Regulation of protein tyrosine phosphatase 1B by sumoylation
Regulation of protein tyrosine phosphatase 1B by sumoylation
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DOI：
10.1038/ncb1522
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发表时间：
2007-01-01
影响因子：
21.3
通讯作者：
Chernoff, Jonathan
中科院分区：
文献类型：
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作者：
Dadke, Shrikrishna;Cotteret, Sophie;Chernoff, Jonathan
蛋白酪氨酸磷酸酶1B （PTP1B）是一种普遍表达的酶，通过结合和去磷酸化关键受体酪氨酸激酶，如胰岛素受体，负调控生长因子信号传导和细胞增殖(1)。目前尚不清楚PTP1B的活性是如何被调节的。利用酵母双杂交实验，分离出活化STAT1的蛋白抑制剂（PIAS1）(2)，作为与ptp1b相互作用的蛋白。在这里，我们发现PIAS1作为一个小的泛素样修饰物（SUMO） E3连接酶，在哺乳动物成纤维细胞中与PTP1B结合并催化PTP1B的sumoylation。PTP1B的sumo化降低了其催化活性，抑制了PTP1B对胰岛素受体信号传导和致癌基因v-crk转化的负面作用。胰岛素刺激的内源性PTP1B的sumoylation导致该酶的短暂下调；当内源性酶被抗summoylation的PTP1B突变体取代时，不会发生这种事件。这些结果表明，主要涉及细胞核和核孔过程的sumoylation也调节了调节代谢和细胞增殖的关键酶-底物信号复合物。
Protein-tyrosine phosphatase 1B (PTP1B) is an ubiquitously expressed enzyme that negatively regulates growth-factor signalling and cell proliferation by binding to and dephosphorylating key receptor tyrosine kinases, such as the insulin receptor(1). It is unclear how the activity of PTP1B is regulated. Using a yeast two-hybrid assay, a protein inhibitor of activated STAT1 (PIAS1)(2) was isolated as a PTP1B-interacting protein. Here, we show that PIAS1, which functions as a small ubiquitin-like modifier (SUMO) E3 ligase, associates with PTP1B in mammalian fibroblasts and catalyses sumoylation of PTP1B. Sumoylation of PTP1B reduces its catalytic activity and inhibits the negative effect of PTP1B on insulin receptor signalling and on transformation by the oncogene v-crk. Insulin-stimulated sumoylation of endogenous PTP1B results in a transient downregulation of the enzyme; this event does not occur when the endogenous enzyme is replaced with a sumoylation-resistant mutant of PTP1B. These results suggest that sumoylation, which has been implicated primarily in processes in the nucleus and nuclear pore, also modulates a key enzyme-substrate signalling complex that regulates metabolism and cell proliferation.