Vav2 is an activator of Cdc42, Rac1, and RhoA

Vav and Vav2 are members of the Dbl family of proteins that act as guanine nucleotide exchange factors (GEFs) for Rho family proteins. Whereas Vav exp ression is restricted to cells of hematopoietic origin, Vav2 is widely expr essed. Although Vav and Vav2 share highly related structural similarities a nd high sequence identity in their Dbl homology domains, it has been report ed that they are active GEFs with distinct substrate specificities toward R ho family members. Whereas Vav displayed GEF activity for Rac1, Cdc42, RhoA , and RhoG, Vav2 was reported to exhibit GEF activity for RhoA, RhoB, and R hoG but not for Rad or Cdc42. Consistent with their distinct substrate targ ets, it was found that constitutively activated versions of Vav and Vav2 ca used distinct transformed phenotypes when expressed in NIH 3T3 cells. In co ntrast to the previous findings, we found that Vav2 can act as a potent GEF for Cdc42, Rac1, and RhoA in vitro. Furthermore, we found that NH2-termina lly truncated and activated Vav and Vav2 caused indistinguishable transform ing actions in NIH 3T3 cells that required Cdc42, Rad, and RhoA function. I n addition, like Vav and Rad, we found that Vav2 activated the Jun NH2-term inal kinase cascade and also caused the formation of lamellipodia and membr ane ruffles in NIH 3T3 cells. Finally, Vav2-transformed NIH 3T3 cells showe d up-regulated levels of Rac-GTP. We conclude that Vav2 and Vav share overl apping downstream targets and are activators of multiple Rho family protein s. Therefore, Vav2 may mediate the same cellular consequences in nonhematop oietic cells as Vav does in hematopoietic cells.