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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Dushukyan N,Dunn DM,Sager RA,Woodford MR,Loiselle DR,Daneshvar M,Baker-Williams AJ,Chisholm JD,Truman AW,Vaughan CK,Haystead TA,Bratslavsky G,Bourboulia D,Mollapour Mdoi
10.1016/j.celrep.2017.10.074subject
Has Abstractpub_date
2017-11-14 00:00:00pages
1883-1895issue
7issn
2211-1247pii
S2211-1247(17)31537-1journal_volume
21pub_type
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