c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription
c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription
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DOI：
10.1210/en.2002-220374
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发表时间：
2002-09-01
期刊：
影响因子：
4.8
通讯作者：
Lobie, PE
中科院分区：
文献类型：
--
作者：
Goh, ELK;Zhu, T;Lobie, PE
我们以前已经证明，细胞刺激GH的结果在形成一个多蛋白信号复合物。这种多蛋白信号复合物的一个组分是衔接分子c-Cbl。在这里，我们研究了c-Cbl在GH信号转导机制中的作用。c-Cbl在NIH 3 T3细胞中的强制表达不改变GH刺激的Janus激酶2酪氨酸磷酸化，也不改变GH刺激的p44/42 MAPK激活和随后的Elk-1介导的转录。然而，c-Cbl过表达确实导致GH刺激的磷脂酰肌醇3-激酶活化增强和延长。c-Cbl的强制表达不影响GH刺激的STAT 5酪氨酸磷酸化，核转位，也不与DNA结合，但显着废除GH刺激的STAT 5介导的反式激活。c-Cbl过表达导致STAT 5的泛素化和蛋白体降解增加，GH刺激的酪氨酸磷酸化STAT 5的降解增加。用蛋白体抑制剂MG 132进行细胞预处理逆转了c-Cbl过表达的作用，延长了GH刺激的STAT 5酪氨酸磷酸化的持续时间，并恢复了STAT 5介导的转录。因此，c-Cbl是GH刺激的STAT 5介导的转录的负调节因子，其通过STAT 5的方向进行蛋白质体降解。
We have previously demonstrated that cellular stimulation with GH results in the formation of a multiprotein signaling complex. One component of this multiprotein signaling complex is the adapter molecule c-Cbl. Here we have examined the role of c-Cbl in the mechanism of GH signal transduction. Forced expression of c-Cbl in NIH3T3 cells did not alter GH-stimulated Janus kinase 2 tyrosine phosphorylation nor GH-stimulated p44/42 MAPK activation and consequent Elk-1-mediated transcription. c-Cbl overexpression did, however, result in enhanced and prolonged GH-stimulated activation of phosphatidylinositol 3-kinase. Forced expression of c-Cbl did not affect GH-stimulated STAT5 tyrosine phosphorylation, nuclear translocation, nor binding to DNA but markedly abrogated GH-stimulated STAT5-mediated transactivation. c-Cbl overexpression resulted in increased ubiquitination and proteosomal degradation of STAT5 and increased degradation of GH-stimulated tyrosine phosphorylated STAT5. Cellular pretreatment with the proteosomal inhibitor MG132 reversed the effect of c-Cbl overexpression with prolonged duration of GH-stimulated STAT5 tyrosine phosphorylation and restoration of STAT5-mediated transcription. Thus, c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription by direction of STAT5 for proteosomal degradation.