-In the absence of Wnt ligands, b-catenin is phosphorylated by CK1 and GSK-3 in the context of a destruction complex with APC and Axin.
Phosphorylated b-catenin is consequently targeted for ubiquitination and degraded.
-In the presence of Wnt lignads, upon ligand binding, DVL1 (dishevelled) recruits the Axin-GSK-3 complex, resulting in the sequential phosphorylation of LRP6 by CK1 and GSK-3.
Phoshorylated LRP6 serves as a docking site for additional Axin-GSK-3 complex, resulting in the disassembly of the destruction complex.
Non phosphorylated and thus stabilized b-catenin translocates to the nucleus where it activates transcription of target genes together with LEF/TCFs
e_re527( EMT ):
When Wnt binds its receptor, Frizzled, beta-catenin is released to translocate from the cytoplasm to the nucleus, where it forms a complex with TCF and/or LEF transcription factors and stimulates cyclin D1 gene transcription
(Beta-catenin/TCF)- mediated cyclin D1 gene transcription is further regulated by active Rac signaling, phosphorylation by protein kinase A (PKA)
Rac1-GTP augments nuclear accumulation of b-catenin and physical association of Rac1 with b-catenin and/or TCF-4 may facilitate this process.
This culminates in the amplification of b-catenin signaling activity, resulting in enhanced transcriptional activation of perhaps a specific subset of Wnt target genes important in cancer progression.
e_re2( EMT ):
In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h.
Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation
TGFB can activate both SNAI1 and SNAI2 and thus promote EMT via both SMAD-dependent and -independent pathways
Activation of Slug (SNAI2) by two mechanisms:
-transcriptional activation of Slug by the CTNNB1and TCF/LEF complex
-activation of the ERK pathway.
When adherens junctions are established in dense cultures, ErbB1/2 and the ERK pathway become inactive, CTNNB1 is localized at adherens junctions, Slug expression is reduced, and E-cadherin transcription is induced.
Antibody-mediated disruption of adherens junctions led to nuclear CTNNB1 localization and enhanced beta-catenin signaling, induction of Slug and inhibition of E-cadherin expression.
Snail1 induces Snail2 transcription.
Snail is able to induce the expression of Slug and all other neural crest markers (Zic5, FoxD3, Twist and Ets1)
Snail2 activates the Snail2 promoter
Twist1 binds to an E-box on the proximate Snail2 promoter to induce its transcription.
HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression.
HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter.
Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1
HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression
Activation of KIT by binding to KITLG induces SNAI2 expression
e_re264( EMT ):
Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis.
The cyclin D1 gene is a direct target for transactivation by the beta-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter.
beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation
Cyclin D1 over-expression correlates with beta-catenin activation
e_re523( EMT ):
Snail binds directly to the E-boxes of the promoters of claudin et occludin genes, resulting in complete repression of their promoter activity
Snail and Slug bind to the E-box motifs present in the human Claudin-1 promoter.
High levels of Snail and Slug correlatedwith lowlevels of Claudin-1 expression.
It is proposed that Claudin-1 is a direct downstream target gene of Snail family factors in epithelial cells
The transcription factors B-catenin/Tcf complex has been shown to bind directly to the claudin-1 and claudin-2 promoters.
SNAI2 represses Claudin-1 expression
SNAI1 represses Claudin-1 expression
e_re1123( EMT ):
Role of TGFB in regulation of cell cycle:
Physiologically, TGFB is a potent inhibitor of cell cycle.
It induces expression of p15INK4B and represses expression of c-Myc
Low levels of c-Myc allows TGFB to induce p15INK4B and p21CIP1 transcription
e_re1247( EMT ):
ID2 is target of HIF1 upon hypoxic conditions
TGFB induces ETS1 transcriptional expression.
TGFB represses ID2 and ID3 transcriptional expression (PMID:15121845 and PMID:15181457)
ID2 may regulate the function of Ets1 to modulate the transcription of ZEB1 and ZEB2 without alteration of the transcription of Ets1.
Ets1 may act as an inducer of ZEB1 in collaboration with E47 (TCF3)
Participates in complexes:
In compartment: Nucleus
Participates in reactions:
As Reactant or Product: