Murine Axin1 is dephosphorylated by PP2A leading to reduced binding affinity with beta-catenin

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).<br> <br><br>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). <br><br>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). <br>

AXIN被认为在WNT通路刺激下发生去磷酸化，从而降低其对β-连环蛋白的结合亲和力（Willert et al, 1999; Jho et al 1999）。研究表明，AXIN是GSK3beta在体外的一个直接靶点（Ikeda et al, 1998; Jho et al, 1999）。在缺乏WNT信号的情况下，AXIN在Thr519和Ser524位点上被GSK3beta磷酸化，而在Ser531位点上被一种未知的激酶磷酸化。这些位点的突变会降低与β-连环蛋白的结合，并导致TCF依赖性信号传导增加（Jho et al, 1999）。

破坏复合物磷酸酶PP2A被认为是WNT的正负调节因子，并是WNT依赖性去磷酸化AXIN的候选者（Willert et al, 1999; 见Kimelman和Xu, 2006年的综述；MacDonald et al, 2009）。WNT通路的刺激会导致AXIN的流动性发生变化，这在体外通过PP2A对免疫沉淀的AXIN去磷酸化得到重现。与此一致，用PP2A抑制剂okadaic酸处理细胞会阻断WNT3A处理后的AXIN去磷酸化（Willert et al, 1999）。WNT通路的刺激导致在β-连环蛋白沉淀中回收的AXIN减少，且通过这种方式分离的AXIN仅是磷酸化形式（Willert et al, 1999）。除了去磷酸化AXIN外，PP2A还被证明可以去磷酸化β-连环蛋白本身以及APC（Su et al, 2008; Ikeda et al, 2000）。

AXIN去磷酸化的另一个候选者是PP1。PP1与AXIN相互作用，PP1依赖性去磷酸化AXIN会降低AXIN-GSK3beta的相互作用并抑制β-连环蛋白的磷酸化（Luo et al, 2007）。