Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer

Natela Dushukyan, Diana M. Dunn, Rebecca A. Sager, Mark R. Woodford, David R. Loiselle, Michael Daneshvar, Alexander J. Baker-Williams, John D. Chisholm, Andrew W. Truman, Cara K. Vaughan, Timothy A. Haystead, Gennady Bratslavsky, Dimitra Bourboulia, Mehdi Mollapour

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post-translational modifications also influence PP5 phosphatase activity. Here, we show an “on/off switch” mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. Overexpression of the phosphomimetic T362E-PP5 mutant hyper-dephosphorylates substrates such as the co-chaperone Cdc37 and glucocorticoid receptor in cells. Our proteomic approach revealed that the tumor suppressor von Hippel-Lindau protein (VHL) interacts with and ubiquitinates K185/K199-PP5 for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. Finally, VHL-deficient clear cell renal cell carcinoma (ccRCC) cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer. Dushukyan et al. show that casein kinase 1δ phosphorylates and activates protein phosphatase 5 (PP5), whereas von Hippel-Lindau protein (VHL) ubiquitinates and degrades PP5 in the proteasome. Kidney cancer cells with mutations and inactivation of VHL have elevated levels of PP5. Downregulation of PP5 causes apoptosis, demonstrating a prosurvival function for PP5 in kidney cancer.

Original languageEnglish (US)
Pages (from-to)1883-1895
Number of pages13
JournalCell Reports
Volume21
Issue number7
DOIs
StatePublished - Nov 14 2017

Keywords

  • PP5
  • VHL
  • casein kinase-1 δ
  • clear cell renal cell carcinoma
  • co-chaperone
  • heat shock protein 90
  • kidney cancer
  • molecular chaperone
  • serine/threonine phosphatase 5
  • von Hippel-Lindau protein

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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