14-3-3 Interacts with regulator of G protein signaling proteins and modulates their activity

Regulator of G protein signaling (RGS) proteins function as GTPase-activati ng proteins (GAPs) that stimulate the inactivation of heterotrimeric G prot eins. We have recently shown that RGS proteins may be regulated on a post-t ranslational level (Benzing, T., Brandes, R., Sellin, L., Schermer, B,, Lec ker, S., Walt, G., and Kim, E. (1999) Naf. Med. 5, 913-918). However, mecha nisms controlling the GAP activity of RGS proteins are poorly understood. H ere we show that 14-3-3 proteins associate with RGS7 and RGS3, Binding of 1 4-3-3 is mediated by a conserved phosphoserine located in the G alpha-inter acting portion of the RGS domain; interaction with 14-3-3 inhibits the GAP activity of RGS7, depends upon phosphorylation of a conserved residue withi n the RGS domain, and results in inhibition of GAP function. Collectively, these data indicate that phosphorylation-dependent binding of 14-3-3 may ac t as molecular switch that controls the GAP activity keeping a substantial fraction of RGS proteins in a dormant state.