title: Integrity of mTORC2 is dependent on the rictor Gly-934 site.
abstract: Growth factor signaling coupled to activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway plays a crucial role in the regulation of cell proliferation and survival. The key regulatory kinase of Akt has been identified as mammalian target of rapamycin complex 2 (mTORC2), which functions as the PI3K-dependent Ser-473 kinase of Akt. This kinase complex is assembled by mTOR and its essential components rictor, Sin1 and mLST8. The recent genetic screening study in Caenorhabditis elegans has linked a specific point mutation of rictor to an elevated storage of fatty acids that resembles the rictor deficiency phenotype. In our study, we show that in mammalian cells the analogous single rictor point mutation (G934E) prevents the binding of rictor to Sin1 and the assembly of mTORC2, but this mutation does not interfere with the binding of the rictor-interacting protein Protor. A substitution of the rictor Gly-934 residue to a charged amino acid prevents formation of the rictor/Sin1 heterodimer. The cells expressing the rictor G934E mutant remain deficient in the mTORC2 signaling, as detected by the reduced phosphorylation of Akt on Ser-473 and a low cell proliferation rate. Thus, although a full length of rictor is required to interact with its binding partner Sin1, a single amino acid of rictor Gly-934 controls its interaction with Sin1 and assembly of mTORC2.
authors: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: R
authors: R
authors: Aimbetov
authors: C-H
authors: CH
authors: Chen
authors: O
authors: O
authors: Bulgakova
authors: D
authors: D
authors: Abetov
authors: A K
authors: AK
authors: Bissenbaev
authors: R I
authors: RI
authors: Bersimbaev
authors: D D
authors: DD
authors: Sarbassov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005998:Glycine; D006801:Humans; D017354:Point Mutation; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493245:CRTC2 protein, human; D002352:Carrier Proteins; C493277:MAPKAP1 protein, human; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors; D005998:Glycine