PAK KINASES ARE DIRECTLY COUPLED TO THE PIX FAMILY OF NUCLEOTIDE EXCHANGE FACTORS

The PAK family of kinases are regulated through interaction with the s mall GTPases cdc42 and Rad, but little is known of the signaling compo nents immediately upstream or downstream of these proteins. We have pu rified and cloned a new class of Rho-p21 guanine nucleotide exchange f actor binding tightly through its N-terminal SH3 domain to a conserved proline-rich PAK sequence with a K-d of 24 nM. This PAK-interacting e xchange factor (PIX), which is widely expressed and enriched in Cdc42- and Rad-driven focal complexes, is required for PAK recruitment to th ese sites. PIX can induce membrane ruffling, with an associated activa tion of Rad. Our results suggest a role for PIX in Cdc42-to-Rac1 signa ling, involving the PIX/PAK complex.