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

• Published in: Cell reports (Cambridge) 2017-11, Vol.21 (7), p.1883-1895
• Main Authors: Dushukyan, Natela, Dunn, Diana M., Sager, Rebecca A., Woodford, Mark R., Loiselle, David R., Daneshvar, Michael, Baker-Williams, Alexander J., Chisholm, John D., Truman, Andrew W., Vaughan, Cara K., Haystead, Timothy A., Bratslavsky, Gennady, Bourboulia, Dimitra, Mollapour, Mehdi
• Format: Article
• Language: English
• Subjects: Apoptosis; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; casein kinase-1 δ; Cell Line, Tumor; clear cell renal cell carcinoma; co-chaperone; Glycoproteins - genetics; Glycoproteins - metabolism; heat shock protein 90; Humans; kidney cancer; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; molecular chaperone; Phosphorylation; PP5; serine/threonine phosphatase 5; Ubiquitination; VHL; von Hippel-Lindau protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.10.074

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. [Display omitted] •Casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5•Phosphorylation activates and enhances the phosphatase activity of PP5•Von Hippel-Lindau protein (VHL) multi-monoubiquitinates PP5 on K185 and K199•PP5 downregulation in VHL-null clear cell renal cell carcinoma causes apoptosis 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.