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Senoo, Hiroshi, Kamimura, Yoichiro, Kimura, Reona, Nakajima, Akihiko, Sawai, Satoshi, Sesaki, Hiromi, Iijima, Miho, (2019) ' Phosphorylated Rho-GDP directly activates mTORC2 kinase towards AKT through dimerization with Ras-GTP to regulate cell migration. ' Nat. Cell Biol. 21 867-878
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Abstract: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.
Status: ppublish Type: Journal article Source: PUBMED PubMed ID: 31263268

 
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gskA lst8 piaA pkbA pkgB racE rasC rasG
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Genes addressed in this paper
ripA tor
Topics in this paper
Disease Related

Protein Physical Properties
X
Protein Functional Domain
X
Non-mammalian Gene Related

Strains/Constructs X X
Post-Translational Modifications

Chemotaxis/Motility

Function/Process X X
Signal Transduction X X
Genetic Interactions

Protein-Protein Interactions X X
Phylogenetic Analysis

Regulatory Role
X
Regulated By

Mutants/Phenotypes X X
Substrates/Ligands/Cofactors