MTOR drives its own activation via SCF βTrCP-dependent degradation of the mTOR inhibitor DEPTOR

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

Research output: Contribution to journalArticle

148 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)290-303
Number of pages14
JournalMolecular Cell
Volume44
Issue number2
DOIs
Publication statusPublished - 2011 Oct 21

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Gao, D., Inuzuka, H., Tan, M. K. M., Fukushima, H., Locasale, J. W., Liu, P., Wan, L., Zhai, B., Chin, Y. R., Shaik, S., Lyssiotis, C. A., Gygi, S. P., Toker, A., Cantley, L. C., Asara, J. M., Harper, J. W., & Wei, W. (2011). MTOR drives its own activation via SCF βTrCP-dependent degradation of the mTOR inhibitor DEPTOR. Molecular Cell, 44(2), 290-303. https://doi.org/10.1016/j.molcel.2011.08.030