Maresco D L, Osborne J M, Cooney D, Coggeshall K M, Anderson C L
Department of Internal Medicine, Ohio State University, Columbus 43210, USA.
J Immunol. 1999 Jun 1;162(11):6458-65.
Current models of Fc gamma R signal transduction in monocytes describe a molecular cascade that begins upon clustering of Fc gamma R with the phosphorylation of critical tyrosine residues in the cytoplasmic domains of Fc gamma RIIa or the gamma-chain subunit of Fc gamma RI and Fc gamma RIIIa. The cascade engages several other tyrosine-phosphorylated molecules, either enzymes or adapters, to manifest ultimately an array of biological responses, including phagocytosis, cell killing, secretion of a variety of inflammatory mediators, and activation. Continuing to assess systematically the molecules participating in the cascade, we have found that the SH2-containing 5'-inositol phosphatase (SHIP) is phosphorylated on tyrosine early and transiently after Fc gamma R clustering. This molecule in other systems, such as B cells and mast cells, mediates an inhibitory signal. We find that clustering of either Fc gamma RIIa or Fc gamma RI is effective in inducing SHIP phosphorylation, that SHIP binds in vitro to a phosphorylated immunoreceptor tyrosine-based activation motif, peptide from the cytoplasmic domain of Fc gamma RIIa in activation-independent fashion, although SHIP binding increases upon cell activation, and that Fc gamma RIIb and Fc gamma RIIc are not responsible for the observed SHIP phosphorylation. These findings prompt us to propose that SHIP inhibits Fc gamma R-mediated signal transduction by engaging immunoreceptor tyrosine-based activation motif-containing cytoplasmic domains of Fc gamma RIIa and Fc gamma RI-associated gamma-chain.
目前关于单核细胞中FcγR信号转导的模型描述了一种分子级联反应，该反应始于FcγR聚集，并伴随着FcγRIIa或FcγRI和FcγRIIIa的γ链亚基胞质结构域中关键酪氨酸残基的磷酸化。该级联反应涉及其他几种酪氨酸磷酸化分子，包括酶或衔接蛋白，最终表现出一系列生物学反应，包括吞噬作用、细胞杀伤、多种炎症介质的分泌和激活。在持续系统评估参与该级联反应的分子过程中，我们发现含SH2结构域的5'-肌醇磷酸酶（SHIP）在FcγR聚集后早期短暂地发生酪氨酸磷酸化。在其他系统，如B细胞和肥大细胞中，该分子介导抑制性信号。我们发现FcγRIIa或FcγRI的聚集均能有效诱导SHIP磷酸化，SHIP在体外以不依赖激活的方式与来自FcγRIIa胞质结构域的磷酸化基于免疫受体酪氨酸的激活基序肽结合，尽管SHIP结合在细胞激活后增加，并且FcγRIIb和FcγRIIc与观察到的SHIP磷酸化无关。这些发现促使我们提出，SHIP通过与FcγRIIa和FcγRI相关γ链含基于免疫受体酪氨酸的激活基序的胞质结构域结合来抑制FcγR介导的信号转导。
