Kegg Pathway: B cell receptor signaling pathway

Bmed.org/fulltext.cgi?uids=19917778">J Exp Med. 2009 Nov 16; <Br>Tusche MW, Ward LA, Vu F, McCarthy D, Quintela-Fandino M, Ruland J, Gommerman JL, Mak TW

B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor kappaB (NF-kappaB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensaBle for canonical NF-kappaB signaling downstream of the B cell receptor, the aBsence of MALT1 results in impaired BAFF-induced phosphorylation of NF-kappaB2 (p100), p100 degradation, and RelB nuclear translocation in B220(+) B cells. This corresponds with impaired survival of MALT1(-/-) marginal zone (MZ) But not follicular B cells in response to BAFF stimulation in vitro. MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numBers, elevated serum immunogloBulin titers, and spontaneous germinal center formation, were found to Be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in Biological outcomes induced By BAFF-mediated signal transduction.

Bmed.org/fulltext.cgi?uids=19909370">Immunol Rev. 2009 Nov; 232(1): 273-85<Br>Mashima R, Hishida Y, Tezuka T, Yamanashi Y

The mammalian Dok protein family has seven memBers (Dok-1-Dok-7). The Dok proteins share structural similarities characterized By the NH2-terminal pleckstrin homology and phosphotyrosine-Binding domains followed By SH2 target motifs in the COOH-terminal moiety, indicating an adapter function. Indeed, Dok-1 was originally identified as a 62 kDa protein that Binds with p120 rasGAP, a potent inhiBitor of Ras, upon tyrosine phosphorylation By a variety of protein tyrosine kinases. Among the Dok family, only Dok-1, Dok-2, and Dok-3 are preferentially expressed in hematopoietic/immune cells. Dok-1 and its closest relative Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is Believed that recruitment of p120 rasGAP By Dok-1 and Dok-2 is critical to their negative regulation. By contrast, Dok-3 does not Bind with p120 rasGAP. However, accumulating evidence has demonstrated that Dok-3 is a negative regulator of the activation of JNK and moBilization of Ca2+ in B-cell receptor-mediated signaling, where the interaction of Dok-3 with SHIP-1 and GrB2 appears to Be important. Here, we review the physiological roles and underlying mechanisms of Dok family proteins.

Bmed.org/fulltext.cgi?uids=19909354">Immunol Rev. 2009 Nov; 232(1): 34-41<Br>Tolar P, Sohn HW, Liu W, Pierce SK

In B cells, antigen drives the formation of B-cell receptor (BCR) clusters that initiate the formation of signaling complexes associated with the cytoplasmic domains of the BCRs. These signaling active complexes contain a numBer of protein and lipid kinases and phosphatases and adapter and scaffolding proteins that together function to trigger downstream signaling cascades leading to the activation of a variety of genes associated with B-cell activation. Although we are learning a consideraBle amount aBout the molecular details of the assemBly of immune receptor signaling complexes, as reviewed in this volume, a fundamental question remains, namely how does antigen Binding outside the cell initiate the assemBly of signaling complexes inside the cell. For B cells, we do not yet understand how the information that the ectodomain of the BCR has Bound to an antigen is translated across the memBrane to induce changes in the cytoplasmic domains that trigger the assemBly of signaling complexes. Here we descriBe what is known aBout the initiation of the antigen-driven BCR signal transduction in the newly emerging context of B-cell recognition of antigens presented By antigen-presenting cells in lymphoid tissues. We also discuss a recently proposed model for the initiation of BCR signaling termed the 'conformation-induced oligomerization model' and address the implications of this model for the mechanisms By which BCR signaling may Be modulated By adapters and coreceptors.

Bmed.org/fulltext.cgi?uids=19901533">cell Cycle. 2009 Dec 9; 8(23): <Br>Nahar R, Müschen M

B cell lineage ALL represents By far the most frequent malignancy in children and is also common in adults. Despite significant advances over the past four decades, cytotoxic treatment strategies have recently reached a plateau with cure rates at 80 percent for children and 55 percent for adults. Relapse after cytotoxic drug treatment, initial drug-resistance and dose-limiting toxicity are among the most frequent complications of current therapy approaches. For this reason, pathway-specific treatment strategies in addition to cytotoxic drug treatment seem promising to further improve therapy options for ALL patients. In a recent study on 111 cases of pre-B cell-derived human ALL, we found that ALL cells carrying a BCR-ABL1-gene rearrangement lack expression of a functional pre-B cell receptor in virtually all cases. In a proof-of-principle experiment, we studied pre-B cell receptor function during progressive leukemic transformation of pre-B cells in BCR-ABL1-transgenic mice: Interestingly, signaling from the pre-B cell receptor and the oncogenic BCR-ABL1 kinase are mutually exclusive and only "crippled" pre-B cells that fail to express a functional pre-B cell receptor are permissive to transformation By BCR-ABL1.

Bmed.org/fulltext.cgi?uids=19896393">Immunity. 2009 Nov 4; <Br>Browne CD, Del Nagro CJ, Cato MH, Dengler HS, Rickert RC

Anergy is a critical physiologic mechanism to censor self-reactive B cells. However, a Biochemical understanding of how anergy is achieved and maintained is lacking. Herein, we investigated the role of the phosphoinositide 3-kinase (PI3K) lipid product PI(3,4,5)P(3) in B cell anergy. We found reduced generation of PI(3,4,5)P(3) in anergic B cells, which was attriButaBle to reduced phosphorylation of the PI3K memBrane adaptor CD19, as well as increased expression of the inositol phosphatase PTEN. Sustained production of PI(3,4,5)P(3) in B cells, achieved through conditional deletion of Pten, resulted in failed tolerance induction and aBundant autoantiBody production. In contrast to wild-type immature B cells, B cell receptor engagement of PTEN-deficient immature B cells resulted in activation and proliferation, indicating a central defect in early B cell responsiveness. These findings estaBlish repression of the PI3K signaling pathway as a necessary condition to avert the generation, activation, and persistence of self-reactive B cells.

Bmed.org/fulltext.cgi?uids=19855403">Nat Rev Immunol. 2009 Nov; 9(11): 767-77<Br>Pillai S, Cariappa A

Bone marrow-derived B cells make an important cell fate choice to develop into either follicular B cells or marginal zone B cells in the spleen, which depends on signalling through the B cell receptor, Notch2, the receptor for B cell-activating factor and the canonical nuclear factor-kappaB pathway, as well as signals involved in the migration and anatomical retention of marginal zone B cells. Recent information discussed in this Review reconciles some of the controversies regarding the role of the B cell receptor in this cell fate decision and a clearer picture has also emerged regarding the anatomical location of ligands for Notch2 in the spleen. This cell fate decision could provide mechanistic insights that are relevant to other commitment events in lymphocytes.

Bmed.org/fulltext.cgi?uids=19855402">Nat Rev Immunol. 2009 Nov; 9(11): 757-66<Br>King C

The seminal studies characterizing T follicular helper (T(FH)) cells descriBed a non-polarized CD4(+) T cell population with a unique aBility to home to B cell follicles and to induce antiBody production By B cells. In the past few years, the study of T(FH) cells has enjoyed a renaissance and there has Been a surge of research activity aimed at understanding the function and differentiation of these important cells. This Review focuses on the current progress in T(FH) cell Biology and the important questions that remain unanswered. Particular attention is paid to recent studies that support the idea that T(FH) cells are a separate T cell lineage and those that proBe the relationship of T(FH) cells to other T helper cell suBsets.

Bmed.org/fulltext.cgi?uids=19855081">Blood. 2009 Oct 23; <Br>Juszczynski P, Chen L, O'Donnell E, Polo JM, Ranuncolo SM, Dalla-Favera R, Melnick A, Shipp MA

Tonic B-cell receptor (BCR) signaling is an important checkpoint during B-cell ontogenesis and a key survival pathway in a suBset of diffuse large B-cell lymphomas (DLBCLs). We previously demonstrated that BCR-dependent DLBCL cell lines and primary tumors underwent apoptosis following treatment with an ATP-competitive inhiBitor of the BCR-associated spleen tyrosine kinase (SYK). These "BCR-type" tumors also have more aBundant expression of the transcriptional repressor, BCL6, and increased sensitivity to BCL6 inhiBition. Herein, we evaluated potential connections Between BCL6-mediated transcriptional repression and SYK-dependent BCR signaling. In transcriptionally profiled normal B-cell suBsets (naive, germinal center [GC], and memory B cells) and in primary DLBCLs, there were reciprocal patterns of expression of BCL6 and the SYK tyrosine phosphatase, PTPROt. BCL6 repressed PTPROt transcription via a direct interaction with functional BCL6 Binding sites in PTPROt promoter. Enforced expression of BCL6 in normal naive B cells and RNAi-mediated depletion of BCL6 in GC B-cells directly modulated PTPROt expression. In "BCR-type" DLBCLs, BCL6 depletion increased PTPROt expression and decreased phosphorylation of SYK and the downstream adaptor protein, BLNK. Since BCL6 augments BCR signaling and BCL6 and SYK are Both promising therapeutic targets in many DLBCLs, comBined inhiBition of these functionally related pathways warrants further study.

Bmed.org/fulltext.cgi?uids=19833725">J Biol Chem. 2009 Oct 15; <Br>Shukla U, Hatani T, Nakashima K, Ogi K, Sada K

Adaptor protein c-ABl SH3 domain-Binding protein-2 (3BP2, also referred to SH3BP2) regulates immune receptor-mediated signal transduction. In this report, we focused on the molecular mechanism of 3BP2 function in B cell receptor (BCR) signaling. Engagement of BCR induces tyrosine phosphorylation of 3BP2. Genetic analysis demonstrated that Syk is critical for BCR-mediated tyrosine phosphorylation of 3BP2. Mutational analysis of 3BP2 revealed that Both Tyr(183) and Src homology 2 (SH2) domain are necessary for 3BP2-mediated BCR-induced activation of nuclear factor of activated T cells (NFAT). Point mutation of Tyr(183) or Arg(486) in the SH2 domain of 3BP2 diminished BCR-mediated tyrosine phosphorylation of 3BP2. Endogenous 3BP2 forms complex with tyrosine phosphorylated cellular signaling molecules. Peptide Binding experiments demonstrated that only phosphorylated Tyr(183) in 3BP2 could form a complex with the SH2 domain(s) of phospholipase C (PLC)-gamma2 and Vav1 from B cell lysates. These interactions were represented By using Bacterial GST-PLC-gamma2 or -Vav1 SH2 domain(s). Furthermore, pull down and far-western experiments showed that 3BP2-SH2 domain directly Binds to B cell linker protein (BLNK) following BCR stimulation. These results demonstrated that 3BP2 induces protein complex with cellular signaling molecules through phosphorylation of Tyr(183) and SH2 domain leading to the activation of NFAT in B cells.

Bmed.org/fulltext.cgi?uids=19770358">Blood. 2009 Sep 21; <Br>Herling M, Patel KA, Weit N, Lilienthal N, Hallek M, Keating MJ, Jones D

Although activation of the B-cell receptor (BCR) signaling pathway has Been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), its clinical impact and the molecular correlates of such response are not clearly defined. The AKT modulator and proto-oncogene T-cell leukemia 1 (TCL1) is differentially expressed in CLL and linked to its pathogenesis Based on CD5+ B-cell expansions arising in TCL1-transgenic mice. We studied here the association of TCL1 levels and its intracellular dynamics with the in vitro responses to BCR-stimulation in 70 cases of CLL. The growth kinetics following BCR-engagement correlated strongly with the degree and timing of induced AKT phospho-activation. signaling intensity was Best predicted By TCL1 levels and kinetics of TCL1-AKT co-recruitment to BCR memBrane activation complexes, which included the kinases LYN, SYK, ZAP70, and PKC. High TCL1 levels were also strongly associated with aggressive disease features, such as advanced clinical stage, higher white Blood cell count, and shorter lymphocyte douBling time. Higher TCL1 levels independently predicted an inferior clinical outcome (i.e. shorter progression-free survival, P=0.0001), regardless of therapy regimen, especially for ZAP70-positive tumors. We propose TCL1 as a marker of the BCR-responsive CLL suBset identifying poor prognostic cases where targeting BCR-associated kinases may Be therapeutically useful.

Bmed.org/fulltext.cgi?uids=19766537">Trends Immunol. 2009 Oct; 30(10): 488-93<Br>Pillai S, Cariappa A, Pirnie SP

The Best studied mechanisms of B cell tolerance are receptor editing, clonal deletion and anergy. All of these mechanisms of B cell tolerance depend on the induction of signaling downstream of the B cell receptor By self-antigens. Another important and distinct mechanism of B cell tolerance involves the repression of antigen receptor signaling rather than its induction, utilizes the Lyn Src-family kinase, the SHP-1 tyrosine phosphatase, inhiBitory memBers of the Siglec family, and a carBohydrate-modifying enzyme that is capaBle of negatively regulating B cell receptor activation known as sialic acid acetylesterase.

Bmed.org/fulltext.cgi?uids=19766202">cell Immunol. 2009; 260(1): 44-50<Br>Cui J, Le G, Yang R, Shi Y

A high fat diet (HFD) has long Been linked to immune dysfunction, including diminished numBers or reactivity of lymphocytes, increased susceptiBility to infection, inhiBited lymphocytes function during antigen-specific responses and developed oxidative stress. Whereas the molecular mechanistic events associated with immune deficiency remain to Be fully determined. Using the DNA microarray system, we analyzed the gene expression patterns of lymphocyte related signal transduction proteins in jejunum of C57BL/6 mice in order to gain insight on the possiBle molecular mechanism By which HFD induced oxidative stress effects on signal transduction of lymphocytes. Results of present study showed that HFD induced oxidative stress and immunosuppression in jejunum. Antioxidant lipoic acid (LA) supplement ameliorated that HFD induced oxidative stress and immunosuppression By recovering transcriptional levels of the gene involved in B cell receptor, T cell differentiation signaling pathway, and free radical scavengers. The present study indicates that a HFD can induce chronic oxidative stress, suppress signal transduction of gut-associated lymphocytes, and lead to an inhiBition of mucosal immunity.

Bmed.org/fulltext.cgi?uids=19761434">Expert Rev Anticancer Ther. 2009 Sep; 9(9): 1305-16<Br>Briones J

In recent years consideraBle progress has Been made in the treatment of patients with B-cell non-Hodgkin lymphoma (NHL). Although responses can Be achieved with comBination chemotherapy regimens, a suBstantial proportion of patients are still not cured. In recent years, the knowledge of the cellular and molecular Biology of distinct types of B-cell NHL have led to the development of a new class of drugs that specifically targets unique disease-specific pathways. This review will focus on novel therapies that are Being developed for the treatment of B-cell NHL including those targeting the B-cell receptor signaling pathway, the proteasome, epigenetic lesions, novel anti-apoptotic drugs, new monoclonal antiBodies and immunomodulatory drugs.

Bmed.org/fulltext.cgi?uids=19758160">Ann N Y Acad Sci. 2009 Sep; 1173: 260-7<Br>Lemoine S, Morva A, Youinou P, Jamin C

B lymphocytes contriBute to the pathogenesis of autoimmune disorders since B-cell depletion treatment improves such diseases. However, B cells seem amBivalent. Murine strains of nonorgan-specific as well as organ-specific autoimmune conditions present with aggravated symptoms when B cells are depleted. It is thus likely that some B cells are pathogenic while other have regulatory function. There is not only one regulatory B cell (Breg) suBset, But different types of Breg cells. Regulatory function can thus Be ascriBed to autoreactive B cells, marginal zone B cells, transitional type 2-like B cells, or CD5(+) B cells. Regulatory activity is induced only following cell activation through a B-cell receptor, CD40, and/or TLR9. Regulatory effects are then mediated By a soluBle agent, such as IL-10, and/or direct cell-to-cell contacts that involve CD40 or B7 co-stimulatory molecules. Targeted cells also vary from one disease to another. Antigen-specific autoreactive T cells, dendritic cells, macrophages, and regulatory T lymphocytes can thus Be either inhiBited or activated to finally modulate the autoimmune response. Taken as a whole, it appears that Breg cells participate in the control of autoimmunity within a complex cellular network that may differ for each pathology. Adapted stimulation and control of regulatory activity would thus Be a prerequisite to an efficient usage of these B cells as an alternative therapy for autoimmune diseases.

Bmed.org/fulltext.cgi?uids=19754898">Immunol Rev. 2009 Sep; 231(1): 189-209<Br>Feske S

Store-operated Ca2+ entry (SOCE) is a mechanism used By many cells types including lymphocytes and other immune cells to increase intracellular Ca2+ concentrations to initiate signal transduction. Activation of immunoreceptors such as the T-cell receptor, B-cell receptor, or Fc receptors results in the release of Ca2+ ions from endoplasmic reticulum (ER) Ca2+ stores and suBsequent activation of plasma memBrane Ca2+ channels such as the well-characterized Ca2+ release-activated Ca2+ (CRAC) channel. Two genes have Been identified that are essential for SOCE: ORAI1 as the pore-forming suBunit of the CRAC channel in the plasma memBrane and stromal interaction molecule-1 (STIM1) sensing the ER Ca2+ concentration and activating ORAI1-CRAC channels. Intense efforts in the past several years have focused on understanding the molecular mechanism of SOCE and the role it plays for cell functions in vitro and in vivo. A numBer of transgenic mouse models have Been generated to investigate the role of ORAI1 and STIM1 in immunity. In addition, mutations in ORAI1 and STIM1 identified in immunodeficient patients provide valuaBle insight into the role of Both genes and SOCE. This review focuses on the role of ORAI1 and STIM1 in vivo, discussing the phenotypes of ORAI1- and STIM1-deficient human patients and mice.

Bmed.org/fulltext.cgi?uids=19754888">Immunol Rev. 2009 Sep; 231(1): 23-44<Br>Taylor CW, Rahman T, Tovey SC, Dedos SG, Taylor EJ, Velamakanni S

Inositol-1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are regulated By IP3 and Ca2+ and are modulated By many additional signals. These properties allow them to initiate and, via Ca2+-induced Ca2+ release, regeneratively propagate Ca2+ signals evoked By receptors that stimulate formation of IP3. The uBiquitous expression of IP3R highlights their importance, But it also presents proBlems when attempting to resolve the Behavior of defined IP3R. DT40 cells are a pre-B-lymphocyte cell line in which high rates of homologous recomBination afford unrivalled opportunities to disrupt endogenous genes. DT40-knockout cells with Both alleles of each of the three IP3R genes disrupted provide the only null-Background for analysis of homogenous recomBinant IP3R. We review the properties of DT40 cells and consider three areas where they have contriButed to understanding IP3R Behavior. Patch-clamp recording from the nuclear envelope and Ca2+ release from intracellular stores loaded with a low-affinity Ca2+ indicator address the mechanisms leading to activation of IP(3)R. We show that IP3 causes intracellular IP3R to cluster and re-tune their responses to IP3 and Ca2+, Better equipping them to mediate regenerative Ca2+ signals. Finally, we show that DT40 cells reliaBly count very few IP3R into the plasma memBrane, where they mediate aBout half the Ca2+ entry evoked By the B-cell antigen receptor.

Bmed.org/fulltext.cgi?uids=19734904">Nat Immunol. 2009 Oct; 10(10): 1110-7<Br>Mandal M, Powers SE, Ochiai K, Georgopoulos K, Kee BL, Singh H, Clark MR

Signals through the pre-B cell antigen receptor (pre-BCR) and interleukin 7 receptor (IL-7R) coordinate pre-B cell population expansion with suBsequent recomBination of the locus encoding immunogloBulin kappa-chain (Igk). Although many 'downstream' effectors of each receptor are known, how they integrate to mediate development has remained unclear. Here we report that pre-BCR-mediated activation of the Ras-MEK-Erk signaling pathway silenced transcription of Ccnd3 (encoding cyclin D3) and coordinated exit from the cell cycle with induction of the transcription factor E2A and the initiation of Igk recomBination. IL-7R-mediated activation of the transcription factor STAT5 opposed this pathway By promoting Ccnd3 expression and concomitantly inhiBiting Igk transcription By Binding to the Igk intronic enhancer and preventing E2A recruitment. Our data show how pre-BCR signaling poises pre-B cells to undergo differentiation after escape from IL-7R signaling.

Bmed.org/fulltext.cgi?uids=19726767">J Immunol. 2009 Sep 15; 183(6): 3561-7<Br>Khan WN

B lymphocyte homeostasis depends on tonic and induced BCR signaling and receptors sensitive to trophic factors, such as B cell-activating factor receptor (BAFF-R or BR3) during development and maintenance. This review will discuss growing evidence suggesting that the signaling mechanisms that maintain B cell survival and metaBolic fitness during selection at transitional stages and survival after maturation rely on cross-talk Between BCR and BR3 signaling. Recent findings have also Begun to unravel the molecular mechanisms underlying this crosstalk. In this review I also propose a model for regulating the amplitude of BCR signaling By a signal amplification loop downstream of the BCR involving Btk and NF-kappaB that may facilitate BCR-dependent B cell survival as well as its functional coupling to BR3 for the growth and survival of B lymphocytes.

Bmed.org/fulltext.cgi?uids=19710450">J Immunol. 2009 Sep 15; 183(6): 3661-71<Br>Haas KM, Poe JC, Tedder TF

Humoral immunity to T cell-independent type 2 Ags (TI-2 Ag) is critical for protection against encapsulated Bacteria such as Streptococcus pneumoniae. The CD21/35 receptor is thought to promote protective humoral immunity to encapsulated Bacteria By enaBling complement-decorated capsular polysaccharides to coligate the CD21/35-CD19 signaling complex with the B cell Ag receptor (BCR), thereBy enhancing Ag-specific B cell activation. However, AB responses to S. pneumoniae type 3 capsular polysaccharide (PPS-3) and other strong TI-2 Ags were significantly impaired in CD21/35(-/-) But not C3(-/-) or C4(-/-) mice. B cells from CD21/35(-/-) mice expressed significantly higher levels of cell surface CD19. CD21/35(-/-) B cells exhiBited enhanced BCR-induced calcium responses and significantly higher expression of the inhiBitory programmed death-1 (PD-1) receptor following immunization with a TI-2 Ag or BCR crosslinking. Reducing CD19 expression in CD21/35(-/-) mice normalized BCR-induced calcium responses, PD-1 induction, and PPS-3-specific IgG3 responses and restored protection during S. pneumoniae infection. PD-1 Blockade also selectively rescued PPS-3-specific IgG3 responses in CD21/35(-/-) mice. ThereBy, CD21/35 promotes protective humoral immunity to S. pneumoniae and other strong TI-2 Ags through a complement-independent pathway By negatively regulating CD19 expression and PD-1 induction.

Bmed.org/fulltext.cgi?uids=19704418">Nat Rev Immunol. 2009 Sep; 9(9): 657-61<Br>Cancro MP

The B cell receptor (BCR) and the receptor for B cell-activating factor (BAFFR) have complementary roles in B cells: BCR signals provide a cell-intrinsic measure of suitaBility for negative or positive selection, whereas BAFFR responds to homeostatic demands Based on a cell-extrinsic measure of the size of the mature B cell pool. Because continuous signals from Both receptors are required for B cell survival, it is proBaBle that there are mechanisms to integrate the selective and homeostatic signals from these receptors. In this Opinion article, I descriBe recent evidence to indicate that crosstalk Between the downstream Biochemical pathways of these receptors mediates this interdependence, such that BCR signals generate a limiting suBstrate for BAFFR signal propagation.