Kiefer F, Brumell J, Al-Alawi N, Latour S, Cheng A, Veillette A, Grinstein S, Pawson T
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5.
Mol Cell Biol. 1998 Jul;18(7):4209-20. doi: 10.1128/MCB.18.7.4209.
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.
细胞质蛋白酪氨酸激酶Syk有两个氨基末端SH2结构域，可与免疫受体信号亚基中基于酪氨酸的磷酸化免疫受体激活基序结合。Syk与Src家族激酶共同参与淋巴细胞和髓细胞中的免疫受体信号传导。我们通过使用用来自Syk-/-胚胎的胎肝细胞重建的小鼠辐射嵌合体，研究了Syk在骨髓来源的巨噬细胞和中性粒细胞中Fcγ受体（FcγR）依赖性和非依赖性反应中的作用。嵌合小鼠在移植后2至3个月开始出现腹部出血，最终导致死亡。源自骨髓的Syk缺陷型中性粒细胞在FcγR结合时无法产生活性氧中间体，但对十四酰佛波醇乙酸酯刺激反应正常。Syk缺陷型巨噬细胞在FcγR诱导的吞噬作用中存在缺陷，但对补体的吞噬作用正常。FcγR刺激后，Syk-/-巨噬细胞中包括FcγRγ链在内的多种细胞多肽的酪氨酸磷酸化以及Erk2激活均受损。相比之下，脂多糖和γ干扰素刺激的巨噬细胞中一氧化氮合酶的诱导不依赖于Syk。令人惊讶的是，Syk缺陷型巨噬细胞在塑料培养皿上存活或增殖的能力受损。综上所述，这些结果表明Syk在中性粒细胞和巨噬细胞中FcγR信号传导中具有特定的生理作用，并增加了Syk在体内参与免疫受体介导之外的信号事件的可能性。
