title: A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages.
abstract: Receptors on macrophages for the Fc region of IgG (FcgammaR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcgammaR cross-linking. Macrophages derived from Syk-deficient (Syk-) mice were defective in phagocytosis of particles bound by FcgammaRs, as well as in many FcgammaR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk- macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk- macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcgammaRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcgammaR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcgammaR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcgammaR engagement, accompanied by a delay in FcgammaR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcgammaR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcgammaR's analogous to models of signaling by the B and T cell antigen receptors.
authors.affiliation: G.W. Hooper Foundation, University of California, San Francisco, California 94143-0552, USA. mtcrow@scripps.edu
authors.forename: M T
authors.initials: MT
authors.lastname: Crowley
authors.forename: P S
authors.initials: PS
authors.lastname: Costello
authors.forename: C J
authors.initials: CJ
authors.lastname: Fitzer-Attas
authors.forename: M
authors.initials: M
authors.lastname: Turner
authors.forename: F
authors.initials: F
authors.lastname: Meng
authors.forename: C
authors.initials: C
authors.lastname: Lowell
authors.forename: V L
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: A L
authors.initials: AL
authors.lastname: DeFranco
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004792:Enzyme Precursors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000196:embryology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008863:Microspheres; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D000077191:Wortmannin; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000730:Androstadienes; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016207:Cytokines; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017452:Receptors, IgG; D000072377:Syk Kinase; D000077191:Wortmannin; D019061:src-Family Kinases; C000606897:Syk protein, mouse