CHARACTERIZATION OF A PROMISCUOUS GTPASE-ACTIVATING PROTEIN THAT HAS A BCR-RELATED DOMAIN FROM CAENORHABDITIS-ELEGANS

Human breakpoint cluster region (bcr) gene product is a member of a gr oup of GTPase-activating proteins that act exclusively on members of t he Ras-related Rho subfamily. A complementary DNA was isolated from Ca enorhabditis elegans that encoded a polypeptide of 1438 amino acid res idues, CeGA-P, which contains a domain with sequence similarity to the COOH-terminal segment (GTPase-activating protein region) of Bcr and o ther known GTPase-activating proteins of the Rho subfamily. It also co ntains a ''pleckstrin homology'' motif, present in many signaling prot eins including GTPase-activating proteins and nucleotide exchange fact ors. The Bcr-like domain of CeGAP exhibited activity not only on membe rs of the C. elegans and human Rho subfamily but surprisingly also on C. elegans Ras protein (let-60), human Ras, and Rab3A. CeGA-P is there fore the first GTPase-activating protein acting on Ras-related protein s across different subfamilies. Together with the presence of the plec kstrin homology motif, our finding suggests a central and integrative role for CeGAP in a signaling pathway common to Ras and related protei ns.