mTORC1- and mTORC2-interacting proteins keep their multifunctional partners focused

IUBMB Life. 2011 Oct;63(10):896-914. doi: 10.1002/iub.558. Epub 2011 Sep 9.

Abstract

The mammalian target of rapamycin, best known as mTOR, is a phylogenetically conserved serine/threonine kinase that controls life-defining cellular processes such as growth, metabolism, survival, and migration under the influence of multiple interacting proteins. Historically, the cellular activities blocked by rapamycin in mammalian cells were considered the only events controlled by mTOR. However, this paradigm changed with the discovery of two signaling complexes differentially sensitive to rapamycin, whose catalytic component is mTOR. The one sensitive to rapamycin, known as mTORC1, promotes protein synthesis in response to growth factors and nutrients via the phosphorylation of p70S6K and 4EBP1; while the other, known as mTORC2, promotes cell migration and survival via the activation of Rho GTPases and the phosphorylation of AKT, respectively. Although mTORC2 kinase activity is not inhibited by rapamycin, hours of incubation with this antibiotic can impede the assembly of this signaling complex. The direct mechanism by which mTORC2 leads to cell migration depends on its interaction with P-Rex1, a Rac-specific guanine nucleotide exchange factor, while additional indirect pathways involve the intervention of PKC or AKT, multifunctional ubiquitous serine/threonine kinases that activate effectors of cell migration upon being phosphorylated by mTORC2 in response to chemotactic signals. These mTORC2 effectors are altered in metastatic cancer. Numerous clinical trials are testing mTOR inhibitors as potential antineoplasic drugs. Here, we briefly review the actions of mTOR with emphasis on the controlling role of mTORC1 and mTORC2-interacting proteins and highlight the mechanisms linked to cell migration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Movement / physiology
  • Cell Proliferation
  • Energy Metabolism / physiology*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Models, Biological*
  • Multiprotein Complexes
  • Signal Transduction / physiology*
  • Sirolimus / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / metabolism*

Substances

  • CRTC2 protein, human
  • Multiprotein Complexes
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus