B Cell Receptor Signaling

Pathway Description:

The B cell antigen receptor (BCR) is composed of membrane immunoglobulin (mIg) molecules and associated Igα/Igβ (CD79a/CD79b) heterodimers (α/β). The mIg subunits bind antigen, resulting in receptor aggregation, while the α/β subunits transduce signals to the cell interior. BCR aggregation rapidly activates the Src family kinases Lyn, Blk, and Fyn as well as the Syk and Btk tyrosine kinases. This initiates the formation of a ‘signalosome’ composed of the BCR, the aforementioned tyrosine kinases, adaptor proteins such as CD19 and BLNK, and signaling enzymes such as PLCγ2, PI3K, and Vav. Signals emanating from the signalosome activate multiple signaling cascades that involve kinases, GTPases, and transcription factors. This results in changes in cell metabolism, gene expression, and cytoskeletal organization. The complexity of BCR signaling permits many distinct outcomes, including survival, tolerance (anergy) or apoptosis, proliferation, and differentiation into antibody-producing cells or memory B cells. The outcome of the response is determined by the maturation state of the cell, the nature of the antigen, the magnitude and duration of BCR signaling, and signals from other receptors such as CD40, the IL-21 receptor, and BAFF-R. Many other transmembrane proteins, some of which are receptors, modulate specific elements of BCR signaling. A few of these, including CD45, CD19, CD22, PIR-B, and FcγRIIB1 (CD32), are indicated here in yellow. The magnitude and duration of BCR signaling are limited by negative feedback loops including those involving the Lyn/CD22/SHP-1 pathway, the Cbp/Csk pathway, SHIP, Cbl, Dok-1, Dok-3, FcγRIIB1, PIR-B, and internalization of the BCR. In vivo, B cells are often activated by antigen-presenting cells that capture antigens and display them on their cell surface. Activation of B cells by such membrane-associated antigens requires BCR-induced cytoskeletal reorganization. Please refer to the diagrams for the PI3K/Akt signaling pathway, the NF-κB signaling pathway, and the regulation of actin dynamics for more details about these pathways.

Selected Reviews:

• Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J (2004) B cell antigen receptor signaling 101. Mol. Immunol. 41(6-7), 599–613.
• Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R (2010) Control systems and decision making for antibody production. Nat. Immunol. 11(8), 681–8.
• Harwood NE, Batista FD (2010) Early events in B cell activation. Annu. Rev. Immunol. 28, 185–210.
• Harwood NE, Batista FD (2008) New insights into the early molecular events underlying B cell activation. Immunity 28(5), 609–19.
• Kurosaki T, Shinohara H, Baba Y (2010) B cell signaling and fate decision. Annu. Rev. Immunol. 28, 21–55.
• Szydłowski M, Jabłońska E, Juszczyński P (2014) FOXO1 transcription factor: a critical effector of the PI3K-AKT axis in B-cell development. Int. Rev. Immunol. 33(2), 146–57.

We would like to thank Prof. Michael R. Gold, University of British Columbia, Vancouver, British Columbia, Canada for reviewing this diagram.