SHP-2 regulates SOCS-1-mediated Janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor
SHP-2 regulates SOCS-1-mediated Janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor
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DOI：
10.1074/jbc.m306758200
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发表时间：
2003-12-26
影响因子：
4.8
通讯作者：
Ali, S
中科院分区：
文献类型：
--
作者：
Ali, S;Nouhi, Z;Ali, S
蛋白酪氨酸磷酸酶SHP-2是细胞因子/催乳素受体家族下游Janus激酶-2（Jak 2）/信号转导和转录激活因子（Stat）途径的重要调节因子。我们报告说，SHP-2去磷酸化酪氨酸（Tyr-1007）的Jak 2激酶，一个关键的招聘网站的泛素连接酶相关的抑制性蛋白抑制因子的细胞因子信号传导-1（SOCS-1），从而有助于Jak 2的稳定性。通过阻断受体/SHP-2结合或通过使用SHP-2的催化失活突变体使SHP-2功能失活，导致Jak 2泛素化/降解、Tyr-1007上的Jak 2磷酸化和Jak 2/SOCS-1结合显著增加。此外，功能研究表明，通过SHP-2调节Jak 2/SOCS-1的相互作用对于催乳素/Stat 5介导的信号传导是必需的。总之，我们的研究结果提供了一个新的功能，SHP-2作为一个积极的调节细胞因子受体信号通过调节泛素化/降解途径。
The protein tyrosine phosphatase SHP-2 is an important regulator of the Janus kinase-2 (Jak2)/signal transducer and activator of transcription (Stat) pathway downstream of the cytokine/prolactin receptor family. We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association. Furthermore, functional studies indicate that modulating the interaction of Jak2/SOCS-1 by SHP-2 is essential for prolactin/Stat5-mediated signaling. Together our results provide a novel function for SHP-2 as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways.