Phosphorylated Rho-GDP directly activates mTORC2 kinase towards AKT through dimerization with Ras-GTP to regulate cell migration
| Autor: | Akihiko Nakajima, Yoichiro Kamimura, Satoshi Sawai, Hiroshi Senoo, Reona Kimura, Hiromi Sesaki, Miho Iijima |
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| Rok vydání: | 2018 |
| Předmět: |
inorganic chemicals
G protein Small G Protein GTPase macromolecular substances Mechanistic Target of Rapamycin Complex 2 mTORC2 Guanosine Diphosphate Article 03 medical and health sciences Glycogen Synthase Kinase 3 0302 clinical medicine Cell Movement GTP-Binding Proteins Animals Humans Phosphorylation Protein kinase B Cytoskeleton 030304 developmental biology 0303 health sciences Kinase Chemistry Cell migration Cell Biology Cell biology 030220 oncology & carcinogenesis Dimerization Proto-Oncogene Proteins c-akt |
| Zdroj: | Nature cell biology |
| ISSN: | 1476-4679 |
| Popis: | mTORC2 plays critical roles in metabolism, cell survival and actin cytoskeletal dynamics through the phosphorylation of AKT. Despite its importance to biology and medicine, it is unclear how mTORC2-mediated AKT phosphorylation is controlled. Here, we identify an unforeseen principle by which a GDP-bound form of the conserved small G protein Rho GTPase directly activates mTORC2 in AKT phosphorylation in social amoebae (Dictyostelium discoideum) cells. Using biochemical reconstitution with purified proteins, we demonstrate that Rho-GDP promotes AKT phosphorylation by assembling a supercomplex with Ras-GTP and mTORC2. This supercomplex formation is controlled by the chemoattractant-induced phosphorylation of Rho-GDP at S192 by GSK-3. Furthermore, Rho-GDP rescues defects in both mTORC2-mediated AKT phosphorylation and directed cell migration in Rho-null cells in a manner dependent on phosphorylation of S192. Thus, in contrast to the prevailing view that the GDP-bound forms of G proteins are inactive, our study reveals that mTORC2-AKT signalling is activated by Rho-GDP. |
| Databáze: | OpenAIRE |
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