Modular components of phagocytosis.
Phagocytosis is an evolutionarily ancient host cell endocytic response to particulate stimuli. Phagocytic leukocytes utilize highly conserved programs of signaling and motility to engulf foreign pathogens. Particle ingestion requires actin assembly and pseudopod extension, two cellular events that coincide spatially and temporally. This review presents evidence that phagocytosis proceeds in discrete but coordinated stages. In the case of receptors for the Fc portion of IgG (FcgammaRs), engagement of the IgG ligands results in receptor aggregation and recruitment of cytosolic tyrosine kinases, most notably Syk. Phosphorylation of tyrosine residues occurs within immunoreceptor tyrosine activation motif (ITAM) consensus sequences found in FcgammaR subunits, which leads to further recruitment and activation of Syk via its SH2 domains. Syk tyrosine kinase activity is required for FcgammaR-mediated actin assembly, which is controlled by several GTPases, including Rac1 and Cdc42. Phagocytosis and Rac-mediated cytoskeletal alterations also require the participation of another low molecular GTPase, ARF6. Simultaneously, phosphatidylinositol 3-kinase is recruited to the plasma membrane, which triggers exocytosis from an intracellular membrane source that is required for pseudopod extension. The source of this membrane is as yet unknown. This review focuses on individual components of phagocytosis and emphasizes that the signaling requirements for each of these is distinct.
Greenberg
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Department of Medicine, Columbia University, New York, NY 10032, USA. greenberg@cuccfa.ccc.columbia.edu
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000276:immunology; D000199:Actins / Q000378:metabolism; D000818:Animals; D006801:Humans; D010587:Phagocytosis / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology*; D020764:cdc42 GTP-Binding Protein / Q000276:immunology; D020830:rac1 GTP-Binding Protein / Q000276:immunology
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D000199:Actins; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D011971:Receptors, Immunologic; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; C084944:TYRO3 protein, human; C000715348:ARF6 protein, human