HSP105 recruits protein phosphatase 2A To dephosphorylate ß-catenin

Nancy Yu, Michael Kakunda, Victoria Pham, Jennie R. Lill, Pan Du, Matthew Wongchenko, Yibing Yan, Ron Firestein, Xiao Dong Huang

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

The Wnt/ß-catenin pathway causes accumulation of ß-catenin in the cytoplasm and its subsequent translocation into the nucleus to initiate the transcription of the target genes. Without Wnt stimulation, ß-catenin forms a complex with axin (axis inhibitor), adenomatous polyposis coli (APC), casein kinase 1α (CK1α), and glycogen synthase kinase 3ß (GSK3ß) 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 ß-catenin degradation complex. HSP105 is required for Wnt signaling, since depletion of HSP105 compromises ß-catenin accumulation and target gene transcription upon Wnt stimulation. Mechanistically, HSP105 depletion disrupts the integration of PP2A into the ß-catenin degradation complex, favoring the hyperphosphorylation and degradation of ß-catenin. HSP105 is overexpressed in many types of tumors, correlating with increased nuclear ß-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.

Original languageEnglish
Pages (from-to)1390-1400
Number of pages11
JournalMolecular and Cellular Biology
Volume35
Issue number8
DOIs
Publication statusPublished - Apr 2015
Externally publishedYes

Cite this

Yu, N., Kakunda, M., Pham, V., Lill, J. R., Du, P., Wongchenko, M., ... Huang, X. D. (2015). HSP105 recruits protein phosphatase 2A To dephosphorylate ß-catenin. Molecular and Cellular Biology, 35(8), 1390-1400. https://doi.org/10.1128/MCB.01307-14
Yu, Nancy ; Kakunda, Michael ; Pham, Victoria ; Lill, Jennie R. ; Du, Pan ; Wongchenko, Matthew ; Yan, Yibing ; Firestein, Ron ; Huang, Xiao Dong. / HSP105 recruits protein phosphatase 2A To dephosphorylate ß-catenin. In: Molecular and Cellular Biology. 2015 ; Vol. 35, No. 8. pp. 1390-1400.
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Yu, N, Kakunda, M, Pham, V, Lill, JR, Du, P, Wongchenko, M, Yan, Y, Firestein, R & Huang, XD 2015, 'HSP105 recruits protein phosphatase 2A To dephosphorylate ß-catenin', Molecular and Cellular Biology, vol. 35, no. 8, pp. 1390-1400. https://doi.org/10.1128/MCB.01307-14

HSP105 recruits protein phosphatase 2A To dephosphorylate ß-catenin. / Yu, Nancy; Kakunda, Michael; Pham, Victoria; Lill, Jennie R.; Du, Pan; Wongchenko, Matthew; Yan, Yibing; Firestein, Ron; Huang, Xiao Dong.

In: Molecular and Cellular Biology, Vol. 35, No. 8, 04.2015, p. 1390-1400.

Research output: Contribution to journalArticleResearchpeer-review

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Yu N, Kakunda M, Pham V, Lill JR, Du P, Wongchenko M et al. HSP105 recruits protein phosphatase 2A To dephosphorylate ß-catenin. Molecular and Cellular Biology. 2015 Apr;35(8):1390-1400. https://doi.org/10.1128/MCB.01307-14