PP2A dephosphorylates AXIN, APC and CTNNB1 in the destruction complex

Stable Identifier
R-HSA-3601585
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
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PP2A dephosphorylates AXIN, APC and CTNNB1 in the destruction complex
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AXIN is believed to be dephosphorylated upon WNT pathway stimulation, decreasing its affinity for beta-catenin (Willert et al, 1999; Jho et al 1999). AXIN has been shown to be a direct target of GSK3beta in vitro (Ikeda et al, 1998; Jho et al, 1999). In the absence of a WNT signal AXIN is phosphorylated at Thr519 and Ser524 by GSK3beta and at Ser531 by an unknown kinase. Mutation of these sites decreases the binding to beta-catenin and results in increased TCF-dependent signaling (Jho et al, 1999).


The destruction complex phosphatase PP2A has been implicated as both a positive and negative regulator of WNT and is a candidate for the WNT-dependent dephosphorylation of AXIN (Willert et al, 1999; reviewed in Kimelman and Xu, 2006; MacDonald et al, 2009). Stimulation of the WNT pathway leads to changes in AXIN mobility that are reproduced in vitro by dephosphorylation of immunoprecipitated AXIN by PP2A. Consistent with this, treatment of cells with the PP2A inhibitor okadaic acid blocks the dephosphorylation of AXIN upon treatment with WNT3A (Willert et al, 1999). Stimulation of the WNT pathway results in the recovery of less AXIN in a beta-catenin pulldown, and the AXIN that is isolated in this way is exclusively the phosphorylated form (Willert et al, 1999). In addition to dephosphorylating AXIN, PP2A has also been shown to dephosphorylate beta-catenin itself, as well as APC (Su et al, 2008; Ikeda et al, 2000).

Another candidate for the dephosphorylation of AXIN is PP1. PP1 interacts with AXIN and PP1-dependent dephosphorylation of AXIN decreases the AXIN-GSK3beta interaction and inhibits beta-catenin phosphorylation (Luo et al, 2007).
Literature References
PubMed ID Title Journal Year
19061640 APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase

Su, Y, Fu, C, Ishikawa, S, Stella, A, Kojima, M, Shitoh, K, Schreiber, EM, Day, BW, Liu, B

Mol. Cell 2008
19619488 Wnt/beta-catenin signaling: components, mechanisms, and diseases

MacDonald, BT, Tamai, K, He, X

Dev Cell 2009
9482734 Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin

Ikeda, S, Kishida, S, Yamamoto, H, Murai, H, Koyama, S, Kikuchi, A

EMBO J. 1998
10421629 Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex

Willert, K, Shibamoto, S, Nusse, R

Genes Dev 1999
17318175 Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex

Luo, W, Peterson, A, Garcia, BA, Coombs, G, Kofahl, B, Heinrich, R, Shabanowitz, J, Hunt, DF, Yost, HJ, Virshup, DM

EMBO J. 2007
10581160 A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression

Jho, E, Lomvardas, S, Costantini, F

Biochem Biophys Res Commun 1999
10698523 GSK-3beta-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with Axin

Ikeda, S, Kishida, M, Matsuura, Y, Usui, H, Kikuchi, A

Oncogene 2000
17143292 beta-catenin destruction complex: insights and questions from a structural perspective

Kimelman, D, Xu, W

Oncogene 2006
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein serine/threonine phosphatase activity of p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complex [cytosol]

Physical Entity
p-S33,S37,T41,S45 CTNNB1:p-AXIN:CK1alpha:GSK3B:phospho-ub-APC (20 aa repeat region):PP2A:AMER1 complex [cytosol] (Homo sapiens)
Activity
protein serine/threonine phosphatase activity (GO:0004722)
Inferred From
Murine Axin1 is dephosphorylated by PP2A leading to reduced binding affinity with beta-catenin (Mus musculus)
Authored
Rothfels, K  (2013-05-27)
Reviewed
Rajakulendran, N  (2014-01-22)
van Amerongen, R  (2014-02-15)
Kikuchi, A  (2014-04-22)
Created
Rothfels, K  (2013-05-22)
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