A NOVEL GTPASE-ACTIVATING PROTEIN FOR RHO INTERACTS WITH A PDZ DOMAINOF THE PROTEIN-TYROSINE-PHOSPHATASE PTPL1

PTPL1 is an intracellular protein-tyrosine phosphatase that contains f ive PDZ domains. Here, we present the cloning of a novel 150-kDa prote in, the four most C-terminal amino acid residues of which specifically interact with the fourth PDZ domain of PTPL1. The molecule contains a GTPase-activating protein (GAP) domain, a cysteine-rich, putative Zn2 +- and diacylglycerol-binding domain, and a region of sequence homolog y to the product of the Caenorhabditis elegans gene ZK669.1a. The GAP domain is active on Rho, Pac, and Cdc42 in vitro but with a clear pref erence for Rho; we refer to the molecule as PTPL1-associated RhoGAP 1, PARG1, Rho is inactivated by GAPs, and protein-tyrosine phosphorylati on has been implicated in Rho signaling. Therefore, a complex between PTPL1 and PARG1 may function as a powerful negative regulator of Rho s ignaling, acting both on Rho itself and on tyrosine phosphorylated com ponents in the Rho signal transduction pathway.