MTOR generates an auto-amplification loop by triggering the ?TrCP- and CK1?-dependent degradation of DEPTOR.

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 ?TrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the ?TrCP degron in DEPTOR is executed by CK1? after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the ?TrCP-dependent degradation of DEPTOR via ?TrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind ?TrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1? and ?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.

SUBMITTER: Duan S 

PROVIDER: S-EPMC3212871 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature