MTOR generates an auto-amplification loop by triggering the βTrCP- and CK1α-dependent degradation of DEPTOR

Shanshan Duan, Jeffrey R. Skaar, Shafi Kuchay, Alfredo Toschi, Naama Kanarek, Yinon Ben-Neriah, Michele Pagano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

Abstract

DEPTOR is a recently identified inhibitor of the mTOR kinase that is highly regulated at the posttranslational level. In response to mitogens, we found that DEPTOR was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the F box protein βTrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the βTrCP degron in DEPTOR is executed by CK1α after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the βTrCP-dependent degradation of DEPTOR via βTrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind βTrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1α and βTrCP to generate an auto-amplification loop to promote its own full activation. Moreover, our results suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR-signaling pathways.

Original languageAmerican English
Pages (from-to)317-324
Number of pages8
JournalMolecular Cell
Volume44
Issue number2
DOIs
StatePublished - 21 Oct 2011

Bibliographical note

Funding Information:
The authors thank D. Foster, D. Sabatini, and W. Wei for reagents and W. Harper and W. Wei for sharing unpublished results. M.P. is grateful to T.M. Thor and K.E. Davidson for continuous support. J.R.S. is supported by the Mr. and Mrs. William G. Campbell Postdoctoral Fellowship in Memory of Carolyn Cabott from the American Cancer Society. This work was funded by grants to M.P. from the National Institutes of Health (R01-GM057587, R37-CA076584, and R21-CA161108) and the Multiple Myeloma Research Foundation. M.P. is an Investigator with the Howard Hughes Medical Institute.

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