The Son of Sevenless (Sos) proteins control receptor-mediated activati
on of Ras by catalyzing the exchange of guanosine diphosphate for guan
osine triphosphate on Ras. The NH2-terminal region of Sos contains a D
bl homology (DH) domain in tandem with a pleckstrin homology (PH) doma
in. In COS-1 cells, the DH domain of Sos stimulated guanine nucleotide
exchange on Rac but not Cdc42 in vitro and in vivo. The tandem DH-PH
domain of Sos (DH-PH-Sos) was defective in Rac activation but regained
Rac stimulating activity when it was coexpressed with activated Ras,
Ras-mediated activation of DH-PH-Sos did not require activation of mit
ogen-activated protein kinase but it was dependent on activation of ph
osphoinositide 3-kinase. These results reveal a potential mechanism fo
r coupling of Ras and Rac signaling pathways.