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

Mol Cell. 2011 Oct 21;44(2):317-24. doi: 10.1016/j.molcel.2011.09.005.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Casein Kinase Ialpha / metabolism*
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Models, Biological
  • Phosphorylation
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transfection
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • beta-Transducin Repeat-Containing Proteins
  • DEPTOR protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Casein Kinase Ialpha