" y="3070.0"/> </glyph> <glyph class="macromolecule" id="s1978_sa1148"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:MLST8 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="MLST8"/> <bbox w="80.0" h="40.0" x="4010.0" y="3070.0"/> </glyph> <glyph class="macromolecule" id="s1979_sa1149"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:DEPTOR Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="DEPTOR"/> <bbox w="80.0" h="40.0" x="4010.0" y="3120.0"/> </glyph> <glyph class="macromolecule" id="s1980_sa1150"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:AKT1S1 Maps_Modules_begin: MODULE:CAF MODULE:CORE Maps_Modules_end References_begin: PMID:16469695, PMID:26159692 mTOR Complex 1 (mTORC1) is composed of mTOR itself, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the recently identified PRAS40 and DEPTOR References_end </body> </html> </notes> <label text="PRAS40*"/> <bbox w="80.0" h="40.0" x="4010.0" y="3010.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4970_sa1151" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLS Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: MODULE METABOLIC PMID:25002027 SQSTM1 (p62) p62 We also observed a decrease in the direct conversion of [U-13C5] glutamine to glutamate in p62 KO fibroblasts, with a relative increase in the fraction of glutamate derived from [1,2-13C2]glucose and reduced levels of the glutamine transporters SLC7A5 and SLC1A5, as well as glutaminase-1 (GLS1) (Figure 4O), a critical enzyme in the pathway that catalyzes the conversion of glutamine into glutamate References_end </body> </html> </notes> <label text="GLS"/> <bbox w="80.0" h="40.0" x="2980.0" y="3630.0"/> </glyph> <glyph class="nucleic acid feature" id="s4971_sa1152" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLS Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: MODULE METABOLIC PMID:25002027 SQSTM1 (p62) p62 We also observed a decrease in the direct conversion of [U-13C5] glutamine to glutamate in p62 KO fibroblasts, with a relative increase in the fraction of glutamate derived from [1,2-13C2]glucose and reduced levels of the glutamine transporters SLC7A5 and SLC1A5, as well as glutaminase-1 (GLS1) (Figure 4O), a critical enzyme in the pathway that catalyzes the conversion of glutamine into glutamate References_end </body> </html> </notes> <label text="GLS"/> <bbox w="90.0" h="25.0" x="2835.0" y="3637.5"/> <glyph class="unit of information" id="_7d160983-86ac-432c-88f5-ff2e3251557a"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="2870.0" y="3632.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4972_sa1153" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:GLS Maps_Modules_begin: MODULE:CAF Maps_Modules_end References_begin: MODULE METABOLIC PMID:25002027 SQSTM1 (p62) p62 We also observed a decrease in the direct conversion of [U-13C5] glutamine to glutamate in p62 KO fibroblasts, with a relative increase in the fraction of glutamate derived from [1,2-13C2]glucose and reduced levels of the glutamine transporters SLC7A5 and SLC1A5, as well as glutaminase-1 (GLS1) (Figure 4O), a critical enzyme in the pathway that catalyzes the conversion of glutamine into glutamate p62 regulates GLS expression via mTOR/myc pathway References_end </body> </html> </notes> <label text="GLS"/> <bbox w="70.0" h="25.0" x="2705.0" y="3637.5"/> </glyph> <glyph class="nucleic acid feature" id="s4973_sa1154" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC HUGO:MYC Maps_Modules_end References_begin: PMID:25002027 We found significantly reduced levels of c-Myc in p62 KO fibroblasts as well as in WT fibroblasts in which p62 has been knocked down by shRNA References_end </body> </html> </notes> <label text="MYC"/> <bbox w="90.0" h="25.0" x="3355.0" y="3407.5"/> <glyph class="unit of information" id="_6119bb82-f62d-494a-b2ef-bce197412537"> <label text="RNA"/> <bbox w="20.0" h="10.0" x="3390.0" y="3402.5"/> </glyph> </glyph> <glyph class="nucleic acid feature" id="s4974_sa1155" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Maps_Modules_begin: MODULE:CAF MODULE:METABOLIC HUGO:MYC Maps_Modules_end References_begin: PMID:25002027 We found significantly reduced levels of c-Myc in p62 KO fibroblasts as well as in WT fibroblasts in which p62 has been knocked down by shRNA References_end </body> </html> </notes> <label text="MYC"/> <bbox w="70.0" h="25.0" x="3365.0" y="3347.5"/> </glyph> <glyph class="macromolecule" id="s4975_sa1157" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CDC42EP3 Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: PMID:27248291 Cdc42 regulates Cdc42EP3 function in cancer-associated ﬁbroblasts Cdc42-binding defective mutant of Cdc42EP3 (Cdc42EP3-IS) could not interact with actin. Inhibiting Cdc42 function by transient expression of the dominant negative Cdc42-N17 protein resulted in a loss of ﬁlamentous Cdc42EP3 structures and reduced F-actin stress ﬁbers and ﬁlamentous SEPT2 PMID:26711338 Cdc42EP3/BORG2 is required for the matrix remodeling, invasion, angiogenesis, and tumor-growth-promoting abilities of CAFs. Cdc42EP3 functions by coordinating the actin and septin networks. Furthermore, depletion of SEPT2 has similar effects to those of loss of Cdc42EP3, indicating a role for the septin network in the tumor stroma. Cdc42EP3 Is Required for Mechano-transduction and YAP Activation References_end </body> </html> </notes> <label text="CDC42EP3"/> <clone/> <bbox w="80.0" h="40.0" x="6060.0" y="3330.0"/> </glyph> <glyph class="macromolecule" id="s4975_sa1161" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:CDC42EP3 Maps_Modules_begin: MODULE:MOTILITY MODULE:CAF Maps_Modules_end References_begin: PMID:27248291 Cdc42 regulates Cdc42EP3 function in cancer-associated ﬁbroblasts Cdc42-binding defective mutant of Cdc42EP3 (Cdc42EP3-IS) could not interact with actin. Inhibiting Cdc42 function by transient expression of the dominant negative Cdc42-N17 protein resulted in a loss of ﬁlamentous Cdc42EP3 structures and reduced F-actin stress ﬁbers and ﬁlamentous SEPT2 PMID:26711338 Cdc42EP3/BORG2 is required for the matrix remodeling, invasion, angiogenesis, and tumor-growth-promoting abilities of CAFs. Cdc42EP3 functions by coordinating the actin and septin networks. Furthermore, depletion of SEPT2 has similar effects to those of loss of Cdc42EP3, indicating a role for the septin network in the tumor stroma. Cdc42EP3 Is Required for Mechano-transduction and YAP Activation References_end </body> </html> </notes> <label text="CDC42EP3"/> <clone/> <bbox w="80.0" h="40.0" x="6060.0" y="3240.0"/> </glyph> <glyph class="macromolecule" id="s4976_sa1158" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> HUGO:SEPT1 HUGO:SEPT2 HUGO:SEPT3 HUGO:SEPT4 HUGO:SEPT5 HUGO:SEPT6 HUGO:SEPT7 HUGO:SEPT8 HUGO:SEPT9 HUGO:SEPT10 HUGO:SEPT11 HUGO:SEPT12 HUGO:SEPT14 MODULE:MOTILITY MODULE:CAF References_begin: PMID:22314400 Septins: the fourth component of the cytoskeleton (REW) PMID:26711338 Cdc42EP3/BORG2 is required for the matrix remodeling, invasion, angiogenesis, and tumor-growth-promoting abilities of CAFs. Cdc42EP3 functions by coordinating the actin and septin networks. Furthermore, depletion of SEPT2 has similar effects to those of loss of Cdc42EP3, indicating a role for the septin network in the tumor stroma. Altered Septin Networks Are a Feature of CAFs EPT2 and SEPT7 formed more extensive networks in CAFs AFs Require Cdc42EP3 and SEPT2 to Promote Angiogenesis and Tumor Growth References_end </body> </html> </notes> <label text="SEPTINS*"/> <bbox w="80.0" h="40.0" x="6120.0" y="3440.0"/> </glyph> <glyph class="phenotype" id="s4977_sa1159" compartmentRef="c5_ca5"> <label text="Septins_polymerization"/> <bbox w="220.0" h="45.0" x="6050.0" y="3607.5"/> </glyph> <glyph class="complex" id="s4979_csa119" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>Identifiers_begin: NAME:LAMA*:LAMB*:LAMC* Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMININS"/> <bbox w="130.0" h="140.0" x="5285.0" y="3990.0"/> <glyph class="macromolecule" id="s4362_sa1163"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: laminin subunit alpha 1 HUGO:LAMA1 hgnc_id:HGNC:6481 HGNC:6481 ENTREZ:284217 UNIPROT:P25391 laminin subunit alpha 2 HUGO:LAMA2 hgnc_id:HGNC:6482 HGNC:6482 ENTREZ:3908 UNIPROT:P24043 laminin subunit alpha 3 HUGO:LAMA3 hgnc_id:HGNC:6483 HGNC:6483 ENTREZ:3909 UNIPROT:Q16787 laminin subunit alpha 4 HUGO:LAMA4 hgnc_id:HGNC:6484 HGNC:6484 ENTREZ:3910 UNIPROT:Q16363 laminin subunit alpha 5 HUGO:LAMA5 hgnc_id:HGNC:6485 HGNC:6485 ENTREZ:3911 UNIPROT:O15230 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:MATRIX_REGULATION MODULE:CAF Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMA*"/> <bbox w="80.0" h="40.0" x="5305.0" y="4000.0"/> </glyph> <glyph class="macromolecule" id="s4363_sa1164"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: laminin subunit beta 1 HUGO:LAMB1 hgnc_id:HGNC:6486 HGNC:6486 ENTREZ:3912 UNIPROT:P07942 laminin subunit beta 2 HUGO:LAMB2 hgnc_id:HGNC:6487 HGNC:6487 ENTREZ:3913 UNIPROT:P55268 laminin subunit beta 3 HUGO:LAMB3 hgnc_id:HGNC:6490 HGNC:6490 ENTREZ:3914 UNIPROT:Q13751 laminin subunit beta 4 HUGO:LAMB4 hgnc_id:HGNC:6491 HGNC:6491 ENTREZ:22798 UNIPROT:A4D0S4 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:MATRIX_REGULATION MODULE:INTEGRINS_SIGNALING_PATHWAYS Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMB*"/> <bbox w="80.0" h="40.0" x="5305.0" y="4030.0"/> </glyph> <glyph class="macromolecule" id="s4364_sa1165"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: laminin subunit gamma 1 HUGO:LAMC1 hgnc_id:HGNC:6492 HGNC:6492 ENTREZ:3915 UNIPROT:P11047 laminin subunit gamma 2 HUGO:LAMC2 hgnc_id:HGNC:6493 HGNC:6493 ENTREZ:3918 UNIPROT:Q13753 laminin subunit gamma 3 HUGO:LAMC3 hgnc_id:HGNC:6494 HGNC:6494 ENTREZ:10319 UNIPROT:Q9Y6N6 Identifiers_end Maps_Modules_begin: MODULE:INTEGRINS_SIGNALING_PATHWAYS MODULE:CAF MODULE:MATRIX_REGULATION Maps_Modules_end References_begin: CASCADE:INTEGRIN PMID:26519775 a3b1 integrin is a Laminin receptor PMID:16572188 Fibroblasts synthesize many of the constituents of the fibrillar ECM such as type I (genes COL1A1, COL1A2), type III (COL3A1) and type V collagen (COL5A1, COL5A2, COL5A3), and fibronectin. They also contribute to the formation of basement membranes by secreting type IV collagen (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6) and laminin. References_end </body> </html> </notes> <label text="LAMC*"/> <bbox w="80.0" h="40.0" x="5305.0" y="4070.0"/> </glyph> </glyph> <glyph class="macromolecule" id="s4983_sa1166" compartmentRef="c6_ca6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: C-X-C motif chemokine ligand 12 HUGO:CXCL12 hgnc_id:HGNC:10672 HGNC:10672 ENTREZ:6387 UNIPROT:P48061 Identifiers_end Maps_Modules_begin: MODULE:CAF MODULE:CYTOKINES_CHEMOKINES_PRODUCTION MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:TREG_MODULATORS Maps_Modules_end References_begin: CASCADE:CXCL12 CASCADE:TGFB CASCADE:HGF PMID:23034983 TGFB upregulates gene expression of CAF markers , FSP1 (S100A4), and TNC. (provably via SMAD3), and gene expression of CCL5, SDF1(CXCL12), BMP4, IL6, CXCL7, IL6R, IL6ST, CXCL5 PMID:15882617 CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1. PMID:23402812 Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. HGF induces expression markers of activated fibroblasts such as FAP, CXCL12 (SDF1),aplpha-SMA PMID:15261139 The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. PMID:24277834 Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. PMID:20535745 CXCR4 receptor and CXCL12 both are expressed in fibroblasts and probably provides positive loop in fibroblast activation PMID:23567181 CAF-mediated recruitment of T lymphocytes is facilitated by secretion of chemokines and cytokines that promote the recruitment of tumor-promoting T cells, including CXCL9, CXCL10, and CXCL12 (SDF-1α) PMID:21521526 Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers Our data show that in the setting of hypoxia and CXCR4 up-regulation in Treg, CXCL12 expression may have the negative consequence of enhancing Treg recruitment and suppressing the anti-tumour immune response. References_end </body> </html> </notes> <label text="CXCL12"/> <bbox w="80.0" h="40.0" x="760.0" y="4760.0"/> </glyph> <glyph class="macromolecule" id="s4984_sa1167" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Fas associated via death domain HUGO:FADD hgnc_id:HGNC:3573 HGNC:3573 ENTREZ:8772 UNIPROT:Q13158 Identifiers_end Maps_Modules_begin: MODULE:INFLAMMATORY_SIGNALING_PATHWAYS Maps_Modules_end </body> </html> </notes> <label text="FADD"/> <bbox w="80.0" h="40.0" x="1239.5385" y="1596.7693"/> </glyph> <glyph class="macromolecule" id="s4985_sa1169" compartmentRef="c5_ca5"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body> Identifiers_begin: Janus kinase 1 HUGO:JAK1 hgnc_id:HGNC:6190 HGNC:6190 ENTREZ:3716 UNIPROT:P23458 Identifiers_end References_begin: MODULE:CAF MODULE:INFLAMMATORY_SIGNALING_PATHWAYS MODULE:CAF_INHIBITION_ANTITUMOR CASCADE:IL6 CASCADE:PLAU CASCADE:LIF CASCADE:IFNG PMID:21840487 CAF-dependent matrix remodelling is essential for collective carcinoma cell invasion JAK kinase inhibitor P6 tested blocked remodelling (Hooper et al., 2010). P6 inhibits multiple members of the JAK family (Pedranzini et al., 2006), so we used JAK isoform-specific inhibitors to probe which JAKs are involved; neither JAK2 nor JAK3-specific inhibitors recapitulated the effect of the pan-JAK inhibitor (P6) on matrix remodelling (Figure 1A), suggesting that JAKI is the family member involved. 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x="4183.015" y="972.0"/> <port id="pr_bd9c8e2c-e0cc-4c37-a926-f4b2a5d7d592_p2" x="4183.015" y="1002.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_9a77b2a4-a0b7-4475-b77b-782243e8acd2"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:15145317 The activated IKK complex, predominantly acting through IKKb in an IKKg-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. PMID:17485448 IL10 Iinhibits IKBa‭ ‬phosphorylation and proteasomal degradation and prevents activation of downstream‭ ‬NFkB‭ ‬signaling. PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1.. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2334.5" y="2939.5"/> <port id="pr_9a77b2a4-a0b7-4475-b77b-782243e8acd2_p1" x="2324.5" y="2944.5"/> <port id="pr_9a77b2a4-a0b7-4475-b77b-782243e8acd2_p2" x="2354.5" y="2944.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_f5c79fd1-e60f-4e79-87a3-69d3986157fe"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:15145317 The activated IKK complex catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of IkBa), polyubiquitination (at sites equivalent to Lys21 and Lys22 of IkBa) and subsequent degradation by the 26S proteasome. The released NF-kB dimers (in this pathway, most commonly the p50– RelA dimer) translocate to the nucleus, bind DNA and activate gene transcription. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2395.3738" y="3176.17"/> <port id="pr_f5c79fd1-e60f-4e79-87a3-69d3986157fe_p1" x="2400.3738" y="3166.17"/> <port id="pr_f5c79fd1-e60f-4e79-87a3-69d3986157fe_p2" x="2400.3738" y="3196.17"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_0e39187b-dc61-4269-8595-f0e50140ef3d"> <bbox w="10.0" h="10.0" x="2039.625" y="2928.5"/> <port id="pr_0e39187b-dc61-4269-8595-f0e50140ef3d_p1" x="2029.625" y="2933.5"/> <port id="pr_0e39187b-dc61-4269-8595-f0e50140ef3d_p2" x="2059.625" y="2933.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_27d89ec7-f89b-4db2-a198-8e6b550a6876"> <bbox w="10.0" h="10.0" x="2099.6426" y="3158.0"/> <port id="pr_27d89ec7-f89b-4db2-a198-8e6b550a6876_p1" x="2104.6426" y="3148.0"/> <port id="pr_27d89ec7-f89b-4db2-a198-8e6b550a6876_p2" x="2104.6426" y="3178.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_079bc99a-514e-4831-9e0a-269d7ef70869"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14660645, PMID:18264787, PMID:11460167 Activated TAK1 phosphorylates IKK-beta proteins leading to activation of NF-κB downstream of HMGB1. PMID:21232017, PMID:21133840, PMID:17301840 PMID:24958845, PMID:24699077 The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex downstream of TNF and upregulates IkBa degradetion. PMID:11280761 VEGF signaling blocs TNF-α induced activation of IκB kinase (IKK complex).This decreased IKK activation correlated with the inhibition of IκBα phosphorylation and degradation of IκBα and IκBε in HPCs, and this inhibition is inhdependent or FLT1 and KDR References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2165.0" y="2240.0"/> <port id="pr_079bc99a-514e-4831-9e0a-269d7ef70869_p1" x="2170.0" y="2230.0"/> <port id="pr_079bc99a-514e-4831-9e0a-269d7ef70869_p2" x="2170.0" y="2260.0"/> </glyph> <glyph class="and" orientation="horizontal" id="logicglyph_57ad1633-748b-4940-ba03-68ad5a2a7d0b"> <bbox w="20.0" h="20.0" x="1600.0" y="1980.0"/> <port id="logicglyph_57ad1633-748b-4940-ba03-68ad5a2a7d0b_p1" x="1590.0" y="1990.0"/> <port id="logicglyph_57ad1633-748b-4940-ba03-68ad5a2a7d0b_p2" x="1630.0" y="1990.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_8cf5fff2-5558-4347-b818-8cb28b34bdfe"> <bbox w="10.0" h="10.0" x="1715.0" y="3172.5"/> <port id="pr_8cf5fff2-5558-4347-b818-8cb28b34bdfe_p1" x="1720.0" y="3192.5"/> <port id="pr_8cf5fff2-5558-4347-b818-8cb28b34bdfe_p2" x="1720.0" y="3162.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_a7a29ab8-8827-4131-a1c4-aed97a6e838a"> <bbox w="10.0" h="10.0" x="2188.8235" y="3452.5"/> <port id="pr_a7a29ab8-8827-4131-a1c4-aed97a6e838a_p1" x="2193.8235" y="3442.5"/> <port id="pr_a7a29ab8-8827-4131-a1c4-aed97a6e838a_p2" x="2193.8235" y="3472.5"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_b8aaa95c-aaea-494e-9ed9-7419a82e8118"> <bbox w="10.0" h="10.0" x="2282.5" y="3463.25"/> <port id="pr_b8aaa95c-aaea-494e-9ed9-7419a82e8118_p1" x="2302.5" y="3468.25"/> <port id="pr_b8aaa95c-aaea-494e-9ed9-7419a82e8118_p2" x="2272.5" y="3468.25"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7a429a94-b3c7-4ca4-a339-5cbbc61da299"> <bbox w="10.0" h="10.0" x="2195.0" y="3545.0"/> <port id="pr_7a429a94-b3c7-4ca4-a339-5cbbc61da299_p1" x="2200.0" y="3535.0"/> <port id="pr_7a429a94-b3c7-4ca4-a339-5cbbc61da299_p2" x="2200.0" y="3565.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_218b0f11-b1f5-43e9-87aa-340a719da2e9"> <bbox w="10.0" h="10.0" x="1981.0945" y="2673.0137"/> <port id="pr_218b0f11-b1f5-43e9-87aa-340a719da2e9_p1" x="1986.0945" y="2663.0137"/> <port id="pr_218b0f11-b1f5-43e9-87aa-340a719da2e9_p2" x="1986.0945" y="2693.0137"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e132ec19-4500-43a1-944e-9ad42ded324d"> <bbox w="10.0" h="10.0" x="2274.3584" y="2658.0095"/> <port id="pr_e132ec19-4500-43a1-944e-9ad42ded324d_p1" x="2279.3584" y="2648.0095"/> <port id="pr_e132ec19-4500-43a1-944e-9ad42ded324d_p2" x="2279.3584" y="2678.0095"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_dea16770-ddea-462f-843e-43385f1da1d8"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:14660645, PMID:18264787, PMID:12620219 IRAK-1 interacts with the downstream adaptor TRAF6, resulting in formation of a complex that also includes TAK1 and TAB2. IRAK-1 mediates the translocation of TRAF6, TAK1, and TAB2 to the cytosol, where they form a multiprotein complex with other cytosolic proteins, which are needed for stimulation of TAK1 kinase activity. PMID:12150927 IRAK3 (IRAK-M) is a negative regulator of Toll-like receptor signaling in macrophages. It prevented dissociation of IRAK and IRAK-4 from MyD88 and formation of IRAK-TRAF6 complexes. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="1895.0" y="1755.0"/> <port id="pr_dea16770-ddea-462f-843e-43385f1da1d8_p1" x="1885.0" y="1760.0"/> <port id="pr_dea16770-ddea-462f-843e-43385f1da1d8_p2" x="1915.0" y="1760.0"/> </glyph> <glyph class="process" orientation="horizontal" id="pr_05437526-0e13-4d52-b4e5-57b18d7ffcc6"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:12620219 MyD88 mediates a close interaction of the two related IRAK molecules, which is essential to allow IRAK-4 to phosphorylate IRAK-1. Phosphorylation of IRAK-1 reduces its affinity for MyD88, while increasing its affinity for TRAF6 References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="2105.0" y="1505.0"/> <port id="pr_05437526-0e13-4d52-b4e5-57b18d7ffcc6_p1" x="2125.0" y="1510.0"/> <port id="pr_05437526-0e13-4d52-b4e5-57b18d7ffcc6_p2" x="2095.0" y="1510.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_1ecb462e-44ca-49d1-a128-59adfc87c582"> <bbox w="10.0" h="10.0" x="1844.0043" y="2236.6414"/> <port id="pr_1ecb462e-44ca-49d1-a128-59adfc87c582_p1" x="1849.0043" y="2226.6414"/> <port id="pr_1ecb462e-44ca-49d1-a128-59adfc87c582_p2" x="1849.0043" y="2256.6414"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3ccffa68-74f4-4b32-996c-165f4e399fc6"> <bbox w="10.0" h="10.0" x="1091.4667" y="1752.0"/> <port id="pr_3ccffa68-74f4-4b32-996c-165f4e399fc6_p1" x="1096.4667" y="1742.0"/> <port id="pr_3ccffa68-74f4-4b32-996c-165f4e399fc6_p2" x="1096.4667" y="1772.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_e36672c1-9f6d-465b-ad22-53d77ead2226"> <bbox w="10.0" h="10.0" x="1385.0625" y="1362.0"/> <port id="pr_e36672c1-9f6d-465b-ad22-53d77ead2226_p1" x="1390.0625" y="1352.0"/> <port id="pr_e36672c1-9f6d-465b-ad22-53d77ead2226_p2" x="1390.0625" y="1382.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_dfbe965e-1dda-4816-a5dc-00f73ce36e58"> <bbox w="10.0" h="10.0" x="1488.0435" y="1645.0"/> <port id="pr_dfbe965e-1dda-4816-a5dc-00f73ce36e58_p1" x="1493.0435" y="1635.0"/> <port id="pr_dfbe965e-1dda-4816-a5dc-00f73ce36e58_p2" x="1493.0435" y="1665.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_3534435b-18aa-4306-9abf-82fa50e10feb"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:22003200 IRF4 is a target of MIR125B1, inhibition of IRF4 by MIR125B1 resulted in increased surface expression of MHC II, CD40, CD86, CD80 and IFNGR. MIR125B potentiate response to IFNG, probably via induction of IFNGR surface expression and induces tumoricidal activity of macrophages. 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References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="4030.0" y="2360.0"/> <port id="pr_4f5e471b-ece6-446b-bcc6-2492846ba3b0_p1" x="4035.0" y="2350.0"/> <port id="pr_4f5e471b-ece6-446b-bcc6-2492846ba3b0_p2" x="4035.0" y="2380.0"/> </glyph> <glyph class="process" orientation="vertical" id="pr_7487cbc5-b1ed-4417-82d9-3cde11ae5301"> <bbox w="10.0" h="10.0" x="3885.0" y="2407.5"/> <port id="pr_7487cbc5-b1ed-4417-82d9-3cde11ae5301_p1" x="3890.0" y="2397.5"/> <port id="pr_7487cbc5-b1ed-4417-82d9-3cde11ae5301_p2" x="3890.0" y="2427.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_88456137-0721-4614-8704-01c95b01d67d"> <bbox w="10.0" h="10.0" x="5151.199" y="2778.75"/> <port id="pr_88456137-0721-4614-8704-01c95b01d67d_p1" x="5156.199" y="2768.75"/> <port id="pr_88456137-0721-4614-8704-01c95b01d67d_p2" x="5156.199" y="2798.75"/> </glyph> <glyph class="process" orientation="vertical" id="pr_0d6dbf5b-f976-476d-9fba-e7dbb3d91e51"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways induce JNK activation and downstrean c-jun phosphorylation. References_end </body> </html> </notes> <bbox w="10.0" h="10.0" x="5120.0" y="3270.5"/> <port id="pr_0d6dbf5b-f976-476d-9fba-e7dbb3d91e51_p1" x="5125.0" y="3260.5"/> <port id="pr_0d6dbf5b-f976-476d-9fba-e7dbb3d91e51_p2" x="5125.0" y="3290.5"/> </glyph> <glyph class="process" orientation="vertical" id="pr_6060a668-654b-4ff1-8770-24972dd9a64a"> <notes> <html xmlns="http://www.w3.org/1999/xhtml" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"> <head> <title/> </head> <body>References_begin: PMID:11875494 IL10-induced p38 phosphorylation. PMID:20435894 SHIP inhibit MAPKp38 activation and prevent MKNK1 phosphorylation by inhibiting the p38MAPK pathway downstream of IL10. PMID:10925299 IL13 induces p38 MAPK phosphorilation and activation, p38 MAPK participates in arginase activation downstream of IL13. PMID:23508573 HMGB1 induces activation (phosphorylation) of p38 via TLR4. PMID:12811837, PMID:16713974 TLR signaling can induces STAT1 phosphorylation via p38 and potentiate IFNG signaling. PMID:16713974 TLR2 activates (induces phosphorylation of) ERKs, JNKs, and p38 rapidly and transiently in control macrophages. This activation is inhibited by IFNG signaling. PMID:11438547, PMID:24378531 Both TNFR1 and TNFR2 signaling pathways are needed for activation of p38 MAPK. 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