Regulation of the p21-activated kinase (PAK) by a human G beta-like WD-repeat protein, hPIP1

The family of p21-activated protein kinases (PAKs) is composed of serine-th reonine kinases whose activity is regulated by the small guanosine triphosp hatases (CTPases) Rac and Cdc42. In mammalian cells, PAKs have been implica ted in the regulation of mitogen-activated protein cascades, cellular morph ological and cytoskeletal changes, neurite outgrowth, and cell apoptosis. A lthough the ability of Cdc42 and Rac GTPases to activate PAK is well establ ished, relatively little is known about the negative regulation of PAK or t he identity of PAK cellular targets. Here, we describe the identification a nd characterization of a human PAK-interacting protein, hPIP1. hPIP1 contai ns C protein beta -like WD repeats and shares sequence homology with the es sential fission yeast PAK regulator, Skb15, as well as the essential buddin g yeast protein, MAK11. Interaction of hPIP1 with PAK1 inhibits the Cdc42/R ac-stimulated kinase activity through the N-terminal regulatory domains of PAK1. Cotransfection of hPIP1 in mammalian cells inhibits PAK-mediated c-Ju n N-terminal kinase and nuclear factor kappa B signaling pathways. Our resu lts demonstrate that hPIP1 is a negative regulator of PAK and PAK signaling pathways.