title: Activation of CR3-mediated phagocytosis by MSP requires the RON receptor, tyrosine kinase activity, phosphatidylinositol 3-kinase, and protein kinase C zeta.
abstract: Macrophage-stimulating protein (MSP) promotes the phagocytosis of C3bi-coated erythrocytes by resident peritoneal macrophages, although the mechanism by which this occurs is largely unknown. We show that MSP-induced complement-mediated phagocytosis requires the RON receptor tyrosine kinase and the alphaMbeta2 integrin, as evidenced by the inability of RON-/- and alphaM-/- peritoneal macrophages to augment phagocytosis of complement-coated sheep erythrocytes in response to MSP. MSP stimulation of macrophages results in tyrosine phosphorylation and AKT activation, and inhibitor studies demonstrate a phagocytic requirement for tyrosine kinase and phosphatidylinositol 3-kinase (PI-3K) activity as well as activity of the atypical protein kinase C (PKC) isoform zeta, which localizes to MSP-induced phagosomes containing complement-coated beads. Additionally, MSP augments the ability of peritoneal macrophages to bind to intercellular adhesion molecule-1 (ICAM-1) via the alphaMbeta2 integrin. MSP-induced ICAM-1 adhesion is also dependent on tyrosine kinase activity, PI-3K, and PKC zeta, indicating that these signaling requirements are upstream of complement receptor 3 activation.
authors.affiliation: Department of Veterinary Science, Pennsylvania State University, Pathobiology Graduate Program, University Park 16802, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lutz
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Correll
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000818:Animals; D002478:Cells, Cultured; D003179:Complement C3b / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D000099221:Protein Kinase C zeta
chemical_list: D003179:Complement C3b; D004075:Diglycerides; D004791:Enzyme Inhibitors; D017228:Hepatocyte Growth Factor; D018799:Intercellular Adhesion Molecule-1; D016177:Macrophage-1 Antigen; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D000099221:Protein Kinase C zeta; C082332:macrophage stimulating protein; C080835:RON protein