Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer.
Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer.
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DOI：
10.1016/j.celrep.2017.10.074
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发表时间：
2017-11-14
期刊：
影响因子：
8.8
通讯作者：
Mollapour M
中科院分区：
文献类型：
--
作者：
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 M
丝氨酸/苏氨酸蛋白磷酸酶-5（PP 5）调节多种细胞信号网络。许多细胞因子，包括热休克蛋白90（Hsp 90）促进PP 5的活化。然而，目前还不清楚翻译后修饰是否也影响PP 5磷酸酶活性。在这里，我们展示了PP 5调节的“开/关开关”机制。酪蛋白激酶-1 δ（CK 1 δ）磷酸化PP 5催化结构域中的T362，从而激活并增强不依赖于Hsp 90的磷酸酶活性。过表达的磷酸模拟T362 E-PP 5突变体过度去磷酸化的底物，如共伴侣Cdc 37和糖皮质激素受体在细胞中。我们的蛋白质组学方法确定了肿瘤抑制因子von Hippel-Lindau蛋白（VHL）以缺氧和脯氨酰羟基化独立的方式与K185/K199-PP 5相互作用并泛素化蛋白酶体降解。最后，VHL缺陷型透明细胞肾细胞癌（ccRCC）细胞系和患者肿瘤表现出升高的PP 5水平。PP 5的下调导致ccRCC细胞发生凋亡，表明PP 5在肾癌中的促生存作用。Dushukyan等人表明，酪蛋白激酶-1-δ磷酸化并激活蛋白磷酸酶-5（PP 5），而von Hippel-Lindau蛋白（VHL）泛素化并降解蛋白酶体中的PP 5。VHL突变和失活的肾癌细胞具有升高的PP 5。PP 5的下调导致细胞凋亡，证明了PP 5在肾癌中的促生存功能。
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-1 δ (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 hyperdephosphorylates the substrates such as the co-chaperone Cdc37 and the glucocorticoid receptor in cells. Our proteomic approach identified the tumor suppressor von Hippel-Lindau protein (VHL) to interact and ubiquitinate 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. Down-regulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer. Dushukyan et al. show that casein kinase-1-δ 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 PP5. Down-regulation of PP5 causes apoptosis, demonstrating a prosurvival function for PP5 in kidney cancer.
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