Figure 3. PI3K and BTK Signaling in Response to BCR activation in B cells.

Antigen engagement of the BCR receptor induces clustering of the BCR, associated CD79A/CD79B heterodimers, and the non-receptor tyrosine kinase (NRTK) LYN which is tethered to the membrane by dual lipid modifications. LYN phosphorylates tyrosine motifs on CD79A/CD79B and the co-receptor CD19 to which the NRTK SYK and PI3K dock respectively and become activated. PIP₃ produced by PI3K recruits BTK to the membrane where it is phosphorylated and activated by SYK and LYN. BTK also forms a complex with the adaptor protein BLNK, the Rho family GEF Vav, and the phospholipase PLCγ. Following its BTK-dependent activation, Vav promotes GTP loading and activation of Cdc42 and Rac which then trigger actin cytoskeleton remodeling through a variety of effectors. Simultaneously, BTK phosphorylates and activates PLCγ which cleaves PI-4,5-P₂ to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG is bound by PKCβ which triggers IKK signaling and NFkB-dependent transcription plus activation of Ras-Raf-MEK-ERK signaling. IP3 stimulates calcium (Ca²⁺) mobilization which results in NFAT-dependent transcription. These signaling events cooperate to control survival, proliferation, and adhesion signals that underlie B cell development and activation.