Insulin like growth factor-1-induced phosphorylation and altered distribution of tuberous sclerosis complex (TSC)1/TSC2 in C2C12 myotubes.
Insulin like growth factor-1-induced phosphorylation and altered distribution of tuberous sclerosis complex (TSC)1/TSC2 in C2C12 myotubes.
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DOI：
10.1111/j.1742-4658.2010.07635.x
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Esser KA
中科院分区：
文献类型：
--
作者：
Miyazaki M;McCarthy JJ;Esser KA
胰岛素样生长因子-1（Insulin like growth factor-1，IGF-1）是一种合成代谢因子，通过激活磷酸肌醇3-激酶（phosphoinositide 3-kinase，PI 3 K）/Akt/mammalian target of rapamycin（mammalian target of rapamycin，mTOR）途径诱导骨骼肌生长。虽然这种信号通路已被大量研究，但在肌肉中将IGF-1结合至mTOR活化的分子机制仍然不清楚。本研究的目的是检验C2 C12肌管中mTOR的IGF-1活化需要结节性硬化症复合物（TSC）1/TSC 2复合物从膜到胞质溶胶的磷酸化依赖性改变的分布的假设。我们发现，IGF-1治疗不影响TSC 1和TSC 2之间的复合物的形成，而是IGF-1诱导改变C2 C12肌管中TSC 1/TSC 2复合物的分布。响应于IGF-1处理，存在由TSC 1和磷酸化TSC 2组成的TSC 1/TSC 2复合物从膜到胞质溶胶的相对重新分布。IGF-1刺激的TSC 1/TSC 2磷酸化和再分布被PI 3 K抑制剂渥曼青霉素完全阻止，但不被下游mTOR抑制剂雷帕霉素阻止。当非磷酸化形式的TSC 2（S939 A）过表达时，支架蛋白14-3-3与TSC 2的磷酸化依赖性结合减弱，并且在IGF-1刺激后没有观察到TSC 1/TSC 2复合物的再分布。这些结果表明，响应于IGF-1处理的TSC 2磷酸化对于TSC 1/TSC 2复合物向胞质溶胶的分布改变是必要的，并且我们通过解离TSC 1/TSC 2复合物差距活性之间的相互作用表明，这种易位可能对mTOR激活至关重要。及其下游靶点Rheb。
Insulin like growth factor-1 (IGF-1) is established as an anabolic factor that can induce skeletal muscle growth through activating the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. While this signaling pathway has been heavily studied, the molecular mechanisms linking IGF-1 binding to mTOR activation are still poorly defined in muscle. The purpose of this study was to test the hypothesis that IGF-1 activation of mTOR in C2C12 myotubes requires a phosphorylation dependent, altered distribution of the tuberous sclerosis complex (TSC)1/TSC2 complex from the membrane to the cytosol. We found that IGF-1 treatment does not affect complex formation between TSC1 and TSC2, but rather IGF-1 induces an altered distribution of the TSC1/TSC2 complex in C2C12 myotubes. In response to IGF-1 treatment, there was a relative re-distribution of the TSC1/TSC2 complex, composed of TSC1 and phosphorylated TSC2, from the membrane to the cytosol. IGF-1 stimulated TSC1/TSC2 phosphorylation and re-distribution were completely prevented by the PI3K inhibitor wortmannin, but were not with the downstream mTOR inhibitor, rapamycin. When a non-phosphorylatable form of TSC2 (S939A) was overexpressed, phosphorylation-dependent binding of the scaffold protein 14-3-3 to TSC2 was diminished and no re-distribution of the TSC1/TSC2 complex was observed following IGF-1 stimulation. These results indicate that TSC2 phosphorylation in response to IGF-1 treatment is necessary for the altered distribution of the TSC1/TSC2 complex to the cytosol and we suggest that this translocation is likely critical for mTOR activation by dissociating the interaction between the GAP activity of the TSC1/TSC2 complex and its downstream target Rheb.
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