mTOR Drives Its Own Activation via SCF beta TrCP-Dependent Degradation of the mTOR Inhibitor DEPTOR

作者：Gao Daming; Inuzuka Hiroyuki; Tan Meng Kwang Marcus; Fukushima Hidefumi; Locasale Jason W; Liu Pengda; Wan Lixin; Zhai Bo; Chin Y Rebecca; Shaik Shavali; Lyssiotis Costas A; Gygi Steven P; Toker Alex; Cantley Lewis C; Asara John M; Harper J Wade^*; Wei Wenyi

来源：Molecular Cell, 2011, 44(2): 290-303.

DOI：10.1016/j.molcel.2011.08.030

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 SCF beta TrCP. DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds beta TrCP. Failure to degrade DEPTOR through either degron mutation or beta 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.

• 出版日期2011-10-21