BCR Pathway
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BCR Pathway

The BCR (B-Cell antigen Receptor) plays a critical role in development, survival, and activation of B cells. The BCR is composed of mIg molecules (Membrane Immunoglobulin) and associated Ig-Alpha/Ig-Beta heterodimer. The mIg subunits bind antigen and cause receptor aggregation, while the Alpha/Beta subunits transduce signals to the cell interior. Engagement of receptor activates three types of intracellular protein tyrosine kinases, Syk (Spleen Tyrosine Kinase), BTK (Bruton agammaglobulinemia Tyrosine Kinase) and several members of the Src-family of tyrosine kinases (Ref.1). Once activated, these tyrosine kinases phosphorylate signaling components and thereby activate various signaling pathways, including PIP2 (Phosphatidyl Inositol 4,5-Bisphosphate) breakdown, Ras activation, the Vav/Rho family pathway, MAPK pathways and PI3K (Phosphoinositide-3 Kinase) activation (Ref.2).

The complexity of BCR signaling permits many distinct outcomes, including proliferation, differentiation, apoptosis, survival and tolerance. The maturation state of the cell, the affinity of the antibody-antigen interaction, the cellular environment and the nature of the antigen determine the outcome of the response. Many other transmembrane receptors are known to modulate specific elements of BCR signaling. A few of these are CD45 and FCGR2B (Fc Fragment Of IgG, Low Affinity IIB, Receptor For CD32). CD45 occurs as a component of a complex of proteins associated with the antigen receptor, and CD45 may regulate signal transduction by modulating the phosphorylation state of the antigen receptor subunits (Ref.3).

Cytoplasmic PTK (Protein Tyrosine Kinase) activation is the earliest of the known signal transduction events. This PTK activation results in the tyrosine phosphorylation of many proteins, including BCR Ig-Alpha and Ig-Beta chains, PI3K, Vav, Cbl and PLC-Gamma2 (Phospholipase-C-Gamma-2). Among the substrates, PLC-Gamma2 is a key enzyme for IP3 (Inositol 1,4,5-Trisphosphate) production. The PLC-Gamma2-calcium pathway is one of the most extensively studied. BCR-induced tyrosine phosphorylation of PLC-Gamma2 is responsible for an increase in its activity, which allows conversion of PIP2 to the second messenger’s IP3 and DAG (Diacylglycerol). DAG activates PKC (Protein Kinase-C). PKC appears to associate and directly phosphorylate IKK (I-KappaB Kinase) activity resulting in the phosphorylation of I-KappaB and translocation of NF-KappaB (Nuclear Factor-Kappa B) to the nucleus. IP3 binds IP3R (IP3 Receptor), which is localized primarily on the ER (Endoplasmic Reticulum) and stimulates the release of calcium from intracellular stores. PLC-Gamma2 activity is also regulated by cellular localization. Recently, an essential role of the adaptor protein BLNK (B-Cell Linker), also called SLP65 or BASH, in PLC-Gamma2 membrane localization and tyrosine phosphorylation was deduced. Upon BCR stimulation, BLNK is phosphorylated by Syk, which recruits BTK and PLC-Gamma2 to BLNK via their respective SH2 domains. The BLNK complex is targeted to the plasma membrane by an unidentified mechanism, in which BTK is thought to phosphorylate and activate PLC-Gamma2, leading to IP3 production and calcium mobilization (Ref.4). One of the targets regulated by calcium elevation is the transcription factor NFAT (Nuclear-Factor of Activated T-cells), whose nuclear translocation is facilitated through its dephosphorylation by Calcineurin (Ref.5).

BCR activates numerous intermediate signaling proteins including the Ras (via SHC, GRB2 and SOS) and Rap1, which are small molecular weight GTPases and these ultimately lead to the activation of MAPK (Mitogen-Activated Protein kinases) kinases including ERK (Extracellular Signal Regulated Kinase), JNK (Jun N-terminal Kinases) and p38. B-Cell also possesses a co-receptor complex, which can modulate BCR signal transduction. The co-receptor complex is composed of CD21, CD19 and CD81. CD21 binds opsinized antigenic particles. CD19 is primarily responsible for signal transduction. Phosphorylation of CD19 generates binding sites for Src-family kinases and PI3K. Binding of PI3K activates PIP3 (Phosphatidylinositol -3, 4, 5-Triphosphate) and Vav. Vav activates Rac, which further activates CDC42 (Cell Division Cycle-42). CDC42 then activates MEKK, which phosphorylate and activates JNK. JNK enters the nucleus and activates transcription factor c-Jun. Activated PI3K also activates PIP3, which further activates PDK. PDK activates Akt. Activated Akt in turn phosphorylates downstream target molecules including BAD (BCL2 Antagonist of Cell Death), Caspase9, FKHR (Forkhead Transcriptional Factor), GLUTs (Glucose Transporters), eNOS (Nitric Oxide Synthase), PFK2 (6-Phosphofructo-2-Kinase), PFK1, mTOR (Mammalian Target of Rapamycin), IKK, NF-KappaB and GSK3 (Glycogen Synthase Kinase-3), which promote induction of its anti-apototic effect. Function of CD81 is unknown. The net effect of second messenger production and activation of intermediate signaling proteins is the concerted regulation of several transcription factors that mediate gene transcription in the B-Cell. Since the immune response in vivo is regulated by alteration of these signaling outcomes, achieving a precise understanding of intracellular molecular events leading to B lymphocyte proliferation, deletion, receptor editing, and survival still remains a challenge for the future.