mTOR/RAFT1/FRAP is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth. We report that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway. Raptor has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and mTOR protein expression. The association of raptor with mTOR also negatively regulates the mTOR kinase activity. Conditions that repress the pathway, such as nutrient deprivation and mitochondrial uncoupling, stabilize the mTOR-raptor association and inhibit mTOR kinase activity. We propose that raptor is a missing component of the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health (R01 AI47389) and the G. Harold and Leila Y. Mathers Charitable Foundation to D.M.S., and fellowships from the Korea Science and Engineering Foundation and Human Frontier Science Program to D.-H.K., the Anna Fuller Fund to D.D.S, and the Howard Hughes Medical Institute to S.M.A. We thank Nir Hacohen for reviewing the manuscript and the Kazusa DNA Research Institute for providing the cDNA for KIAA1303.