Reaction known_transition_omitted e_re464
APC|pho:AXIN1|pho:_beta_-Catenin*@Cytoplasm → APC|pho:AXIN1|pho:_beta_-Catenin*|pho@Cytoplasm
CSNK1 (casein kinase 1) but not CSNK2 (casein kinase 2) phosphorylates CTNNB1 at S45.
This priming phosphorylation results in subsequent phosphorylation by GSK3B at T41, S37, S33.
CTNNB1 that is phosphorylated at S33 and S37 is ultimately recognized by E3-ligase and targeted for proteasomal destruction.
Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes.
The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton.
decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction
Activation of the canonical Wnt signalling pathway results in stabilisation and nuclear translocation of b-catenin.
In the absence of a Wnt signal, b-catenin is phosphorylated at four conserved serine and threonine residues at the N-terminus of the protein, which results in b-catenin ubiquitination and proteasome-dependent degradation.
The phosphorylation of 3 of these residues, Thr41, Ser37, and Ser33, is mediated by glycogen synthase kinase-3 (GSK-3) in a sequential manner, beginning from the C-terminal Thr41.
It has recently been shown that the GSK-3 dependent phosphorylation of b-catenin requiresprior priming through phosphorylation of Ser45
GSK-3b wasfound to be unable to phosphorylate b-catenin at Ser45 in vitro and in intact cells.
In vitro, CK1, but not CK2, phosphorylates Ser45. Ser45 phosphorylation in intact cells is not mediated by CK1e, a known positive regulator of Wnt signalling.
Wnt regulation of b-catenin degradation is essential for development and carcinogenesis.
b-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation.
This phosphorylation is believed to be performed by GSK3B in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).
There is another Axin-associated kinase, whose phosphorylation of b-catenin precedes and is required for subsequent GSK-3 phosphorylation of b-catenin.
This priming kinase is casein kinase I -alpha (CSNK1A1).
Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity.
Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling