Center for Immunobiology and Department of Investigative Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 300 Portage Street, Kalamazoo, MI 49007, United States.
Center for Immunobiology and Department of Investigative Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 300 Portage Street, Kalamazoo, MI 49007, United States.
J Mol Biol. 2021 Jan 8;433(1):166667. doi: 10.1016/j.jmb.2020.10.002. Epub 2020 Oct 13.
BCR signaling triggers a cascade of intracellular mediators that eventuates in transcription factor activation. Signaling is proximally mediated by Src family tyrosine kinases, the most abundant being Lyn. Key mediators are grouped together as the signalosome, and failure of any single member of this group leads to failure of signaling via this classical pathway. Recent work has revealed an alternate pathway for BCR signaling, in which signalosome elements are bypassed for downstream events such as ERK and PKCδ phosphorylation. This pathway is created by B cell treatment with IL-4 prior to BCR triggering. After IL-4 treatment, the alternate pathway for pERK operates in parallel with the classical pathway for pERK, whereas PKCδ phosphorylation is specific to the alternate pathway. Remarkably, Lyn is not required for B cell activation via the classical pathway; however, Lyn is indispensable and irreplaceable for B cell activation via the alternate pathway. Thus, Lyn operates at a branch point that determines the nature of the B cell response to BCR activation. The mechanism underlying the absolute dependence of alternate pathway signaling on Lyn is unknown. Here, our current understanding of receptor crosstalk between IL-4R and BCR is summarized along with several possible mechanisms for the role of Lyn in alternate pathway signaling. Further dissection of alternate pathway signaling and the role of Lyn is likely to provide important information relating to normal B cell responses, malignant B cell expansion, and generic principles relating to receptor interactions and crosstalk.
BCR 信号触发细胞内介质的级联反应，最终导致转录因子激活。信号的近程介导由 Src 家族酪氨酸激酶完成，其中最丰富的是 Lyn。关键介质被归为信号体，该组中任何单个成员的失败都会导致通过该经典途径的信号传导失败。最近的工作揭示了 BCR 信号的另一种途径，其中信号体元件被绕过，用于下游事件，如 ERK 和 PKCδ 的磷酸化。该途径是通过 B 细胞在 BCR 触发前用 IL-4 处理而创建的。在 IL-4 处理后，替代途径的 pERK 与经典途径的 pERK 并行运行，而 PKCδ 的磷酸化则是替代途径特有的。值得注意的是，Lyn 对于经典途径中的 B 细胞激活不是必需的；然而，Lyn 对于替代途径中的 B 细胞激活是不可或缺且不可替代的。因此，Lyn 在分支点上运作，决定了 B 细胞对 BCR 激活的反应性质。替代途径信号对 Lyn 的绝对依赖性的机制尚不清楚。在这里，我们总结了目前对 IL-4R 和 BCR 之间受体串扰的理解，以及 Lyn 在替代途径信号中的作用的几种可能机制。进一步剖析替代途径信号和 Lyn 的作用可能为正常 B 细胞反应、恶性 B 细胞扩增以及与受体相互作用和串扰相关的一般原则提供重要信息。
