A Rac1 effector site controlling mitogenesis through superoxide production

The Rac GTP-binding protein controls signal transduction pathways that are critical for mitogenesis and oncogenesis (1, 2). The biochemical nature of these signaling pathways is presently unknown. Here we report that a region in Rad (residues 124-135), previously defined as the insert region (3), is essential for its mitogenic activity. Deletion of this region does not interfere with the ability of Rad to induce cytoskeletal changes or to activate the Jun kinase mitogen-activated protein kinase cascade but abrogates Rad-induced stimulation of DNA synthesis and Rad-mediated superoxide production in quiescent fibroblasts. Treatment of cells with agents that abolish superoxide generation inhibits specifically the mitogenic effect of Rad. Our results identify an effector site in Rad that is necessary for mitogenic signaling and implicate superoxide generation as a candidate effector pathway of Rac1 dependent cell growth.