Figure 1. . Signaling pathways of the B-cell receptor, its role in B-cell malignancies and targets of inhibition.

Schematic of the B-cell receptor signaling pathway. (A) Antigen engagement initiates receptor clustering and facilitates Lyn-medated phosphorylation of tyrosines within CD79 and CD19. In chronic lymphocytic leukemia, the SFK Lck mediates phosphorylation of CD79. (B) Syk binds to phospho-tyrosine residues within the ITAM of CD79 and is activated. Adaptor proteins such as BLNK, LAB, NCK, BCAP and Grb2 associate with phospho-tyrosines outside the ITAM on CD79. Proteins such as BLNK and BCAP are substrates of Syk. (C) Phospho-tyrosine residues within BCAP and CD19 attract the regulatory subunit of PI3Kδ leading to the activation of catalytic p110. PI(4,5)P₂ is converted to PI(3,4,5)P₃ which attracts PH domain containing proteins such as BTK, PLCγ2, Akt and Vav to the plasma membrane. (D) Phospho-tyrosine residues within BLNK act as a scaffold for membrane-associated BTK and PLCγ2, facilitating activation of the former to phosphorate and activate the latter. This catalyzes distal signaling pathway activation leading to NF-κB, JNK and ERK activation. (E) Further distal signals include activation of Vav leading to cytoskeletal rearrangement, and of Akt leading to activation of mTORC1 and inhibition of FoxO.

CLL: Chronic lymphocytic leukemia; DLBCL: Diffuse large B-cell lymphoma; FL: Follicular lymphoma; ITAM: Immuno-receptor tyrosine-based activation motifs; MCL: Mantle cell lymphoma.