L1CAM

Protein L1CAM map

Identifiers
L1 cell adhesion molecule
HUGO:L1CAM HGNC:6470 ENTREZ:3897 UNIPROT:P32004 GENECARDS:L1CAM REACTOME:51346 KEGG:3897 ATLASONC:L1CAMID44110chXq28 WIKI:L1CAM

Maps_Modules
 EMT  map  / EMT_REGULATORS  map
 EMT  map  / CELL_CELL_ADHESIONS  map
 EMT  map  / ADHERENS_JUNCTIONS  map

References
ISBN:978-953-51-0410-0
PMID:8893017
PMID:20044598
The adhesion molecule L1CAM (CD171) is a 220 kD transmembrane glyocoprotein and belongs to the immunoglobulin superfamily.
The extracellular part of the molecule comprises six Ig-like domains followed by 5 fibronectin type III repeats.
The transmembrane domain is followed by a short cytoplasmic tail of 32kD
PMID:10413675
L1CAM can be expressed and mediate its effects as a membrane-bound form.
L1CAM can also be proteolytically cleaved by different proteases releasing a soluble ectodomain that is likewise functionally active.
PMID:16199880
PMID:11706054
The metalloproteases ADAM 10 and 17 as well as plasmin have been described to cleave L1CAM generating a soluble 200 kD and 150 kD form, respectively
After ADAM-mediated cleavage, the membrane-bound intracellular C-terminal fragment of L1CAM can be further processed by the presenilin/gamma-secretase complex giving rise of a 28 kD fragment.
PMID:19260824
This small intracellular fragment translocates into the nucleus where it is thought to contribute to L1CAM-dependent gene regulation.
L1CAM can bind to different substrates/molecules in a cell and context dependent manner.
PMID:10469653
LACAM can undergo homophilic binding to itself as a membrane-bound or shedded form.
PMID:9003039
L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons
Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism.
L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin.
Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin.
PMID:8898967
PMID:8636223
PMID:11553709
PMID:10455125
PMID:16377081
PMID:7613634
PMID:1720120
L1CAM can interact with a plethora of other proteins, e.g. integrins aVb1, aVb3, aVb5, a5b1, neuropilin-1, CD24, neurocan, and axonin-1/TAX-1.
PMID:6368220
L1CAM was originally identified in cells of the nervous system
PMID:9127006
L1CAM expression has been also found in certain populations of hematopoietic cells.
PMID:19273627
Potential role for L1CAM in transendothelial migration and trafficking of murine dendritic cells.
PMID:9864376
Furthermore, L1CAM is expressed by renal tubular epithelial cells under physiological conditions being involved in branching of renal tubes in the kidney
However, distribution of L1CAM in adults is quite restricted so that its elevated expression in cancerous tissues which is discussed in the next paragraph favours its suitability as therapeutic target in anti-cancer therapy.
PMID:19356150
PMID:21195665
L1CAM expression in tumors can be associated with the activation of several signalling pathways that are known to play a pivotal role in tumor progression e.g. the MAPK/ERK and AKT pathway or FAK-mediated signalling
PMID:15716380
PMID:17699774
PMID:20501702
L1CAM is a target gene of b-catenin-TCF signaling in colorectal cancer cells.
L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis
The transmembrane localization and shedding of L1CAM by metalloproteases, including ADAM10 could be useful for detection and as target for colon cancer therapy.
Expression of L1CAM and ADAM10 in human colon cancer cells induces metastasis. NFkB signaling and ezrin are essential for L1CAM-mediated metastasis of colon cancer cells.
PMID:21123622
Gavert and al. showed that L1CAM-mediated colon cancer cell metastasis does not require changes in EMT and cancer stem cell markers.
BUT in other context,
PMID:19435915
PMID:21109948
Geismann and al. showed that upregulation of L1CAM in pancreatic duct cells is TGFB1- and SNAI2-dependent.
Binding of SNAI2 to the L1CAM promoter is essential for TGFB1-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells.
TGFB1–mediated L1CAM expression is SMAD independent but requires JNK activation.
In the context of the human PDAC (pancreatic ductal epithelial cell) line H6c7 which mimics the early steps in PDAC tumorigenesis,TGFB1 induces SNAI2 expression in H6c7 cells through JNK activation.
THUS, the impact of L1CAM on EMT might be either tumor specific and/or tumor stage dependent.
Further studies are required to elaborate whether upregulation of L1CAM is part of the EMT or even the inducing event.
If it is the case, elevated cell migration and apoptosis resistance could be abolished by interfering wih TGFB1 signaling or by supression of SNAI2 or L1CAM.
PMID:16506207
PMID:17952127
PMID:21373966
Binding of L1CAM to aVb3 or aVb5 seemed to be pivotal for L1CAM-mediated cell migration leading to the activation of Erk1/2 and FAK signalling
In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes
L1CAM-mediated Erk1/2 activate genes encoding for pro-migratory proteins such as cathepsin-B or b3-integrins were upregulated.
A mechanism in the glioma cells context was proposed: upregulated ADAM10 proteolyzes surface L1CAM and the resultant ectodomain of L1CAM increases human glioma cell migration and invasion by binding to integrin receptors, activating FAK, and increasing turnover of focal complexes.
Besides its ability to induce Erk1/2 and FAK signalling pathways, L1CAM can also lead to the activation of NF-kB, so that inhibition of NF-kB reduced L1CAM-mediated metastasis of colon cancer cells.
PMID:17145883
Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases B-catenin transcriptional activity, thus increases scattering and motility of MCF7 breast carcinoma cells.

L1CAM@Cytoplasm

References
e_re417( EMT  map ):
PMID:15501236
VEGFR2 and aVb3 were observed to co-associate after stimulation with either L1 (Ig6 domain) or VEGFA (isoform of 165 amino acids)
VEGFR2 was tyrosine phosphorylated after stimulation with L1 (via Ig6 domain), even in the absence of exogenous VEGFA ( (isoform of 165 amino acids), indicating close cooperation between VEGFR2 and aVb3
e_re420( EMT  map ):
PMID:19161977
In the endoplasmic reticulum, integrin subunits find their binding partners and form heterodimers.
Monomeric integrins never reach the cell surface.
PMID:8636223
Integrin aVb3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components.
aVb3 can also interact with the neural cell adhesion molecule L1CAM; a member of the immunoglobulin superfamily (IgSF). In other words, aVb3 undergoes heterophilic binding with L1CAM
M21 cells display some aVb3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and aVb3 was also observed to promote significant haptotactic cell migration.
Significant aVb3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6.
Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion.
Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction.
These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent.
Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM.
aVb3 may recognize L1 in a cell-cell or cell-substrate interaction.
PMID:11553709
Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin aVb3 has been associated with the metastatic potential of tumor cells.
In the context of in vitro monolayer of human lung microvascular, L1CAM was shown to serve as a potential ligand for aVb3 during melanoma transendothelial migration.
Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells.
However, addition of both L1 and aVb3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system.
Together, the data suggest that interactions between the integrin aVb3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells.
Integrin aVb3 on melanoma cells, and not endothelial cells, is involved in the transmigration process.
Because L1 is expressed in both melanoma and endothelial cells, it is possible that L1-L1 homophilic interactions at the heterotypic contacts might play a role in the transmigration of melanoma cells.
The data thus indicate that transendothelial migration does not involve L1-L1 homophilic binding.
These results led us to speculate that L1 on endothelial cells, and not melanoma cells, has a role during transendothelial migration of melanoma cells
PMID:9003039
L1 also interacts heterophilically with laminin in the context of mouse small cerebellar neurons
Integrins (b1, a3, a6) could be shown to bind to laminin by a b1-dependent adhesion mechanism.
L1 was demonstrated to bind in a concentration-dependent and saturating manner to laminin.
Furthermore, antibodies to the Ig-like domains of L1 and b1 integrin inhibited partially cell adhesion to laminin.
e_re422( EMT  map ):
PMID:19401151
The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor.
Soluble L1CAM was able to stimulate growth and invasion of bovine aortic endothelial cells to a similar extent as the VEGF-A (isoform 165 amino acids)
Stimulation with soluble L1CAM led to tube formation of bovine aortic endothelial cells in vitro and increased angiogenesis in vivo.
The pro- angiogenic effect of soluble L1CAM could be abolished by treatment with the L1CAM specific antibody chCE7.
PMID:18931829
PDAC Endothelial cells are characterized by elevated L1CAM expression compared to HUVEC cells where L1CAM expression can be induced by TNFaIFNgor TGFB1
Antibody-mediated blockade of L1CAM abolished tube formation and tumor endothelial cell transmigration.
Integrins, especiallyv3, play a role in the activation ofVEGFR-
2, a key player in angiogenesis. Because both sL1 and VEGF are present in ascites fluid of ovarian carcinoma patients (Fogel et al., 2003a;Zebrowskiet al.,1999),weanalyzedtheactivation ofVEGFR-
2 in BAE cells in the presence of sL1 and VEGF-A165 (Fig. 6). The three-fold higher stimulation of VEGFR-2 with the combination of bothcomponents incomparison tothe single treatmentwithVEGF-
A165 could be explained by the activation of v3 integrin through the RGD sequence in the L1 molecule. v3 integrin is involved in the full activation of VEGFR-2 triggered by VEGF-A165 (Soldi et al., 1999). These findings are consistent with results published by Hall and co-workers (2004); Hall and Hubbell (2004). They showed that ligation of mouse L1Ig6 to v3 integrin stimulates VEGFR-2 and induces angiogenesis in vivo
Overall, these data point to a role of L1CAM as a pro-angiogenic factor and the potential of an anti-L1CAM antibody therapy in interfering with tumor angiogenesis (see below).


Modifications:
In compartment: Cytoplasm
  1. L1CAM@Cytoplasm map

  2. L1CAM|​hm2@Cytoplasm map

In compartment: Extracellular space

  1. L1CAM@Extracellular space map

Participates in complexes:
In compartment: Cytoplasm

  1. L1CAM:​VEGFR2*|​hm2@Cytoplasm map

  2. ITGAV:​ITGB3:​L1CAM@Cytoplasm map

Participates in reactions:
As Reactant or Product:

  1. L1CAM|​hm2@Cytoplasm map map Adherens junctions@Cytoplasm map

  2. L1CAM@Cytoplasm map + VEGFR2*@Cytoplasm map map L1CAM:​VEGFR2*|​hm2@Cytoplasm map
  3. L1CAM@Extracellular space map + L1CAM@Cytoplasm map map L1CAM|​hm2@Cytoplasm map
  4. L1CAM@Cytoplasm map + ITGAV:​ITGB3@Cytoplasm map map ITGAV:​ITGB3:​L1CAM@Cytoplasm map
  5. L1CAM@Cytoplasm map map Angiogenesis@Nucleus map
  6. ITGAV:​ITGB3:​L1CAM@Cytoplasm map map Cell migration@Cytoplasm map

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