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 ) . 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 , . 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. 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 . 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, . Lyn phosphorylates and activates co-receptor CD19 molecule ( CD19 ) andreceptor Fc-gamma-RII , . 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 ) . 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 ) . 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 . 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). 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 , .