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 [Ref.1]. 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.2&3]. 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 (Mitogen-Activated Protein Kinase) pathways and PI3K (Phosphoinositide-3 Kinase) activation [Ref.4].

Many other transmembrane receptors such as CD45 and FCGR2B (Fc Fragment of IgG, Low Affinity IIB, Receptor for CD32) are known to modulate specific elements of BCR signaling. CD45 occurs as a component of a complex of proteins associated with the antigen receptor, and CD45 regulates the signal transduction by modulating the phosphorylation state of the antigen receptor subunits [Ref.5].

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 PLCG2 (Phospholipase-C-Gamma-2).BCR-induced tyrosine phosphorylation of PLCG2 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 IK-B and translocation of NF-KB (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. Recently, an essential role of the adaptor protein BLNK (B-Cell Linker), also called SLP65 or BASH, in PLCG2 membrane localization and tyrosine phosphorylation was deduced. Upon BCR stimulation, BLNK is phosphorylated by SYK, which recruits BTK and PLCG2 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 PLCG2, leading to IP3 production and calcium mobilization [Ref.6].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.7].

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 MAP (Mitogen-Activated Protein) kinases including ERK (Extracellular Signal Regulated Kinase), JNK (Jun N-terminal Kinases) and p38 [Ref.8]. 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 [Ref.6 & 9]. 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), FOXO, MTOR (Mammalian Target of Rapamycin), MDM2 and GSK3 (Glycogen Synthase Kinase-3), which promote induction of its anti-apototic effect [Ref.7 & 10].

B-cell receptor (BCR) signaling is essential for normal B-cell development, selection, survival, proliferation, and differentiation into antibody-secreting cells. It plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies. Hence inhibition of this pathway may represent a promising new strategy for treating these diseases [Ref.11].