title: Activity of the Bcr GTPase-activating domain is regulated through direct protein/protein interaction with the Rho guanine nucleotide dissociation inhibitor.
abstract: The cycling of Rac GTPases, alternating between an active GTP- and an inactive GDP-bound state, is controlled by guanine nucleotide exchange factors, GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). Little is known about how these controlling activities are coordinated. Studies using null mutant mice have demonstrated that Bcr and Abr are two physiologically important GAPs for Rac. Here, we report that in the presence of RhoGDIalpha, Bcr is unable to convert Rac-GTP to Rac-GDP because RhoGDI forms a direct protein complex with Bcr. Interestingly, RhoGDIalpha binds to the GAP domain in Bcr and Abr, a domain that also binds to Rac-GTP and catalyzes conversion of the bound GTP to GDP on Rac. The presence of activated Rac diminished the Bcr/RhoGDIalpha interaction. Moreover, a Bcr mutant that lacks the ability to promote hydrolysis of Rac-GTP bound to its GAP domain did not bind to RhoGDIalpha in cell lysates, indicating that binding of RhoGDIalpha and Rac-GTP to the Bcr GAP domain is mutually exclusive. Our results provide the first identification of a protein that regulates BcrGAP activity.
authors: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027.
authors: Soo-Mi
authors: SM
authors: Kweon
authors: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027.
authors: Young Jin
authors: YJ
authors: Cho
authors: Department of Pediatrics, University of Southern California, Los Angeles, California 90033.
authors: Parviz
authors: P
authors: Minoo
authors: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors: John
authors: J
authors: Groffen
authors: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033. Electronic address: heisterk@hsc.usc.edu.
authors: Nora
authors: N
authors: Heisterkamp
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020558:GTP Phosphohydrolases / Q000737:chemistry*; D005786:Gene Expression Regulation; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051562:Proto-Oncogene Proteins c-bcr / Q000737:chemistry*; D020741:rho GTP-Binding Proteins / Q000737:chemistry*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: C569638:ARHGDIA protein, human; C569639:Arhgdia protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D020558:GTP Phosphohydrolases; D020741:rho GTP-Binding Proteins