The Syk protein tyrosine kinase is essential for Fcgamma receptor signaling in macrophages and neutrophils.
The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcgamma receptor (FcgammaR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk-/- embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcgammaR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcgammaR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcgammaR gamma chain, as well as Erk2 activation, was compromised in Syk-/- macrophages after FcgammaR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcgammaRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.
Kiefer
F
F
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5.
Brumell
J
J
Al-Alawi
N
N
Latour
S
S
Cheng
A
A
Veillette
A
A
Grinstein
S
S
Pawson
T
T
D000005:Abdomen / Q000002:abnormalities; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D016026:Bone Marrow Transplantation; D019556:COS Cells; D002478:Cells, Cultured; D004790:Enzyme Induction; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D006470:Hemorrhage; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010587:Phagocytosis; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG; D016897:Respiratory Burst; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D017452:Receptors, IgG; D014443:Tyrosine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human