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

Molecular cell | Oct 21, 2011

http://www.ncbi.nlm.nih.gov/pubmed/22017877

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.

Pubmed ID: 22017877 RIS Download

Mesh terms: Casein Kinase Ialpha | Cell Line | Humans | Intracellular Signaling Peptides and Proteins | Models, Biological | Phosphorylation | Signal Transduction | TOR Serine-Threonine Kinases | Transfection | beta-Transducin Repeat-Containing Proteins

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM057587
  • Agency: NIGMS NIH HHS, Id: R01 GM057587-12
  • Agency: NIGMS NIH HHS, Id: R01 GM057587-13
  • Agency: NIGMS NIH HHS, Id: R01-GM057587
  • Agency: NCI NIH HHS, Id: R21 CA161108
  • Agency: NCI NIH HHS, Id: R21 CA161108-01
  • Agency: NCI NIH HHS, Id: R21-CA161108
  • Agency: NCI NIH HHS, Id: R37 CA076584
  • Agency: NCI NIH HHS, Id: R37 CA076584-13
  • Agency: NCI NIH HHS, Id: R37 CA076584-14
  • Agency: NCI NIH HHS, Id: R37-CA076584
  • Agency: Howard Hughes Medical Institute, Id:

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