title: Abr and Bcr, two homologous Rac GTPase-activating proteins, control multiple cellular functions of murine macrophages.
abstract: Small GTPases of the Rho family are key regulators of phagocytic leukocyte function. Abr and Bcr are homologous, multidomain proteins. Their C-terminal domain has GTPase-activating protein (GAP) activity that, in vitro, is specific for Rac and Cdc42. To address the in vivo relevance of these entire proteins, of which little is known, the current study examined the effect of the genetic ablation of Abr and Bcr in murine macrophages. The concomitant loss of Abr and Bcr induced multiple alterations of macrophage cellular behavior known to be under the control of Rac. Macrophages lacking both Abr and Bcr exhibited an atypical, elongated morphology that was reproduced by the ectopic expression of GAP domain mutant Abr and Bcr in a macrophage cell line and of constitutively active Rac in primary macrophages. A robust increase in colony-stimulating factor 1 (CSF-1)-directed motility was observed in macrophages deficient for both proteins and, in response to CSF-1 stimulation, Abr and Bcr transiently translocated to the plasma membrane. Phagocytosis of opsonized particles was also increased in macrophages lacking both proteins and correlated with sustained Rac activation. Bcr and Abr GAP mutant proteins localized around phagosomes and induced distinct phagocytic cup formation. These results identify Abr and Bcr as the only GAPs to date that specifically negatively regulate Rac function in vivo in primary macrophages.
authors.affiliation: Division of Hematology/Oncology Ms#54, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Cho
authors.forename: Jess M
authors.initials: JM
authors.lastname: Cunnick
authors.forename: Sun-Ju
authors.initials: SJ
authors.lastname: Yi
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.forename: John
authors.initials: J
authors.lastname: Groffen
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D001216:Asparagine / Q000235:genetics; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010587:Phagocytosis / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000172:deficiency / Q000378:metabolism*; D017385:Sequence Homology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C484145:Abr protein, mouse; D020690:GTPase-Activating Proteins; D050505:Mutant Proteins; D011506:Proteins; D001216:Asparagine; D016173:Macrophage Colony-Stimulating Factor; D001120:Arginine; D051562:Proto-Oncogene Proteins c-bcr; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins