The Alternate Pathway for BCR Signaling Induced by IL-4 Requires Lyn Tyrosine Kinase

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.