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 GβL proteins [1-3] 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 [6, 7]. 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 GβL 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 α (PKCα) and the actin cytoskeleton, suggesting that this aspect of TOR signaling is conserved between yeast and mammals.
Bibliographical noteFunding Information:
This work was supported by a grant from the NIH (R01 AI47389) to D.M.S. and a NCI Cancer Center Support Grant (P30 CA08748) to P.T. as well as fellowships from the Anna Fuller Fund to D.D.S., the Korea Science and Engineering Foundation and Human Frontier Science Program to D.-H.K, the Howard Hughes Medical Institute to S.M.A, and a Damon Runyon Fellowship to D.A.G. We thank Mary Stewart for the gift of the dS6K antibody, Lynne Lacomis for help with mass spectrometry, Anne Carpenter for helpful comments on the manuscript, Ittai Ben-Porath for providing immunostaining protocol, and Joon-Ho Sheen for technical help. The human rictor sequence has been deposited with GenBank accession number AY515854. The authors declare that we have no competing financial interests.