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Inositol hexakisphosphate kinase-2: Novel modes of regulation and signaling.

机译：肌醇六磷酸激酶-2：新的调节和信号传导方式。

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摘要

Inositol hexakisphosphate kinase-2 (IP6K2) was shown to modulate a variety of cellular signaling events, the best-studied of which is the enhancement of apoptosis. The mechanisms by which IP6K2 and its role in cell death are regulated remain poorly understood. We demonstrate that the oncogene kinase CK2 promotes cell survival by regulating IP6K2. CK2 physiologically phosphorylates IP6K2 at serines 347 and 356 within a PEST consensus site for ubiquitination. Pharmacologic inhibition of CK2 activity prevents ubiquitnylation of IP6K2. Mutation of 5347 and 5356 on IP6K2 extends the half-life of IP6K2 from 90 minutes to 8 hours. Cell death in the colon cancer line, HCT116, elicited by CK2 inhibitors is diminished in cells depleted of IP6K2. These studies suggest a role for IP6K2 in suppressing CK2-mediated tumorigenesis. The mechanism by which IP6K2 ubiquitinylation is regulated may also involve a novel binding partner, USP9x, a deubiquitinylating enzyme. USP9x depletion causes IP6K2 levels to decrease, and USP9x interaction with IP6K2 is regulated by protein kinase C activity.;Next, we show that IP6K2 interacts with the tumor suppressor, PML. Similar to IP6K2, PML is a pro-apoptotic protein, which is already known to be phosphorylated and degraded by CK2 under conditions of osmotic stress. We show that the enzymatic product of IP6K2, 5-PP inositolpentakisphosphate (IP7) can inhibit PML phosphorylation by CK2 in vitro and in vivo. When IP6K2 is depleted acutely, PML ubiquitinylation increases while PML protein levels decrease. Overexpression of kinase active IP6K2 stabilizes PML in HeLa cells subjected to osmotic stress, whereas kinase inactive IP6K2 does not. These results demonstrate a role for IP7 in PML stability and another pathway by which IP6K2 may exert proapoptotic activity.
机译：肌醇六磷酸激酶2（IP6K2）被证明可以调节多种细胞信号传导事件，其中研究得最好的是凋亡的增强。对IP6K2及其在细胞死亡中的作用进行调控的机制仍知之甚少。我们证明癌基因激酶CK2通过调节IP6K2促进细胞存活。 CK2在PEST共有位点内的丝氨酸347和356处将IP6K2生理磷酸化，以进行泛素化。 CK2活性的药理抑制作用可防止IP6K2泛素化。 IP6K2上5347和5356的突变将IP6K2的半衰期从90分钟延长到8小时。由CK2抑制剂引起的结肠癌HCT116细胞死亡在减少IP6K2的细胞中减少。这些研究表明IP6K2在抑制CK2介导的肿瘤发生中的作用。调节IP6K2泛素化的机制还可能涉及新型结合伴侣USP9x（一种去泛素化酶）。 USP9x的消耗会导致IP6K2的水平降低，并且USP9x与IP6K2的相互作用受蛋白激酶C活性的调节。;接下来，我们证明IP6K2与肿瘤抑制物PML相互作用。与IP6K2相似，PML是一种促凋亡蛋白，已知它在渗透胁迫下会被CK2磷酸化和降解。我们表明，在体外和体内，IP6K2的酶促产物5-PP肌醇五磷酸酯（IP7）可以抑制CK2引起的PML磷酸化。当IP6K2急剧耗尽时，PML泛素化增加，而PML蛋白水平降低。激酶活性IP6K2的过表达可稳定受到渗透压的HeLa细胞中的PML，而激酶活性IP6K2则不能。这些结果证明了IP7在PML稳定性中的作用，以及IP6K2可能通过其发挥促凋亡活性的另一种途径。

著录项

  • 作者

    Werner, J. Kent, Jr.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 57 p.
  • 总页数 57
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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