PP2A and Wnt Signaling

During embryogenesis, the Wnt signaling pathway regulates cell proliferation and development [26]. An inappropriate activation of the Wnt pathway has been found in a wide variety of human cancers [24], where it promotes the growth of cancer cells by inducing cyclin D and c-myc. Currently, three genetic changes that cause an increase in p-catenin levels and activation of the Wnt signaling pathway are known. First, some mutations in the p-catenin gene alter specific N-terminal serine or threonine residues, thereby preventing p-catenin phosphorylation by GSK3p and degradation by the ubiquitin/proteosome pathway. Second, mutations in the APC gene that cause loss of APC binding to axin prevent recruitment of p-catenin into the p-catenin-destabilizing complex. Therefore, p-catenin escapes from degradation. Third, axin mutations in the p-catenin binding site destroy the ability of axin to recruit p-catenin into the destabilizing complex, also resulting in p-catenin accumulation. In addition, mutating PP2A may represents a fourth mechanism to activate the Wnt pathway as suggested by Seeling et al. [21], who reported that regulatory B' subunits bind to APC (Fig. 2, site Z). Furthermore, they found that overexpression of B' in 293 cells dramatically decreases the level of p-catenin. Importantly, B' inhibits p-catenin-dependent transcription by the transcription factor LEF. Seeling et al. proposed that PP2A may act as a tumor suppressor by down-regulating Wnt signaling through dephosphorylation and activation of GSK3p. Cancer-associated Aa or Ap mutations might prevent B'-mediated recruitment of PP2A into the p-catenin-destabilizing complex, resulting in downregu-lation of GSK3p and upregulation of Wnt signaling [37]. Yamamoto et al. [23] discovered that B' also binds to axin. The site of interaction (site X) is different from the binding sites for GSK3p, p-catenin, APC, and dishevelled (Dvl) (Fig. 2). They also found that B' suppresses p-catenin- and Tcf-dependent transcription [21]. Axin associates not only with the B' subunit but also with the catalytic C subunit [22]. The C subunit binding region (site Y) is separate from the B' binding region. It has been suggested that binding to site Y may stimulate Wnt signaling [41]. Ratcliffe et al. [42] studied the role of PP2A in early Xenopus embryos. They discovered that the B' subunit strongly inhibits secondary axis formation and Wnt signaling. The C subunit, on the other hand, appears to stimulate Wnt signaling [23,42].

The precise mechanism by which PP2A affects Wnt signaling remains to be elucidated. Willert et al. [43] suggested that PP2A dephosphorylates axin, resulting in release of p-catenin from the p-catenin-destabilizing complex [43]; however, according to this model, PP2A would actually

Figure 2 Multiple binding sites of PP2A in the P-catenin degradation complex.

Figure 2 Multiple binding sites of PP2A in the P-catenin degradation complex.

stimulate Wnt signaling. Yamamoto et al. [23] discussed whether PP2A controls APC-mediated nuclear export of P-catenin or acts on the transcription factor Tcf. In order to resolve these questions, it is important to identify the substrates for each PP2A molecule bound to the different sites on the P-catenin-destabilizing complex. At present, GSK3P, axin, P-catenin, and APC all have to be considered as potential substrates. While published reports on the role of PP2A in Wnt signaling are conflicting, there is general agreement that the B' subunit inhibits the Wnt pathway. All findings are consistent with the idea that the B' subunit, or the B'-containing holoenzyme, is a tumor suppressor that functions by downregulating the Wnt pathway. It is important to note that CKI5 and CKIe, which phosphorylate several components of the P-catenin degradation complex, are regulators of the Wnt signaling pathway[44,45].

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