Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway That Regulates the Cytoskeleton

Curr Biol. 2004 Jul 27;14(14):1296-302. doi: 10.1016/j.cub.2004.06.054.

Abstract

The mammalian TOR (mTOR) pathway integrates nutrient- and growth factor-derived signals to regulate growth, the process whereby cells accumulate mass and increase in size. mTOR is a large protein kinase and the target of rapamycin, an immunosuppressant that also blocks vessel restenosis and has potential anticancer applications. mTOR interacts with the raptor and GbetaL proteins to form a complex that is the target of rapamycin. Here, we demonstrate that mTOR is also part of a distinct complex defined by the novel protein rictor (rapamycin-insensitive companion of mTOR). Rictor shares homology with the previously described pianissimo from D. discoidieum, STE20p from S. pombe, and AVO3p from S. cerevisiae. Interestingly, AVO3p is part of a rapamycin-insensitive TOR complex that does not contain the yeast homolog of raptor and signals to the actin cytoskeleton through PKC1. Consistent with this finding, the rictor-containing mTOR complex contains GbetaL but not raptor and it neither regulates the mTOR effector S6K1 nor is it bound by FKBP12-rapamycin. We find that the rictor-mTOR complex modulates the phosphorylation of Protein Kinase C alpha (PKCalpha) and the actin cytoskeleton, suggesting that this aspect of TOR signaling is conserved between yeast and mammals.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Conserved Sequence
  • Cytoskeleton / metabolism*
  • DNA Primers
  • Drosophila
  • Electrophoresis, Polyacrylamide Gel
  • Fluorescent Antibody Technique
  • Gene Components
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Molecular Sequence Data
  • Phosphorylation
  • Precipitin Tests
  • Protein Kinase C / metabolism
  • Protein Kinase C-alpha
  • Protein Kinases / metabolism*
  • Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Sirolimus / metabolism
  • TOR Serine-Threonine Kinases
  • Transfection

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Primers
  • Proteins
  • RICTOR protein, human
  • RNA, Small Interfering
  • RPTOR protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Sirolimus

Associated data

  • GENBANK/AY515854