Journal
MOLECULAR CELL
Volume 44, Issue 2, Pages 290-303Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2011.08.030
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Funding
- DOD Prostate New Investigator award
- National Institutes of Health [CA122099, GM089763, AG011085, GM0089877, GM054137]
- Lady Tata Memorial Trust International Awards
- A-STAR Predoctoral Fellowship
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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.
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