Chan V W, Lowell C A, DeFranco A L
George Williams Hooper Foundation, University of California, San Francisco 94143, USA.
Curr Biol. 1998 May 7;8(10):545-53. doi: 10.1016/s0960-9822(98)70223-4.
To elucidate the role of the Src family kinase Lyn in B cell receptor (BCR) signaling, we and others previously generated lyn-/- mice and analyzed their B cell responses. Although the initiation of BCR signaling in lyn-/- B cells is delayed, BCR-induced ERK2 activation and proliferation are enhanced. As the co-receptors Fc gamma RIIb1 and CD22 have been shown to be negative regulators of BCR signaling, we have now examined their functional roles in lyn-/- B cells.
B cells from lyn-/- mice have increased expression of the protein product of the early response gene egr-1, enhanced activation of Jun N-terminal kinase (JNK), and elevated calcium responses upon BCR cross-linking. Tyrosine phosphorylation of Fc gamma RIIb1 in lyn-/- B cells was reduced but negative regulation of the BCR signal by Fc gamma RIIb1 was only modestly impaired. In contrast, tyrosine phosphorylation of CD22 was greatly decreased in lyn-/- B cells, correlating with the inability of CD22 to downregulate the BCR-induced calcium response in these cells. Surprisingly, CD22 remains capable of regulating the ERK2 and JNK pathways in lyn-/- B cells, which may relate to the small residual increase in BCR-induced CD22 phosphorylation.
BCR signal initiation and negative regulation by Fc gamma RIIb1 is not critically dependent on Lyn. In contrast, Lyn plays a particularly important role in the tyrosine phosphorylation of CD22 and in the consequent inhibition of BCR-induced calcium influx. The net result of the Lyn deficiency in B cells is hyperresponsiveness to antigen stimulation, which may explain the autoimmunity observed in lyn-/- mice.
为阐明Src家族激酶Lyn在B细胞受体（BCR）信号传导中的作用，我们和其他研究团队之前构建了lyn基因敲除小鼠，并分析了其B细胞反应。尽管lyn基因敲除B细胞中BCR信号传导的起始延迟，但BCR诱导的ERK2激活和增殖增强。由于共受体FcγRIIb1和CD22已被证明是BCR信号传导的负调节因子，我们现在研究了它们在lyn基因敲除B细胞中的功能作用。
lyn基因敲除小鼠的B细胞中早期反应基因egr-1的蛋白质产物表达增加，Jun N末端激酶（JNK）的激活增强，并且在BCR交联后钙反应升高。lyn基因敲除B细胞中FcγRIIb1的酪氨酸磷酸化减少，但FcγRIIb1对BCR信号的负调节仅受到轻微损害。相比之下，lyn基因敲除B细胞中CD22的酪氨酸磷酸化大大降低，这与CD22无法下调这些细胞中BCR诱导的钙反应相关。令人惊讶的是，CD22在lyn基因敲除B细胞中仍能够调节ERK2和JNK途径，这可能与BCR诱导的CD22磷酸化的小幅度残余增加有关。
BCR信号传导的起始和FcγRIIb1的负调节并不严重依赖于Lyn。相反，Lyn在CD22的酪氨酸磷酸化以及随后对BCR诱导的钙内流的抑制中起特别重要的作用。B细胞中Lyn缺乏的最终结果是对抗原刺激的反应过度，这可能解释了在lyn基因敲除小鼠中观察到的自身免疫现象。
