Reactome | Signaling by the B Cell Receptor (BCR)

Signaling by the B Cell Receptor (BCR)

Stable Identifier

R-HSA-983705

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, extracellular region, plasma membrane

Synonyms

B Cell Activation

ReviewStatus

5/5

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Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane 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 Noesel 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 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, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), 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.
PLC-gamma associated with BLNK 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 calcium 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 in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.
Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006).

Literature References

PubMed ID	Title	Journal	Year
15489917	Src-family kinases in B-cell development and signaling Gauld, SB, Cambier, JC	Oncogene	2004
18818202	Molecular mechanism of the Syk activation switch Shaw, D, Papp, E, Gandhi, S, Tsang, E, Giannetti, AM, Tse, JK, Dinh, M, Wang, S, Ho, H, Bradshaw, JM	J Biol Chem	2008
7524079	Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement Saouaf, SJ, Bolen, JB, Tsukada, S, Fargnoli, J, Mahajan, S, Burkhardt, AL, Kut, SA, Rowley, RB, Witte, ON	Proc Natl Acad Sci U S A	1994
11901194	Transient receptor potential 1 regulates capacitative Ca(2+) entry and Ca(2+) release from endoplasmic reticulum in B lymphocytes Iino, M, Kurosaki, M, Gotoh, K, Hara, Y, Okada, T, Kurosaki, T, Miyakawa, T, Hirose, K, Mizushima, A, Nishida, M, Penner, R, Wakamori, M, Fleig, A, Mori, Y, Hermosura, M, Mori, E	J Exp Med	2002
6335036	Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin Nel, AE, Galbraith, RM, Goldschmidt-Clermont, PJ, Tung, HE, Landreth, GE	Biochem Biophys Res Commun	1984
17052215	Regulation of Ras in lymphocytes: get a GRP Stone, JC	Biochem Soc Trans	2006
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 Van Noesel, CJ, Mason, DY, Bende, RJ, van Schijndel, GM, Borst, J, van Lier, RA, Brouns, GS	J Exp Med	1992
20206686	The Src, Syk, and Tec family kinases: distinct types of molecular switches Bradshaw, JM	Cell Signal	2010
2011584	Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes Rhee, SG, Carter, RH, Fearon, DT, Park, DJ	Proc Natl Acad Sci U S A	1991
15509800	Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2 Kim, YJ, Bae, YS, Rhee, SG, Sekiya, F, Poulin, B	Mol Cell Biol	2004
19249086	STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 Bachhawat, P, Dolmetsch, RE, Hoover, PJ, Raunser, S, Park, CY, Covington, ED, Garcia, KC, Lewis, RS, Mullins, FM, Walz, T	Cell	2009
7927516	Tyrosine phosphorylation of MB-1, B29, and HS1 proteins in human B cells following receptor crosslinking Kawakami, T, Nakamura, T, Hata, D, Mayumi, M, Herren, B, Kawakami, Y	Immunol Lett	1994
1702903	Association of B cell antigen receptor with protein tyrosine kinase Lyn Yamamoto, T, Yamanashi, Y, Mizuguchi, J, Toyoshima, K, Kakiuchi, T	Science	1991
7592958	Reconstitution of the B cell antigen receptor signaling components in COS cells Saouaf, SJ, Mahajan, S, Bolen, JB, Fargnoli, J, Kut, SA, Rowley, RB	J Biol Chem	1995
4589993	Occurrence of surface IgM, IgD, and free light chains of human lymphocytes Winchester, RJ, Fu, SM, Kunkel, HG	J Exp Med	1974
803528	Similar idiotypic specificity for the membrane IgD and IgM of human B lymphocytes Winchester, RJ, Fu, SM, Kunkel, HG	J Immunol	1975
18596693	Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation Prakriya, M, Wu, MM, Wang, B, Lewis, RS, Luik, RM	Nature	2008
19909372	Comprehending the complex connection between PKCbeta, TAK1, and IKK in BCR signaling Shinohara, H, Kurosaki, T	Immunol Rev	2009
19065780	B-cell receptor Brezski, RJ, Monroe, JG	Adv Exp Med Biol	2008
7688784	Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta Bolen, JB, Mahajan, S, Franke, R, Costa, T, Burkhardt, AL, Sanchez, M, Nussenzweig, M, Misulovin, Z	J Exp Med	1993
20192804	Early events in B cell activation Batista, FD, Harwood, NE	Annu Rev Immunol	2010
8580068	Tyrosine-phosphorylated forms of Ig beta, CD22, TCR zeta and HOSS are major ligands for tandem SH2 domains of Syk Baumann, G, Wienands, J, Freuler, F	Int Immunol	1995
16849466	Kinetics of B cell receptor signaling in human B cell subsets mapped by phosphospecific flow cytometry Nolan, GP, Irish, JM, Czerwinski, DK, Levy, R	J Immunol	2006
7538118	Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation Chao, HG, Bolen, JB, Burkhardt, AL, Rowley, RB, Matsueda, GR	J Biol Chem	1995
1376928	Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes McHugh, JC, Coggeshall, KM, Altman, A	Proc Natl Acad Sci U S A	1992
8163536	Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex Chandran, KA, Law, CL, Clark, EA, Weiss, A, Chan, AC, Sidorenko, SP, Edelhoff, S, Draves, KE, Disteche, CM	J Biol Chem	1994
1081164	Surface markers of human lymphocytes Kunkel, HG	Johns Hopkins Med J	1975
8306975	Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor Reth, M, Flaswinkel, H	EMBO J	1994
18187424	Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation Gruber, H, Frischauf, I, Romanin, C, Derler, I, Fahrner, M, Madl, J, Schindl, R, Eder, P, Polzinger, B, Hesch, C, Kahr, H, Muik, M, Fritsch, R, Bergsmann, J, Groschner, K	J Biol Chem	2008
10648173	Purification and characterization of human Syk produced using a baculovirus expression system Akhlaq, M, Graham, B, Jones, CE, Graff, P, Menear, K, Baldock, D	Protein Expr Purif	2000