Striatum specific protein, Rhes regulates AKT pathway.

The Rhes/RASD2 GTPase complex is involved in dopamine D1/D2 receptor-mediated signaling and behavior. This GTP binding protein belongs to the RAS superfamily, along with Dexras1/RASD1, and is primarily expressed in the striatum. RASDs differ from typical small GTPases as they have an extended C-terminal tail of roughly 7 kDa. Previously, it has been shown that dopamine depletion reduces Rhes mRNA expression in the brain. Here we show that Rhes interacts with p85, the regulatory subunit of PI3K. Specifically, the C-terminal unique tail region of Rhes is responsible for this interaction. The interaction between p85 and the C-terminal region of Rhes is enhanced upon growth factor treatment in vitro, while AKT translocation to the membrane is facilitated in the presence of Rhes or the Rhes-p85 complex. These findings suggest that Rhes is a novel striatal regulator of the AKT-mediated pathway in the striatum.