Central role of BTK in the regulation of BCR- and CD40L/IL-4–induced signaling. (A) BTK is centrally involved in the BCR-signaling pathway, sitting distal to Syk and PI3Kδ, to phosphorylate and activate PLCγ2 and WASp, leading to further signal pathway activation and actin cytoskeleton rearrangements, respectively. (B) The mechanism of how BTK is activated by CD40 ligation is unknown, but could involve PI3K isoforms other than PI3Kδ (involved in BCR signaling). Active BTK then potentially interacts with a protein tyrosine phosphatase, which subsequently dephosphorylates JAK1 and STAT6 to deactivate their function in promoting cell proliferation (through the PI3K pathway) and induction of AID expression. Ag, antigen; BLNK, B-cell linker protein; ERK, extracellular signal-regulated kinase; IL-4R, IL-4 receptor; NFAT, nuclear factor of activated T cells; P, phosphorylated tyrosine motif; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; TRAF, tumor necrosis factor receptor–associated factor.