Reactome: A Curated Pathway Database

Antigen activates B Cell Receptor (BCR) leading to generation of second messengers

Stable Identifier
R-HSA-983695
Type
Pathway
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

Mature B cells express IgM and IgD immunoglobulins which are complexed with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesal et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010). The protein kinase SYK may also be involved in phosphorylating the ITAMs.
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Irish et al. 2006, Baldock et al. 2008, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65, BASH) and BCAP. LYN and FYN phosphorylate CD19. Phosphorylated BLNK, BCAP, and CD19 serve as scaffolds which recruit effectors to the plasma membrane and assemble large complexes, the signalosomes. BCAP and CD19 recruit phosphoinositol 3-kinase (PI3K). BLNK recruits phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
Phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphorylated CD19 likewise recruits PIP3K. PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) to the plasma membrane via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates PLC-gamma2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC-gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).
PLC-gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of Ca2+ ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels (and possibly other TRP channels) in the plasma membrane, resulting in an influx of extracellular calcium ions (Mori et al. 2002, Muik et al. 2008, Luik et al. 2008, Park et al. 2009).

Literature References
PubMed ID Title Journal Year
10770799 A novel B lymphocyte-associated adaptor protein, Bam32, regulates antigen receptor signaling downstream of phosphatidylinositol 3-kinase J Exp Med 2000
9468499 Activation of phospholipase C-gamma by phosphatidylinositol 3,4,5-trisphosphate J Biol Chem 1998
1702903 Association of B cell antigen receptor with protein tyrosine kinase Lyn Science 1991
7929028 B-cell antigen receptor stimulation activates the human Bruton's tyrosine kinase, which is deficient in X-linked agammaglobulinemia J Biol Chem 1994
19065780 B-cell receptor Adv Exp Med Biol 2008
11226282 BLNK mediates Syk-dependent Btk activation Proc Natl Acad Sci U S A 2001
9697839 BLNK: a central linker protein in B cell activation Immunity 1998
12456653 BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins EMBO J 2002
1375264 Comparison of human B cell antigen receptor complexes: membrane-expressed forms of immunoglobulin (Ig)M, IgD, and IgG are associated with structurally related heterodimers J Exp Med 1992
8918697 Cross-linking of B cell antigen receptor-related structure of pre-B cell lines induces tyrosine phosphorylation of p85 and p110 subunits and activation of phosphatidylinositol 3-kinase Int Immunol 1996
8306975 Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor EMBO J 1994
18187424 Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation J Biol Chem 2008
20192804 Early events in B cell activation Annu Rev Immunol 2010
6335036 Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin Biochem Biophys Res Commun 1984
9341187 Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation J Biol Chem 1997
16849466 Kinetics of B cell receptor signaling in human B cell subsets mapped by phosphospecific flow cytometry J Immunol 2006
15509800 Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2 Mol Cell Biol 2004
15161916 Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1. Tyrosine 783 phosphorylation is not sufficient for lipase activation J Biol Chem 2004
8163536 Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex J Biol Chem 1994
18818202 Molecular mechanism of the Syk activation switch J Biol Chem 2008
4589993 Occurrence of surface IgM, IgD, and free light chains of human lymphocytes J Exp Med 1974
18596693 Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation Nature 2008
1550550 Phospholipase C-gamma 1 and phospholipase C-gamma 2 are substrates of the B cell antigen receptor associated protein tyrosine kinase Biochem Biophys Res Commun 1992
1376928 Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes Proc Natl Acad Sci U S A 1992
10648173 Purification and characterization of human Syk produced using a baculovirus expression system Protein Expr Purif 2000
7592958 Reconstitution of the B cell antigen receptor signaling components in COS cells J Biol Chem 1995
19249086 STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 Cell 2009
7688784 Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta J Exp Med 1993
803528 Similar idiotypic specificity for the membrane IgD and IgM of human B lymphocytes J Immunol 1975
15489917 Src-family kinases in B-cell development and signaling Oncogene 2004
1081164 Surface markers of human lymphocytes Johns Hopkins Med J 1975
7538118 Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation J Biol Chem 1995
7524079 Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement Proc Natl Acad Sci U S A 1994
20206686 The Src, Syk, and Tec family kinases: distinct types of molecular switches Cell Signal 2010
11901194 Transient receptor potential 1 regulates capacitative Ca(2+) entry and Ca(2+) release from endoplasmic reticulum in B lymphocytes J Exp Med 2002
7927516 Tyrosine phosphorylation of MB-1, B29, and HS1 proteins in human B cells following receptor crosslinking Immunol Lett 1994
2011584 Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes Proc Natl Acad Sci U S A 1991
11606584 Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling J Biol Chem 2001
8580068 Tyrosine-phosphorylated forms of Ig beta, CD22, TCR zeta and HOSS are major ligands for tandem SH2 domains of Syk Int Immunol 1995
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