Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
Eur J Immunol. 2013 Jun;43(6):1643-50. doi: 10.1002/eji.201242830. Epub 2013 Apr 12.
BCR signaling initiates multiple activities critical for B-cell function. Recently, we identified an alternate BCR signaling pathway, induced by IL-4, that is signalosome-independent, unlike the classical signalosome-dependent pathway, and that leads to activation of the MAP kinase, ERK. Here we questioned whether alternate pathway signaling extends to other key downstream events, especially protein kinase D (PKD) activation. We found that in murine spleen-derived B cells the IL-4-induced alternate pathway for BCR signaling results in PKD and PKD substrate phosphorylation, and that alternate pathway phosphorylation of HDAC5/7 and other key substrates requires PKD. Furthermore, we found that tyrosine phosphorylation of PKCδ/ε occurs as a result of alternate but not classical pathway signaling and is required for phosphorylation of PKD and PKD substrates. This result identifies PKCδ/ε tyrosine phosphorylation as a unique outcome of the alternate pathway. The alternate pathway is mediated by Lyn that is not required for classical pathway signaling and we found that Lyn associates directly with PKCδ/ε and is required for phosphorylation of PKCδ/ε and of PKD. These findings indicate that IL-4 influences B-cell activation by inducing a novel signaling pathway from BCR to Lyn to PKCδ/ε to PKD.
BCR 信号转导启动多个对 B 细胞功能至关重要的活动。最近，我们鉴定了一种替代的 BCR 信号通路，由 IL-4 诱导，该信号通路与经典的信号转导依赖信号小体不同，而是信号转导非依赖信号小体，并且导致 MAP 激酶 ERK 的激活。在这里，我们想知道替代途径信号是否会扩展到其他关键下游事件，特别是蛋白激酶 D (PKD) 的激活。我们发现，在鼠脾源性 B 细胞中，BCR 信号的 IL-4 诱导的替代途径导致 PKD 和 PKD 底物磷酸化，并且替代途径的 HDAC5/7 和其他关键底物的磷酸化需要 PKD。此外，我们发现 PKCδ/ε 的酪氨酸磷酸化是替代途径而不是经典途径信号的结果，并且是 PKD 和 PKD 底物磷酸化所必需的。这一结果表明 PKCδ/ε 的酪氨酸磷酸化是替代途径的一个独特结果。替代途径是由 Lyn 介导的，而 Lyn 不参与经典途径信号，我们发现 Lyn 直接与 PKCδ/ε 结合，并且是 PKCδ/ε 和 PKD 的磷酸化所必需的。这些发现表明，IL-4 通过诱导从 BCR 到 Lyn 到 PKCδ/ε 到 PKD 的新信号通路来影响 B 细胞的激活。
