mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR.
mTOR drives its own activation via SCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR.
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DOI：
10.1016/j.molcel.2011.08.030
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发表时间：
2011-10-21
期刊：
影响因子：
16
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Gao D;Inuzuka H;Tan MK;Fukushima H;Locasale JW;Liu P;Wan L;Zhai B;Chin YR;Shaik S;Lyssiotis CA;Gygi SP;Toker A;Cantley LC;Asara JM;Harper JW;Wei W
mTORC 1和mTORC 2的活性均受其内源性抑制剂DEPTOR的负调控。因此，DEPTOR的丰度是mTOR网络活性状态的关键决定因素。DEPTOR稳定性由26 S-蛋白酶体通过一种很大程度上未知的机制控制。在这里，我们描述了一种mTOR依赖性磷酸化驱动的途径，通过SCFβ-TRCP破坏DEPTOR。mTOR对生长信号的反应使DEPTOR磷酸化，并与酪蛋白激酶I（CKI）协同作用，产生结合β-TRCP的磷酸降解决定子。未能通过降解决定子突变或β-TRCP耗竭降解DEPTOR导致mTOR活性降低、S6激酶活性降低和自噬激活以减少细胞生长。这项工作通过揭示涉及mTOR及其抑制剂DEPTOR的CKI依赖性周转的正反馈回路扩展了目前对mTOR调节的理解，表明DEPTOR破坏途径的错误调节可能导致疾病中mTOR的异常激活。
The activities of both mTORC1 and mTORC2 are negatively regulated by their endogenous inhibitor, DEPTOR. As such, the abundance of DEPTOR is a critical determinant in the activity status of the mTOR network. DEPTOR stability is governed by the 26S-proteasome through a largely unknown mechanism. Here we describe an mTOR-dependent phosphorylation-driven pathway for DEPTOR destruction via SCFβ-TRCP. DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds β-TRCP. Failure to degrade DEPTOR through either degron mutation or β-TRCP depletion leads to reduced mTOR activity, reduced S6 kinase activity, and activation of autophagy to reduce cell growth. This work expands the current understanding of mTOR regulation by revealing a positive feedback loop involving mTOR and CKI-dependent turnover of its inhibitor, DEPTOR, suggesting that misregulation of the DEPTOR destruction pathway might contribute to aberrant activation of mTOR in disease.
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