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

2004; Elsevier BV; Volume: 14; Issue: 14 Linguagem: Inglês

10.1016/j.cub.2004.06.054

1879-0445

Dos D. Sarbassov, Siraj M. Ali, Do‐Hyung Kim, David A. Guertin, Robert Latek, Hediye Erdjument‐Bromage, Paul Tempst, David M. Sabatini,

Protein Kinase Regulation and GTPase Signaling

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 [1Kim D.-H Sarbassov D.D Ali S.M King J.E Latek R.R Erdjument-Bromage H Tempst P Sabatini D.M mTOR interacts with Raptor to form a nutrient-sensitive complex that signals to the cell growth machinery.Cell. 2002; 110: 163-175Abstract Full Text Full Text PDF PubMed Scopus (2355) Google Scholar, 2Kim D.-H Sarbassov D.D Ali S.M Latek R.R Guntur K.V.P Erdjument-Bromage H Tempst P Sabatini D.M Gβl a positive regulator of the rapamycin-sensitive pathway required for a nutrient-sensitive interaction between mTOR and raptor.Mol. Cell. 2003; 11: 895-904Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar, 3Hara K Maruki Y Long X Yoshino K Oshiro N Hidayat S Tokunaga C Avruch J Yonezawa K Raptor, a binding partner of Target of Rapamycin (TOR), mediates TOR action.Cell. 2002; 110: 177-189Abstract Full Text Full Text PDF PubMed Scopus (1441) Google Scholar] 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[4Chen M.Y Long Y Devreotes P.N A novel cytosolic regulator, Pianissimo, is required for chemoattractant receptor and G protein-mediated activation of the 12 transmembrane domain adenylyl cyclase in Dictyostelium.Genes Dev. 1997; 11: 3218-3231Crossref PubMed Scopus (115) Google Scholar], STE20p from S. pombe[5Hilti N Baumann D Schweingruber A.M Bigler P Schweingruber M.E Gene ste20 controls amiloride sensitivity and fertility in Schizosaccharomyces pombe.Curr. Genet. 1999; 35: 585-592Crossref PubMed Scopus (20) Google Scholar], and AVO3p from S. cerevisiae[6Loewith R Jacinto E Wullschleger S Lorberg A Crespo J.L Bonenfant D Oppliger W Jenoe P Hall M.N Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.Mol. Cell. 2002; 10: 457-468Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar, 7Wedaman K.P Reinke A Anderson S Yates 3rd, J McCaffery J.M Powers T Tor Kinases are in distinct membrane-associated protein complexes in Saccharomyces cerevisiae.Mol. Biol. Cell. 2003; 14: 1204-1220Crossref PubMed Scopus (195) Google Scholar]. 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 [6Loewith R Jacinto E Wullschleger S Lorberg A Crespo J.L Bonenfant D Oppliger W Jenoe P Hall M.N Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.Mol. Cell. 2002; 10: 457-468Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar]. 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.