IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling

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Abstract
Neural Wiskott-Aldrich syndrome protein (N-WASP)1 functions in several intracellular events including filopodium formation2, vesicle transport3 and movement of Shigella frexneri4,5 and vaccinia virus6, by stimulating rapid actin polymerization through the Arp2/3 complex. N-WASP is regulated by the direct binding of Cdc42 (refs 7, 8 ), which exposes the domain in N-WASP that activates the Arp2/3 complex2,9. A WASP-related protein, WAVE/Scar, functions in Rac-induced membrane ruffling10,11; however, Rac does not bind directly to WAVE10, raising the question of how WAVE is regulated by Rac. Here we demonstrate that IRSp53, a substrate for insulin receptor12 with unknown function, is the ‘missing link’ between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex.