A novel Lyn‐protein kinase Cδ/ε‐protein kinase D axis is activated in B cells by signalosome‐independent alternate pathway BCR signaling

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.