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 Rac1 (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 Rac1 to induce cytoskeletal changes or to activate the Jun kinase mitogen-activated protein kinase cascade but abrogates Rac1-induced stimulation of DNA synthesis and Rac1-mediated superoxide production in quiescent fibroblasts. Treatment of cells with agents that abolish superoxide generation inhibits specifically the mitogenic effect of Rac1. Our results identify an effector site in Rac1 that is necessary for mitogenic signaling and implicate superoxide generation as a candidate effector pathway of Rac1-dependent cell growth.