title: HSP105 recruits protein phosphatase 2A to dephosphorylate β-catenin.
abstract: The Wnt/β-catenin pathway causes accumulation of β-catenin in the cytoplasm and its subsequent translocation into the nucleus to initiate the transcription of the target genes. Without Wnt stimulation, β-catenin forms a complex with axin (axis inhibitor), adenomatous polyposis coli (APC), casein kinase 1α (CK1α), and glycogen synthase kinase 3β (GSK3β) 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 β-catenin degradation complex. HSP105 is required for Wnt signaling, since depletion of HSP105 compromises β-catenin accumulation and target gene transcription upon Wnt stimulation. Mechanistically, HSP105 depletion disrupts the integration of PP2A into the β-catenin degradation complex, favoring the hyperphosphorylation and degradation of β-catenin. HSP105 is overexpressed in many types of tumors, correlating with increased nuclear β-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.
authors: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.
authors: Nancy
authors: N
authors: Yu
authors: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.
authors: Michael
authors: M
authors: Kakunda
authors: Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, USA.
authors: Victoria
authors: V
authors: Pham
authors: Department of Protein Chemistry, Genentech, Inc., South San Francisco, California, USA.
authors: Jennie R
authors: JR
authors: Lill
authors: Department of Bioinformatics, Genentech, Inc., South San Francisco, California, USA.
authors: Pan
authors: P
authors: Du
authors: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, USA.
authors: Matthew
authors: M
authors: Wongchenko
authors: Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, USA.
authors: Yibing
authors: Y
authors: Yan
authors: Department of Pathology, Genentech, Inc., South San Francisco, California, USA.
authors: Ron
authors: R
authors: Firestein
authors: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA huang.xiaodong@gene.com.
authors: XiaoDong
authors: X
authors: Huang
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D050957:HSP110 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011379:Prognosis; D060066:Protein Interaction Maps; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D050957:HSP110 Heat-Shock Proteins; C097205:HSPH1 protein, human; D034741:RNA, Small Interfering; D051176:beta Catenin; D054648:Protein Phosphatase 2
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