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 (Dictyosteliumdiscoideum) 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.
Original language | English (US) |
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Pages (from-to) | 867-878 |
Number of pages | 12 |
Journal | Nature cell biology |
Volume | 21 |
Issue number | 7 |
DOIs | |
State | Published - Jul 1 2019 |
ASJC Scopus subject areas
- Cell Biology