HSP105 Recruits Protein Phosphatase 2A To Dephosphorylate β-Catenin

Abstract

The Wnt/␤-catenin pathway causes accumulation of ␤-catenin in the cytoplasm and its subsequent translocation into the nucleus to initiate the transcription of the target genes. Without Wnt stimulation, ␤-catenin forms a complex with axin (axis inhibitor), adenomatous polyposis coli (APC), casein kinase 1␣ (CK1␣), and glycogen synthase kinase 3␤ (GSK3␤) 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 ␤-catenin degradation complex. HSP105 is required for Wnt signaling, since depletion of HSP105 compromises ␤-catenin accumulation and target gene transcription upon Wnt stimulation. Mechanistically, HSP105 depletion disrupts the integration of PP2A into the ␤-catenin degradation complex, favoring the hyperphosphorylation and degradation of ␤-catenin. HSP105 is overexpressed in many types of tumors, correlating with increased nuclear ␤-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.

Molecular regulation and pharmacological targeting of the β‐catenin destruction complex

“…PP2A is composed of a core catalytic subunit (PPP2CA), a structural subunit (PR65/A) and variable regulatory B subunits (Janssens and Goris, ). A consistent finding across numerous studies is that PP2A dephosphorylates β‐catenin to prevent its ubiquitination and support the Wnt activation pathway (Su et al, ; Zhang et al, ; Yu et al, ). In the first model, PP2A‐mediated dephosphorylation of the APC 20R region was proposed to mark the end of a destruction complex cycle, allowing phosphorylated β‐catenin to leave the complex and so initiate a new round of β‐catenin modifications (Xu and Kimelman, ).…”

“…PP1 interacts with axin (Luo et al, ), while PP2A was reported to bind both axin and APC (Hsu et al, ; Seeling et al, ; Yamamoto et al, ). Of note, PP2A binding to axin might be indirect, involving the heat shock protein 70 (HSP70) family member HSP105 (Yu et al, ). PP2A is composed of a core catalytic subunit (PPP2CA), a structural subunit (PR65/A) and variable regulatory B subunits (Janssens and Goris, ).…”

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

“…Colon cancer cells in which HSP110 has been shRNA-mediated and knocked down hardly proliferate, but proliferation is reactivated by the re-expression of HSP110 in these cells. Tumors from patients with high levels of HSP110 show high STAT3 phosphorylation levels and strong expression of proliferation markers [154,156]. Therefore, both the protein homeostasis function and the role of HSP110 on proliferative pathways may explain why this protein is linked to aggressive tumors.…”

“…Conversely, HSP110β can induce HSP70 expression through STAT3 in mammalian cells (Figure 4) [153]. It is now clearly established that HSP110 favors several signaling pathways, including the Wnt/β-Catenin, MyD88/TLR, and STAT3 pathways [154,155]. Localization and described functions of HSP110 and HSP70 within the STAT3 and STAT5 signaling pathways.…”

Identifying Molecular Chaperones as Therapeutic Targets for Cancer: A Mini Review

“…Hsp110 has been observed to participate in Wnt-mediated proliferation. Knockdown of Hsp110 results in degradation of β-catenin and inhibition of proliferation in colon cancer cell lines [85].…”