B cell receptor signaling pathway
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Journal: Nature Reviews Immunology
January/13/2003
Abstract
Recent evidence indicates that B cells are instructed continuously by B-cell receptor (BCR) signals to make crucial cell-fate decisions at several checkpoints during their development. Targeted disruption of BCR signalling components leads to distinct blocks in B-cell maturation, which indicates that key kinases and adaptors fine-tune BCR signalling to direct appropriate cell fates. Recent progress in unravelling the molecular mechanisms of the BCR signalling pathways has helped to clarify how BCR signals regulate the proliferation, survival and apoptosis of developing B cells.
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Journal: Immunity
August/31/1998
Abstract
Linker or adapter proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. We describe here the identification of a novel B cell linker protein, termed BLNK, that interfaces the B cell receptor-associated Syk tyrosine kinase with PLCgamma, the Vav guanine nucleotide exchange factor, and the Grb2 and Nck adapter proteins. Tyrosine phosphorylation of BLNK by Syk provides docking sites for these SH2-containing effector molecules that, in turn, permits the phosphorylation and/or activation of their respective signaling pathways. Hence, BLNK represents a central linker protein that bridges the B cell receptor-associated kinases with a multitude of signaling pathways and may regulate the biologic outcomes of B cell function and development.
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Journal: Annual Review of Immunology
August/30/1999
Abstract
In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B cell antigen receptor (BCR). Data from knockout experiments in cell lines and mice have revealed distinct functions for the intracellular protein tyrosine kinases (Lyn, Syk, Btk) in BCR signaling and B cell development. Combinations of intracellular signaling pathways downstream of these PTKs determine the quality and quantity of BCR signaling. For example, concerted actions of the PLC-gamma 2 and PI3-K pathways are required for proper calcium responses. Similarly, the regulation of ERK and JNK responses involves both PLC-gamma 2 and GTPases pathways. Since the immune response in vivo is regulated by alteration of these signaling outcomes, achieving a precise understanding of intracellular molecular events leading to B lymphocyte proliferation, deletion, anergy, receptor editing, and survival still remains a challenge for the future.
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Journal: Immunity
February/7/2001
Abstract
Tyrosine phosphorylation of adaptor proteins permits the B cell antigen receptor (BCR)-associated protein tyrosine kinases to regulate downstream effector molecules. Here, we report the identification of a novel B cell adaptor for phosphoinositide 3-kinase (PI3K), termed BCAP. Tyrosine phosphorylation of BCAP is mediated by Syk and Btk, thereby providing binding site(s) for the p85 subunit of PI3K. Disruption of the BCAP gene in the DT40 B cell line inhibits BCR-mediated phosphatidylinositol 3,4,5-trisphosphate generation, leading to impaired Akt response. Moreover, recruitment of PI3K to glycolipid-enriched microdomains (GEMs) is significantly attenuated in the absence of BCAP. Hence, these data suggest that BCAP bridges BCR-associated kinases to the PI3K pathway by regulating PI3K localization.
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Journal: Current Opinion in Immunology
August/3/2005
Abstract
Inhibitory co-receptors downmodulate B-cell receptor (BCR) signalling by setting a signalling threshold that prevents overstimulation of B cells. Activation of these inhibitory co-receptors occurs by phosphorylation on their cytoplasmic inhibitory immunoreceptor tyrosine-based inhibition motifs (ITIMs), followed by recruitment of the tyrosine phosphatase SHP-1 or the lipid phosphatase SHIP, and depends on their association with the BCR. Recent evidence shows that B-cell signal inhibition is regulated by ligand binding of inhibitory receptors.
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Journal: Immunology Letters
July/17/2005
Abstract
The complement system, a pillar of innate immunity, has belatedly become recognised as a key modulator of adaptive immunity, acting to direct, modulate and modify the responses of lymphocytes to stimuli. These effects are mediated by interactions between complement components or activation-derived fragments and specific binding proteins--complement receptors and regulators--on the target cells. This review will describe the current state of knowledge in this swiftly moving field. It is hoped that the recognition of these properties will help to establish complement in the role it richly deserves as the lynchpin of immunity.
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Journal: Nature Reviews Immunology
June/6/2002
Abstract
An important role has emerged for adaptor molecules in linking cell-surface receptors, such as the B-cell antigen receptor, with effector enzymes. Adaptor proteins direct the appropriate subcellular localization of effectors and regulate their activity by inducing conformational changes, both of which, in turn, contribute to the spatio-temporal precision of B-cell signal-transduction events. In addition, adaptor molecules participate in establishing negative- or positive-feedback regulatory loops in signalling networks, thereby fine-tuning the B-cell response.
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Journal: Journal of Experimental Medicine
January/6/2008
Abstract
Protein kinase C (PKC) beta has been reported (Shinohara, H., T. Yasuda, Y. Aiba, H. Sanjo, M. Hamadate, H. Watarai, H. Sakurai, and T. Kurosaki. 2005. J. Exp. Med. 202:1423-1431; Sommer, K., B. Guo, J.L. Pomerantz, A.D. Bandaranayake, M.E. Moreno-Garcia, Y.L. Ovechkina, and D.J. Rawlings. 2005. Immunity. 23:561-574) to play a crucial role in B cell receptor (BCR)-mediated IkappaB kinase (IKK) activation through phosphorylation of caspase recruitment domain 11, Bimp3 (CARMA1). However, it remains unclear whether this PKCbeta-mediated phosphorylation accounts fully for the activation status of CARMA1, because involvement of other kinases, such as phosphoinositide 3-kinase-dependent kinase 1, has also been suggested. We show that PKCbeta mediates phosphorylation of CARMA1 on Ser668, which in turn is essential for BCR-mediated CARMA1-Bcl10-mucosal-associated lymphoid tissue 1 (MALT1) association and subsequent IKK activation. Our analyses also demonstrate that the downstream kinase IKKbeta contributes to facilitating formation of the complex CARMA1-Bcl10-MALT1 by mediating phosphorylation of CARMA1. Hence, our data suggest that PKCbeta is crucial for initial activation of IKK. The activated IKKbeta does not merely function as an effector enzyme but also modifies the upstream signaling complex through a feedback mechanism, thereby optimizing the strength and duration of the nuclear factor kappaB signal.
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Journal: Annual Review of Immunology
June/29/2005
Abstract
The proliferation and differentiation of lymphocytes are regulated by receptors localized on the cell surface. Engagement of these receptors induces the activation of intracellular signaling proteins that transmit the receptor signals to distinct targets and control the cellular responses. The first signaling proteins to be discovered in higher organisms were the products of oncogenes. For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes. Now, as many cellular signaling molecules have been discovered and ordered into certain pathways, we can better understand why particular signaling proteins are associated with tumorigenesis. In this review, we discuss recent progress in unraveling the molecular mechanisms of signaling pathways that control the proliferation and differentiation of early B cells. We point out the concepts of auto-inhibition and subcellular localization as crucial aspects in the regulation of B cell signaling.
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Journal: Current Opinion in Immunology
August/3/2005
Abstract
Complement is an essential innate immune mechanism that recognizes and eradicates microbes and associated toxins. In addition, complement receptors (CD21 and CD35) on B cells cooperate with the B-cell antigen receptor (BCR) to efficiently recognize and respond to antigens bearing complement C3d(g). Fixation of C3d(g) to antigen confers adjuvant properties and therefore its deposition may need to be carefully regulated to avoid autoreactivity. CD21 and/or CD35 engagement is nonmitogenic, and B-cell activation via BCR-CD21 coligation is enhanced through the recruitment of CD19. Recent efforts have sought a better understanding of the topological and biochemical properties of BCR and coreceptor (CD19-CD21-CD81) signaling, as well as the context for complement activation in the response to foreign and self antigens.
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Journal: Journal of Immunology
September/20/2004
Abstract
Abs produced by B lymphocytes play an essential role in humoral immunity against pathogens. This response is dependent upon the extent of genome replication, which in turn allows clonal expansion of Ag-specific B cell precursors. Thus, there is considerable interest in understanding how naive B cells commit to genome replication following Ag challenge. The BCR is a key regulator of B cell growth responses in the bone marrow and the periphery. The importance of identifying BCR-coupled signaling networks and their cell cycle targets is underscored by the recognition that aberrant cell cycle control can lead to lymphoproliferative disorders or lymphoid malignancies. This review focuses on recent progress toward understanding the function of cyclin D2 in cell cycle control, and in the development of murine B lymphocytes.
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Journal: Immunology Letters
June/20/2005
Abstract
Adaptor proteins play critical roles in lymphocyte activation by mediating intermolecular interactions and assembling signaling complexes at the activated plasma membrane. Bam32/DAPP1 and the related adaptor proteins TAPP1 and TAPP2 were identified by multiple groups about 5 years ago and considerable progress has been made in elucidating the structure, interaction partners and function of these molecules. These cytoplasmic adaptor proteins are recruited to the plasma membrane through interaction of their PH domains with the lipid products of phosphatidylinositol 3-kinases. They share a unique mode of regulation in that they bind with high affinity to phosphatidylinositol-3,4-bisphosphate and their recruitment is enhanced rather than inhibited by the lipid phosphatase SHIP. Two knockout mouse studies and several gain-and-loss of function studies in cell lines have recently been published, demonstrating multiple functions of Bam32 in B cell activation. Bam32 is required for biological responses including B cell antigen receptor (BCR)-induced proliferation and antibody responses to type II T-independent antigens. Bam32 regulates multiple BCR signaling events including activation of the mitogen activated protein kinases ERK and JNK, remodeling of the actin cytoskeleton through the GTPase Rac1 and BCR internalization. Several studies have emerged suggesting that TAPP1 and TAPP2 may play roles in B and T cell activation; however, the biological functions regulated by these molecules remain to be defined. Here we will comprehensively review the available data on the structure and function of Bam32, TAPP1 and TAPP2 and present an integrated working model for Bam32 function in B cell activation and a general model for distinct effector pathways of PI 3-kinases.
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Journal: Arthritis and rheumatism
October/25/2004
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Journal: Trends in Immunology
November/18/2004
Abstract
The inhibitory coreceptors CD22 and CD72 downmodulate B-cell receptor (BCR) signaling and function as a molecular switch, determining whether antigen-stimulated B cells undergo apoptosis or proliferation. These coreceptors carry an intrinsic property for associating with the BCR, and this association is crucial for the initiation of signal inhibition through phosphorylation of these coreceptors by BCR-associated kinases. Recent findings have demonstrated that signal inhibition by these coreceptors is regulated by ligands for the coreceptors and by molecules binding to the coreceptors or the BCR. Moreover, signal inhibition by CD22 depends on the BCR isotype. These findings suggest a dynamic regulation of these coreceptors through molecular interactions on the B-cell surface.
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Journal: Trends in Pharmacological Sciences
September/19/2002
Abstract
Antibodies produced by B cells play an essential role in protecting against disease-causing pathogens. B cells detect the presence of pathogens via B-cell antigen receptors (BCRs), which consist of a transmembrane form of an antibody that is associated with a signaling subunit. Signaling by BCRs not only initiates antibody production but also regulates B-cell development, B-cell survival and the elimination of B cells that recognize components of one's own body. Identifying the intracellular signals generated by BCRs and determining how these signals specify such diverse responses is the key to understanding how the immune system functions normally and how defects in BCR signaling can lead to either immunodeficiency diseases or autoimmune diseases.
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