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-kappaB 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.