The pseudo-immunoreceptor tyrosine-based activation motif of CD5 mediates its inhibitory action on B-cell receptor signaling
The pseudo-immunoreceptor tyrosine-based activation motif of CD5 mediates its inhibitory action on B-cell receptor signaling
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DOI：
10.1074/jbc.275.1.548
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发表时间：
2000-01-07
影响因子：
4.8
通讯作者：
Bismuth, G
中科院分区：
文献类型：
--
作者：
Gary-Gouy, H;Bruhns, P;Bismuth, G
遗传学研究表明，CD5可能是b细胞抗原受体（BCR）的负调节因子。我们在此探讨人类CD5对bcr触发反应的影响。B细胞表达Fc γ型IIB受体的细胞外和跨膜结构域与CD5细胞质结构域（CD5cyt）融合的嵌合体。嵌合体与BCR结合可诱导CD5cyt酪氨酸磷酸化。观察到bcr诱导的钙反应的快速抑制，以及磷脂酶C γ -1磷酸化的部分但延迟的抑制。细胞外调节激酶-2的激活也严重受损。此外，在功能水平上，白细胞介素-2的产生被取消。Src同源2结构域酪氨酸磷酸酶SHP-1和Src同源2结构域肌醇5′-磷酸酶SHIP通常参与BCR的负调控。我们发现它们不与磷酸化的CD5嵌合体相关联。我们最终证明，CD5cyt中存在的基于伪免疫受体酪氨酸的激活基序参与其中，因为它的缺失在生化和功能水平上消除了嵌合体的抑制作用。这些结果证明了CD5伪免疫受体酪氨酸激活基序酪氨酸磷酸化对BCR信号的抑制作用。他们进一步支持了CD5使用不同于已经描述的机制来负性调节BCR通路的观点。
Genetic studies revealed that CD5 could be a negative regulator of the B-cell antigen receptor (BCR). We explore here the effect of human CD5 on BCR-triggered responses. B cells were obtained expressing a chimera composed of extracellular and transmembrane domains of Fc gamma type IIB receptor fused to CD5 cytoplasmic domain (CD5cyt). Coligation of the chimera with the BCR induces CD5cyt tyrosine phosphorylation. A rapid inhibition of BCR-induced calcium response is observed, as well as a partial but delayed inhibition of phospholipase C gamma-1 phosphorylation. Activation of extracellular regulated kinase-2 is also severely impaired. Moreover, at the functional level, interleukin-2 production is abolished. Src homology 2 domain-bearing tyrosine phosphatase SHP-1 and Src homology 2 domain-bearing inositol 5'-phosphatase SHIP usually participate in negative regulation of the BCR. We show that they do not associate with the phosphorylated CD5 chimera. We finally demonstrate that the pseudo-immunoreceptor tyrosine based activation motif present in CD5cyt is involved because its deletion eliminates the inhibitory effect of the chimera, both at biochemical and functional levels. These results demonstrate the inhibitory role of CD5 pseudo-immunoreceptor tyrosine based activation motif tyrosine phosphorylation on BCR signaling. They further support the idea that CD5 uses mechanisms different from those already described to negatively regulate the BCR pathway.