Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.
Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.
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DOI：
10.1083/jcb.201007176
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发表时间：
2011-04-04
期刊：
影响因子：
--
通讯作者：
Thurmond DC
中科院分区：
文献类型：
--
作者：
Jewell JL;Oh E;Ramalingam L;Kalwat MA;Tagliabracci VS;Tackett L;Elmendorf JS;Thurmond DC
SNARE复合物组装和GLUT 4囊泡的动员通过胰岛素受体酪氨酸激酶直接靶向Munc 18 c来协调。Sec 1/Munc 18-syntaxin复合物如何转变为SNARE核心复合物仍不清楚。为此，Munc 18 c酪氨酸磷酸化与其从突触融合蛋白4的解离相关。使用3 T3-L1脂肪细胞进行小干扰核糖核酸减少Munc 18 c作为受损的胰岛素刺激的GLUT 4囊泡胞吐的模型，我们发现，协调表达Munc 18 c野生型或选择磷酸化模拟Munc 18 c突变体，但不是磷酸缺陷突变体，恢复GLUT 4囊泡胞吐，这表明Munc 18 c酪氨酸磷酸化在Tyr 219和Tyr 521的要求。令人惊讶的是，发现胰岛素受体（IR）酪氨酸激酶在体外靶向Munc 18 c的Tyr 521，快速结合和磷酸化脂肪细胞和骨骼肌内的内源性Munc 18 c。IR，而不是磷脂酰肌醇3-激酶，激活是必需的。总之，我们确定IR作为第一个已知的酪氨酸激酶Munc 18 c作为一个新的胰岛素信号步骤的一部分，在GLUT 4囊泡胞吐，例证了一个新的模型的协调SNARE组装和囊泡动员事件响应于一个单一的细胞外刺激。
SNARE complex assembly and mobilization of GLUT4 vesicles is coordinated through direct targeting of Munc18c by the insulin receptor tyrosine kinase. How the Sec1/Munc18–syntaxin complex might transition to form the SNARE core complex remains unclear. Toward this, Munc18c tyrosine phosphorylation has been correlated with its dissociation from syntaxin 4. Using 3T3-L1 adipocytes subjected to small interfering ribonucleic acid reduction of Munc18c as a model of impaired insulin-stimulated GLUT4 vesicle exocytosis, we found that coordinate expression of Munc18c–wild type or select phosphomimetic Munc18c mutants, but not phosphodefective mutants, restored GLUT4 vesicle exocytosis, suggesting a requirement for Munc18c tyrosine phosphorylation at Tyr219 and Tyr521. Surprisingly, the insulin receptor (IR) tyrosine kinase was found to target Munc18c at Tyr521 in vitro, rapidly binding and phosphorylating endogenous Munc18c within adipocytes and skeletal muscle. IR, but not phosphatidylinositol 3-kinase, activation was required. Altogether, we identify IR as the first known tyrosine kinase for Munc18c as part of a new insulin-signaling step in GLUT4 vesicle exocytosis, exemplifying a new model for the coordination of SNARE assembly and vesicle mobilization events in response to a single extracellular stimulus.
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