Journal
MOLECULAR CELL
Volume 44, Issue 2, Pages 317-324Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2011.09.005
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Funding
- American Cancer Society
- National Institutes of Health [R01-GM057587, R37-CA076584, R21-CA161108]
- Multiple Myeloma Research Foundation
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DEPTOR is a recently identified inhibitor of the mTOR kinase that is highly regulated at the post-translational 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 beta TrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the beta TrCP degron in DEPTOR is executed by CK1 alpha after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the beta TrCP-dependent degradation of DEPTOR via beta TrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind beta TrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1 alpha and beta TrCP 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.
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