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 group of GTPase-activating proteins that act exclusively on members of the Ras-related Rho subfamily. A complementary DNA was isolated from Caenorhabditis elegans that encoded a polypeptide of 1438 amino acid residues, CeGAP, which contains a domain with sequence similarity to the COOH-terminal segment (GTPase-activating protein region) of Bcr and other known GTPase-activating proteins of the Rho subfamily. It also contains a "pleckstrin homology" motif, present in many signaling proteins including GTPase-activating proteins and nucleotide exchange factors. The Bcr-like domain of CeGAP exhibited activity not only on members of the C. elegans and human Rho subfamily but surprisingly also on C. elegans Ras protein (let-60), human Ras, and Rab3A. CeGAP is therefore the first GTPase-activating protein acting on Ras-related proteins across different subfamilies. Together with the presence of the pleckstrin homology motif, our finding suggests a central and integrative role for CeGAP in a signaling pathway common to Ras and related proteins.