BAD, CD22, Bcl-XL, PI3K reg class IA, 22.214.171.124, VAV-1, Rac1, AKT(PKB), CD79 complex, VAV-2, Bcl-6, DAG, Shc, GRB2, PtdIns(3,4,5)P3, Ca('2+) cytosol, Erk (MAPK1/3), 126.96.36.199, CD81, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), Elk-1, NF-AT1(NFATC2), CD19, Calcineurin A (catalytic), CD45, PI3K cat class IA, CD21, PTEN, PLC-gamma, Lyn, SHP-1, EGR1, PKC-beta, p70 S6 kinase1, 188.8.131.52, Btk, SOS, SHIP, Syk, PtdIns(3,4)P2, BLNK, IgM, NF-kB, Ca('2+) endoplasmic reticulum lumen, IP3, GSK3 beta, Calmodulin, IP3 receptor, 3.1.3.-, H-Ras, PDK (PDPK1), PtdIns(4,5)P2, Fc gamma RII beta, CDC42
BCR signaling pathway
The BCR (B-Cell antigen Receptor) plays a critical role in development, survival, and activation of B lymphocytes. The BCR is composed of membrane immunoglobulin ( IgM ) molecules associated with CD79a molecule, immunoglobulin-associated alpha - CD79b molecule, immunoglobulin-associated beta heterodimers ( CD79 complex ) . The IgM subunits bind antigens and cause receptor aggregation, while the CD79 complex subunits transduce intracellular signaling cascades. Upon activation, BCRs activate the Spleen tyrosine kinase ( Syk ) and v-yes-1 Yamaguchi sarcoma viral related oncogene homolog ( Lyn ), which phosphorylate and activate Phospholipases C, gamma ( PLC-gamma ), and Bruton agammaglobulinemia tyrosine kinase ( BTK ), respectively. BTK also activates both PLC-gamma isoforms , .
Once activated, these tyrosine kinases phosphorylate activate several signaling pathways, including Ras-ERK and PLC-gamma signal cascades, which lead to the activation of transcription factors, such as ELK1, member of ETS oncogene family ( ELK1 ), Early growth response 1 ( EGR1 ), Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 ( NF-AT1(NFATC2) ) and Nuclear factor of kappa light polypeptide gene enhancer in B-cells ( NF-kB ), and inhibit transcription 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 Inositol 1,4,5-triphosphate receptor ( IP3 Receptor ), which is localized primarily on the endoplasmic reticulum and stimulates the release of calcium from intracellular stores. Calcium-bound Calmodulin 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 in particular, is a critical component of the BCR signalosome, and is essential for recruitment and activation of the IKK complex resulting in the translocation of NF-kB to the nucleus .
Several transmembrane receptors are known to modulate specific elements of BCR signaling. 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-1 Yamaguchi sarcoma viral related oncogene homolog ( Lyn ) activity by dephosphorylation leading to reduction in CD45 's negative regulatory effects , .
Lyn phosphorylates and activates co-receptor CD19 molecule ( CD19 ) and receptor Fc-gamma-RII , . CD19 is a cell surface molecule, which assembles with the antigen receptor of B lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation. This co-receptor complex is composed of CD19, Complement component receptor 2 ( CD21 ) and CD81 molecule ( CD81 ) . CD21 binds to opsinized antigenic particles and is primarily responsible for signal transduction. Phosphorylation of CD19 by Lyn generates binding sites for Phosphoinositide-3-kinase, catalytic ( PI3K cat class IA ). PI3K cat class IA activates Phosphatidylinositol-3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) and Vav 1 and 2 guanine nucleotide exchange factors ( VAV-1 and VAV-2). The CD19 co-receptor physically interacts with VAV-1 and VAV-2 and synergistically enhances their phosphorylation induced by the BCR. VAV-1 and VAV-2 activate small GTP binding proteins Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) and cell division cycle 42 ( CDC42 ) .
PtdIns(3,4,5)P3 associates with the inner phospholipid bilayer of the plasma membrane to promote the recruitment of pleckstrin homology (PH) domain-rich proteins such as 3-phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) ) and V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ). PDK (PDPK1) activates AKT(PKB), which phosphorylates downstream target including BCL2 Antagonist of Cell Death ( BAD ), Glycogen synthase kinase 3 beta ( GSK3 beta ) and Ribosomal protein S6 kinase, 70kDa, polypeptide 1 ( P70 S6 kinase1 ), thereby regulating 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. Lyn phosphorylates CD22 molecule ( CD22 ), which binds to the Protein tyrosine phosphatase, non-receptor type 6 ( SHP-1 ) and induces Lyn dephosphorylation by SHP-1, thereby down-regulating Btk -dependent IP3 production and calcium mobilization , .