Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism

Rac is a member of the Ras superfamily of GTPases and functions as a GDP/GTP-regulated switch 1 . Formation of active Rac-GTP is stimulated by Dbl family guanine nucleotide exchange factors (GEFs), such as Tiam1 (ref. 2 ). Once activated, Rac stimulates signalling pathways that regulate actin organization, gene expression and cellular proliferation. Rac also functions downstream of the Ras oncoprotein in pathways that stimulate membrane ruffling 3 , growth transformation 4 , 5 , activation of the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase 6 , activation of the NF-κB transcription factor and promotion of cell survival 7 , 8 . Although recent studies support phosphatidylinositol 3-OH kinase (PI(3)K)-dependent mechanisms through which Ras might activate Rac (refs 9 , 10 ), the precise mechanism remains to be determined. Here we demonstrate that Tiam1, a Rac-specific GEF, preferentially associates with activated GTP-bound Ras through a Ras-binding domain. Furthermore, activated Ras and Tiam1 cooperate to cause synergistic formation of Rac-GTP in a PI(3)K-independent manner. Thus, Tiam1 can function as an effector that directly mediates Ras activation of Rac.