Signaling by the B Cell Receptor (BCR)

Stable Identifier
Homo sapiens
B Cell Activation
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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
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