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.
ASJC Scopus subject areas
- Cell Biology