HSP105 recruits protein phosphatase 2A to dephosphorylate β-catenin.

The Wnt/beta-catenin pathway causes accumulation of beta-catenin in the cytoplasm and its subsequent translocation into the nucleus to initiate the transcription of the target genes. Without Wnt stimulation, beta-catenin forms a complex with axin (axis inhibitor), adenomatous polyposis coli (APC), casein kinase 1 alpha (CK1 beta), and glycogen synthase kinase 3 beta (GSK3 beta) and undergoes phosphorylation-dependent ubiquitination. Phosphatases, such as protein phosphatase 2A (PP2A), interestingly, also are components of this degradation complex; therefore, a balance must be reached between phosphorylation and dephosphorylation. How this balance is regulated is largely unknown. Here we show that a heat shock protein, HSP105, is a previously unidentified component of the beta-catenin degradation complex. HSP105 is required for Wnt signaling, since depletion of HSP105 compromises beta-catenin accumulation and target gene transcription upon Wnt stimulation. Mechanistically, HSP105 depletion disrupts the integration of PP2A into the beta-catenin degradation complex, favoring the hyperphosphorylation and degradation of beta-catenin. HSP105 is overexpressed in many types of tumors, correlating with increased nuclear beta-catenin protein levels and Wnt target gene upregulation. Furthermore, overexpression of HSP105 is a prognostic biomarker that correlates with poor overall survival in breast cancer patients as well as melanoma patients participating in the BRIM2 clinical study.