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

• DOI: 10.1016/j.cub.2004.06.054
• Publication Date: 2004-07-27T21:39:35Z
• Authors: Dos D. Sarbassov; Siraj M Ali; Do-Hyung Kim; David A Guertin; Robert R Latek; Hediye Erdjument-...; Paul Tempst; David M Sabatini
• Keywords: 0301 basic medicine; Protein Kinase C-alpha; Agricultural and Biological Sciences(all); Biochemistry, Genetics and Molecular Biology(all); Immunoblotting; Molecular Sequence Data; Fluorescent Antibody Technique; Precipitin Tests; Actins; 03 medical and health sciences; Gene Components; Animals; Humans; Drosophila; Electrophoresis, Polyacrylamide Gel; Amino Acid Sequence; Phosphorylation; Carrier Proteins; Conserved Sequence; Cytoskeleton; Protein Kinase C; Adaptor Proteins, Signal Transducing; DNA Primers; HeLa Cells

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.