The complex life of a GEF

Receptor tyrosine kinases (RTKs) that are bound to appropriate growth factors activate PI3K, which initiates Rac-induced cytoskeletal alterations. The signaling steps between PI3K and Rac are uncovered on page 17 in an article by Innocenti et al. that reveals the importance of complexes in activating guanine nucleotide exchange factors (GEFs).

Genetic evidence has supported the involvement of the GEF Sos-1 for stimulating Rac activity in response to growth factors. Sos-1 is found in complex with Abi1 and Eps8, and interference with any of these proteins is known to block actin remodeling in response to RTK activation. Innocenti et al. now show biochemically that Sos-1 is indeed the GEF that activates Rac in response to PI3K.

Full GEF activation was a stepwise process. The physical presence of PI3K itself stimulated low levels of the Sos-1 GEF activity, perhaps by inducing a conformational change in Sos-1. PI3K gets to the Sos-1 complex through Abi1. PI3K bound to Abi1 in vitro and colocalized with Abi1 and Eps8 in PDGF-induced membrane ruffles.

PIP3, the product of PI3K, further stimulated the basal Sos-1 GEF activity. Thus, strong GEF activity would be unleashed only by activation of PI3K by growth factor-stimulated RTKs. As expected, inhibition of Sos-1 GEF activity by interfering with the interaction of PI3K and Abi1 blocked PDGF-induced membrane ruffling. The assembly of the tetrameric complex therefore allows for a number of biological consequences important for growth factor responses, including two levels of Sos-1 activation and the recruitment of both PI3K and PIP3 to sites where they are most needed for actin reorganization. ▪