title: The 3BP2 adapter protein is required for chemoattractant-mediated neutrophil activation.
abstract: 3BP2 is a pleckstrin homology and Src homology 2 domain-containing adapter protein mutated in cherubism, a rare autosomal-dominant human bone disorder. Previously, we have demonstrated a functional role for 3BP2 in peripheral B cell development and in peritoneal B1 and splenic marginal zone B cell-mediated Ab responses. In this study, we show that 3BP2 is required for G protein-coupled receptor-mediated neutrophil functions. Neutrophils derived from 3BP2-deficient (Sh3bp2-/-) mice failed to polarize their actin cytoskeleton or migrate in response to a gradient of chemotactic peptide, fMLF. Sh3bp2-/- neutrophils failed to adhere, crawl, and emigrate out of the vasculature in response to fMLF superfusion. 3BP2 is required for optimal activation of Src family kinases, small GTPase Rac2, neutrophil superoxide anion production, and for Listeria monocytogenes bacterial clearance in vivo. The functional defects observed in Sh3bp2-/- neutrophils may partially be explained by the failure to fully activate Vav1 guanine nucleotide exchange factor and properly localize P-Rex1 guanine nucleotide exchange factor at the leading edge of migrating cells. Our results reveal an obligate requirement for the adapter protein 3BP2 in G protein-coupled receptor-mediated neutrophil function.
authors: Department of Immunology, University of Toronto, Toronto, Ontario M5S 148, Canada.
authors: Grace
authors: G
authors: Chen
authors: Ioannis
authors: I
authors: Dimitriou
authors: Laura
authors: L
authors: Milne
authors: Karl S
authors: KS
authors: Lang
authors: Philipp A
authors: PA
authors: Lang
authors: Noah
authors: N
authors: Fine
authors: Pamela S
authors: PS
authors: Ohashi
authors: Paul
authors: P
authors: Kubes
authors: Robert
authors: R
authors: Rottapel
mesh_terms: D000199:Actins / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D008088:Listeriosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000502:physiology*; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D011897:Random Allocation; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C484644:Sh3bp2 protein, mouse; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases