B lymphocyte antigen receptor signaling: initiation, amplification, and regulation

Abstract

B lymphocytes and their differentiated daughters are charged with responding to the myriad pathogens in our environment and production of protective antibodies. A sample of the protective antibody produced by each clone is utilized as a component of the cell's antigen receptor (BCR). Transmembrane signals generated upon antigen binding to this receptor provide the primary directive for the cell's subsequent response. In this report, we discuss recent progress and current controversy regarding B cell receptor signal initiation, transduction and regulation.

Figure 1.. B cell receptor signaling and regulation. Upper panel B cell activation

Upon ligation of the BCR (1), ITAMs become phosphorylated via activity of SFKs (such as Lyn) and Syk. Syk and SFKs then phosphorylate signalosome components (2). The signalosome is associated with CD79a non-ITAM phosphotyrosine residues via binding of the adaptor protein Blnk (not illustrated). Activated Btk phosphorylates PLCγ2, which in turn cleaves the phosphoinositide PI(4,5)P_2, releasing IP₃ into the cytosol and forming DAG (3). IP₃ binds IP3R in the endoplasmic reticulum, releasing Ca²⁺ into the cytoplasm. The decrease in endoplasmic reticulum [Ca²⁺] activates STIM1, which binds ORAI in the plasma membrane, forming the CRAC channel and allowing for the influx of extracellular Ca²⁺ ions (4). RasGRP and protein kinase C (PKC) are activated by binding DAG, and feed into the MEK/MAP kinase (5) and NFκB activation pathways, respectively. CD19 plays an important role in amplifying the BCR signal via processive activation of Lyn, and activation of PI3K (6). Along with the recruitment of PH domain-containing signalosome components, the accumulation of PI(3,4,5)P₃ drives activation of Akt (7). Lower panel B cell deactivation: Lyn phosphorylates immunoreceptor tyrosine-based inhibition motifs (ITIMs) in CD22 and FCγRIIb. These ITIMs activate SHP1 and SHIP1, which function to inhibit BCR signaling. The protein phosphatase SHP1 has many substrates, including CD79, Syk, Grb2, and Vav, as well as others not shown. Additionally, ITIMs and mono-phosphorylated ITAMs can activate the lipid phosphatase SHIP1. SHIP1 hydrolyzes the phosphate at position 5 of PI(3,4,5)P₃, while PTEN removes that at position 3. This decrease in PI(3,4,5)P₃ concentration results in the disassociation of many PH domain-containing molecules, inhibiting signalosome assembly and downstream signaling. Illustrated structures not to scale, references in text.