Immune response BCR pathway
BCR signaling pathway
The BCR (B-Cell antigen Receptor) plays a critical role in development, survival, andactivation of B lymphocytes. The BCR is composed of membrane immunoglobulin ( IgM) molecules associated with CD79a molecule, immunoglobulin-associated alpha - CD79bmolecule, immunoglobulin-associated beta heterodimers ( CD79 complex ) [1]. The IgM subunits bind antigens and cause receptor aggregation, whilethe CD79 complex subunits transduce intracellular signaling cascades. Uponactivation, BCRs activate the Spleen tyrosine kinase ( Syk ) and v-yes-1 Yamaguchisarcoma viral related oncogene homolog ( Lyn ), which phosphorylate and activatePhospholipases C, gamma ( PLC-gamma ), and Bruton agammaglobulinemia tyrosinekinase ( BTK ), respectively. BTK also activates both PLC-gammaisoforms [2], [3].
Once activated, these tyrosine kinases phosphorylate activate several signalingpathways, including Ras-ERK and PLC-gamma signal cascades, which lead to theactivation of transcription factors, such as ELK1, member of ETS oncogene family (ELK1 ), Early growth response 1 ( EGR1 ), Nuclear factor of activatedT-cells, cytoplasmic, calcineurin-dependent 2 ( NF-AT1(NFATC2) ) and Nuclearfactor of kappa light polypeptide gene enhancer in B-cells ( NF-kB ), and inhibittranscription factors, such as B-cell CLL/lymphoma 6 ( Bcl-6 ).
PLC-gamma activation that is mediated by BTK and B-cell linker (BLNK ), leads to the conversion of phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2 ) to the second messengers inositol-1,4,5-trisphosphate ( IP3) and Diacylglycerol ( DAG ). IP3 binds to I nositol 1,4,5-triphosphatereceptor ( IP3 Receptor ), which is localized primarily on the endoplasmicreticulum and stimulates the release of calcium from intracellular stores. Calcium-boundCalmodulin 2 ( Calmodulin ) associates with and activates Protein phosphatase 3,catalytic subunit ( Calcineurin A (catalytic) ). Calcineurin A (catalytic)dephosphorylates NF-AT1(NFATC2) leading to theirs translocation to the nucleus[4].
DAG activates Protein kinase C, beta ( PKC-beta ). PKC-beta inparticular, is a critical component of the BCR signalosome, and is essential forrecruitment and activation of the IKK complex resulting in the translocation ofNF-kB to the nucleus [5].
Several transmembrane receptors are known to modulate specific elements of BCRsignaling. These include Protein tyrosine phosphatase, receptor type, C ( CD45 )and Fc fragment of IgG, low affinity IIb, receptor ( Fc gamma RII beta ).CD45 has its own protein tyrosine phosphatase activity and inhibits v-yes-1Yamaguchi sarcoma viral related oncogene homolog ( Lyn ) activity bydephosphorylation leading to reduction in CD45 's negative regulatory effects[6], [7].
Lyn phosphorylates and activates co-receptor CD19 molecule ( CD19 ) andreceptor Fc-gamma-RII [8], [9]. CD19 is a cellsurface molecule, which assembles with the antigen receptor of B lymphocytes in order todecrease the threshold for antigen receptor-dependent stimulation. This co-receptorcomplex is composed of CD19, Complement component receptor 2 ( CD21 ) andCD81 molecule ( CD81 ) [10]. CD21 binds to opsinized antigenicparticles and is primarily responsible for signal transduction. Phosphorylation ofCD19 by Lyn generates binding sites for Phosphoinositide-3-kinase,catalytic ( PI3K cat class IA ). PI3K cat class IA activatesPhosphatidylinositol-3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) and Vav 1 and 2guanine nucleotide exchange factors ( VAV-1 and VAV-2). The CD19co-receptor physically interacts with VAV-1 and VAV-2 and synergisticallyenhances their phosphorylation induced by the BCR. VAV-1 and VAV-2 activatesmall GTP binding proteins Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) andcell division cycle 42 ( CDC42 ) [11].
PtdIns(3,4,5)P3 associates with the inner phospholipid bilayer of the plasmamembrane to promote the recruitment of pleckstrin homology (PH) domain-rich proteins suchas 3-phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) ) and V-akt murinethymoma viral oncogene homolog 1 ( AKT(PKB) ). PDK (PDPK1) activatesAKT(PKB), which phosphorylates downstream target including BCL2 Antagonist ofCell Death ( BAD ), Glycogen synthase kinase 3 beta ( GSK3 beta ) andRibosomal protein S6 kinase, 70kDa, polypeptide 1 ( P70 S6 kinase1 ), therebyregulating apoptosis, cell cycle, cell growth and other cellular processes [12].
Fc-gamma-RII activates the Inositol polyphosphate-5-phosphatase, 145kDa (SHIP ). SHIP converts PtdIns(3,4,5)P3 into PtdIns (3,4)P2,which is the second messenger that activates PDK (PDPK1) and AKT(PKB)[13].
Lyn also participates in the negative regulation of BCR signaling. Lynphosphorylates CD22 molecule ( CD22 ), which binds to the Protein tyrosinephosphatase, non-receptor type 6 ( SHP-1 ) and induces Lyndephosphorylation by SHP-1, thereby down-regulating Btk -dependentIP3 production and calcium mobilization [14], [15].
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