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Thomas F. Tedder - One of the best experts on this subject based on the ideXlab platform.

  • CD22 Forms a Quaternary Complex with SHIP, GrB2, and Shc A PATHWAY FOR REGULATION OF B Lymphocyte Antigen RECEPTOR-INDUCED CALCIUM FLUX
    Journal of Biological Chemistry, 2000
    Co-Authors: Jonathan C. Poe, Manabu Fujimoto, Ann S. Miller, Paul J. Jansen, Thomas F. Tedder
    Abstract:

    CD22 is a cell surface molecule that regulates signal transduction in B Lymphocytes. Tyrosine-phosphorylated CD22 recruits numerous cytoplasmic effector molecules including SHP-1, a potent phosphotyrosine phosphatase that down-regulates B cell Antigen receptor (BCR)- and CD19-generated signals. Paradoxically, B cells from CD22-deficient mice generate augmented intracellular calcium responses following BCR ligation, yet proliferation is decreased. To understand further the mechanisms through which CD22 regulates BCR-dependent calcium flux and proliferation, interactions Between CD22 and effector molecules involved in these processes were assessed. The adapter proteins GrB2 and Shc were found to interact with distinct and specific regions of the CD22 cytoplasmic domain. Src homology-2 domain-containing inositol polyphosphate-5'-phosphatase (SHIP) also Bound phosphorylated CD22, But Binding required an intact CD22 cytoplasmic domain. All three molecules were Bound to CD22 when isolated from BCR-stimulated splenic B cells, indicating the formation of a CD22.GrB2.Shc.SHIP quaternary complex. Therefore, SHIP associating with CD22 may Be important for SHIP recruitment to the cell surface where it negatively regulates calcium influx. Although augmented calcium responses in CD22-deficient mice should facilitate enhanced c-Jun N-terminal kinase (JNK) activation, BCR ligation did not induce JNK activation in CD22-deficient B cells. These data demonstrate that CD22 functions as a molecular "scaffold" that specifically coordinates the docking of multiple effector molecules, in addition to SHP-1, in a context necessary for BCR-dependent SHIP activity and JNK stimulation.

  • modulation of B Lymphocyte Antigen receptor signal transduction By a cd19 cd22 regulatory loop
    Immunity, 1999
    Co-Authors: Manabu Fujimoto, Alice P. Bradney, Jonathan C. Poe, Douglas A. Steeber, Thomas F. Tedder
    Abstract:

    CD19 and CD22 are B Lymphocyte cell-surface molecules that positively and negatively regulate Antigen receptor signal transduction, respectively. Biochemical studies with B cells from CD19-deficient and CD22-deficient mice indicated that these two regulatory molecules influenced each other's functions: CD22 expression negatively regulated CD19 tyrosine phosphorylation, while optimal CD22 function was dependent on CD19 expression. Functional CD19 and CD22 interactions were also assessed in vivo By generating CD19/CD22 douBle-deficient mice. RemarkaBly, the CD19 mutation was dominant to the CD22 mutation in most instances. B Lymphocytes from CD19/CD22-deficient and CD19-deficient mice were functionally equivalent despite the negative influence normally provided By CD22 expression. These data collectively suggest that CD19 activates the CD22/SHP1 inhiBitory pathway that then acts primarily on CD19.

  • CD22 negatively and positively regulates signal transduction through the B Lymphocyte Antigen receptor.
    Seminars in Immunology, 1998
    Co-Authors: Shinichi Sato, Joseph Tuscano, Makoto Inaoki, Thomas F. Tedder
    Abstract:

    ABstract The CD22 cell-surface adhesion molecule is capaBle of modulating B Lymphocyte Antigen receptor (BCR)-mediated sig"- nals, as well as the generation of BCR-independent signals. Within the cytoplasmic domain of CD22 are motifs that are structurally homologous to known activation and inhiBitory motifs. These motifs demonstrate physiologic significance via associations with known effector proteins that likely mediate their corresponding inhiBitory and activation roles. Further more, the targeted deletion of CD22 in mice results in phenotypic changes and alterations in BCR-mediated signal transduction that are consistent with Both positive and negative roles for CD22 in B cell development and activation.

  • CD22 Is Both a Positive and Negative Regulator of B Lymphocyte Antigen Receptor Signal Transduction: Altered Signaling in CD22-Deficient Mice
    Immunity, 1996
    Co-Authors: Shinichi Sato, Makoto Inaoki, Ann S. Miller, Cheryl B. Bock, Paul J. Jansen, Mimi L.k. Tang, Thomas F. Tedder
    Abstract:

    B cell activation following Antigen receptor cross-linking can Be augmented in vitro By ligation of cell surface CD22, which associates with the SHP1 protein tyrosine phosphatase. The targeted deletion of CD22 in mice demonstrated that CD22 differentially regulates Antigen receptor signaling in resting and Antigen-stimulated B Lymphocytes. B cells from CD22-deficient mice exhiBited the cell surface phenotype and augmented intracellular calcium responses characteristic of chronically stimulated B cells, as occurs in SHP1-defective mice. Thus, CD22 negatively regulates Antigen receptor signaling in the aBsence of Antigen. However, activation of CD22-deficient B Lymphocytes By prolonged IgM cross-linking resulted in modest B cell proliferation, demonstrating that CD22 positively regulates Antigen receptor signaling in the presence of Antigen.

Anthony L Defranco - One of the best experts on this subject based on the ideXlab platform.

  • role of the mu immunogloBulin heavy chain transmemBrane and cytoplasmic domains in B cell Antigen receptor expression and signal transduction
    Journal of Biological Chemistry, 1993
    Co-Authors: Jonathan H Blum, Tracy L Stevens, Anthony L Defranco
    Abstract:

    ABstract MemBrane immunogloBulins (mIg) serve as the recognition components of B Lymphocyte Antigen receptors. Binding of Antigen to these receptors leads to dramatic effects on B cell growth and viaBility. We have examined the structural elements of mIgM that are involved in Antigen receptor assemBly and function. Expression of transfected wild-type mIgM in a B cell line led to assemBly with the other two known components of the Antigen receptor, Ig-alpha and Ig-Beta, expression on the cell surface, and when cross-linked By anti-IgM antiBodies, stimulation of signal transductin reactions, including tyrosine protein phosphorylation, inositol phosphate production, and increases in cytoplasmic calcium concentration. Replacement of the highly conserved COOH-terminal 41 amino acids of mIgM heavy chain (mu m) with the transmemBrane and cytoplasmic domains of human CD8 alpha resulted in a molecule which was expressed on the B cell surface at levels comparaBle to wild-type mIgM, But which did not form a complex with Ig-alpha or Ig-Beta and did not stimulate any of the signaling reactions mentioned aBove. Replacement of the Basic three-amino-acid cytoplasmic domain of mu m with a different But similarly charged sequence had no effect on cell-surface expression or signaling function. On the other hand, removal of the entire cytoplasmic domain resulted in a molecule which did not Bind Ig-alpha and Ig-Beta and which did not transduce signals. This effect is proBaBly due to altered post-translational processing of this mutant molecule. Finally, a series of eight single-amino-acid suBstitutions in the transmemBrane domain was constructed. Most of these resulted in the removal of hydroxyl groups from conserved residues postulated to Be important for interactions with other components. Each of these mutant molecules was capaBle of transducing signals when cross-linked By anti-IgM, But one was partially defective. Since alteration of any single residue was not sufficient to disrupt signaling completely, the interactions required for signaling are likely to involve multiple residues, so that elimination of one hydroxyl group does not prevent the interaction. We propose that the cytoplasmic domain of mu m does not play a critical role in receptor function But that the transmemBrane domain specifies interactions with other components, proBaBly Ig-alpha and Ig-Beta, required for proper Antigen receptor signal transduction.

  • targets of B Lymphocyte Antigen receptor signal transduction include the p21ras gtpase activating protein gap and two gap associated proteins
    Journal of Immunology, 1993
    Co-Authors: Michael R Gold, Mary T Crowley, G A Martin, F Mccormick, Anthony L Defranco
    Abstract:

    Cross-linking memBrane Ig (mIg) on B cells stimulates tyrosine phosphorylation of proteins involved in signal transduction including the mIg-associated proteins Ig-alpha and Ig-Beta, the tyrosine kinases p53/p56lyn, p55Blk, p59fyn, and PTK72, phosphatidylinositol 3-kinase, phospholipase C gamma 1 and gamma 2, and the mitogen-activated protein kinase. We now show that the p21ras GTPase-activating protein (GAP) is also a suBstrate for mIg-activated tyrosine kinases. p21ras is a key regulator of cell growth and GAP may act as Both a regulator of p21ras activity and as a downstream effector of p21ras. We found that mIg cross-linking caused a rapid increase in tyrosine phosphorylation of GAP in the immature B cell line WEHI-231, the mature B cell lines BAL 17 and Daudi, and the IgG-Bearing B cell line A20. In fiBroBlasts, tyrosine kinase activation causes GAP to associate with two other tyrosine-phosphorylated proteins, p62 and p190, which have homologies to an RNA-Binding protein and a transcriptional repressor, respectively. Similarly, mlg cross-linking induced the association of GAP with a 62-kDa tyrosine-phosphorylated protein in BAL 17, WEHI-231, and Daudi cells. Anti-Ig treatment also increased the amount of a 190-kDa tyrosine-phosphorylated protein associated with GAP in WEHI-231 and Daudi cells. After separation By SDS-PAGE and transfer to nitrocellulose, the tyrosine-phosphorylated p62 and p190 present in anti-GAP immunoprecipitates from B cells were capaBle of Binding radiolaBeled recomBinant GAP, as previously reported for the GAP-associated p62 and p190 from fiBroBlasts. The amount of p62 that could Be detected in this way after immunoprecipitation with antiphosphotyrosine antiBodies was much greater from anti-IgM-treated BAL 17 cells than from unstimulated BAL 17 cells. This proBaBly reflects anti-Ig-induced tyrosine phosphorylation of p62. In any case, GAP, p62, and/or p190 may Be involved in signal transduction By mIg in B cells.

  • Tyrosine phosphorylation and the mechanism of signal transduction By the B-Lymphocyte Antigen receptor.
    European Journal of Biochemistry, 1992
    Co-Authors: Anthony L Defranco
    Abstract:

    In the 1950s, Burnet developed the theory of clonal selection to explain the specificity of antiBody responses. He postulated that each antiBody-producing cell makes antiBody molecules with a single specificity, and, moreover, that it makes these antiBodies in two forms, a secreted form and a cell-surface form, the latter of which serves as an Antigen receptor. According to this theory, Antigen Binding to cell-surface Ig leads to proliferation of Antigen-Binding cells. Following clonal expansion, a significant proportion of these cells would initiate high-level antiBody production, whereas other cells would Become memory B cells and Be reserved for the secondary immune response oBserved upon return of the Antigen.

Christian Bonnerot - One of the best experts on this subject based on the ideXlab platform.

  • Fc receptors for IgG and Antigen presentation on MHC class I and class II molecules.
    Seminars in Immunology, 1999
    Co-Authors: Sebastian Amigorena, Christian Bonnerot
    Abstract:

    Antigens internalized through specific memBrane receptors are presented to helper CD4(+) T cells at Antigen concentrations 10(3) to 10(4) fold lower than Antigens internalized By fluid phase. B Lymphocyte Antigen receptors, mannose receptors and receptors for the Fc region of immunogloBulins, promote Both internalization and efficient presentation at low Antigen concentrations. Thus, Binding to specific memBrane receptors concentrate Antigens on Antigen presenting cells and mediates efficient uptake. Is this 'quantitative' concentration of Antigens on Antigen presenting cells the end of the story? Or may 'quality', i.e. selective intracellular Antigen targeting, somehow influence the efficiency or specificity of MHC class I and class II-restricted Antigen presentation?

  • Different patterns of calcium signaling triggered through two components of the B Lymphocyte Antigen receptor.
    The Journal of biological chemistry, 1994
    Co-Authors: Daniel Choquet, Sylvanie Cassard, Bernard Malissen, Henri Korn, Wolf H. Fridman, Christian Bonnerot
    Abstract:

    ABstract The engagement of the B cell Antigen receptor is the first step of Antigenic stimulation of B Lymphocytes. This step is followed By a series of Biochemical events, including the activation of protein-tyrosine kinases, phosphoinositide turnover, and multiple patterns of calcium moBilization, which lead to the regulation of gene transcription and cellular responses. The B cell Antigen receptor complex is composed of memBrane immunogloBulins (as Antigen recognition suBunits) and associated chains (Ig-alpha and Ig-Beta) that couple the receptor to cytoplasmic protein kinases. To investigate independently the relative signaling capacity of Ig-alpha and Ig-Beta, chimeric proteins containing their cytoplasmic domains were expressed in a B cell line. We found that Ig-alpha and Ig-Beta activate two distinct intracellular signaling pathways. The engagement of Ig-alpha chimeras induces a complete release of calcium from intracellular stores, followed By transmemBrane calcium influx and late cell activation signals, detected By lymphokine secretion. In contrast, Ig-Beta chimeras do not induce lymphokine secretion or calcium influx, But induce short oscillatory release of calcium, dependent on the activity of the Ca-ATPase pump of the endoplasmic reticulum. These results provide a structural Basis for the diversity of B cell responses.

Manabu Fujimoto - One of the best experts on this subject based on the ideXlab platform.

  • novel Binding site for src homology 2 containing protein tyrosine phosphatase 1 in cd22 activated By B Lymphocyte stimulation with Antigen
    Journal of Biological Chemistry, 2008
    Co-Authors: Motohiko Sato, Takahiro Adachi, Manabu Fujimoto, Teruhiko Yanagisawa, Takeshi Tsubata
    Abstract:

    ABstract CD22, a B Lymphocyte memBrane glycoprotein, contains immunoreceptor tyrosine-Based inhiBition motifs (ITIMs) in the cytoplasmic region and recruits Src homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) to the phosphorylated ITIMs upon ligation of B Lymphocyte Antigen receptor (BCR), thereBy negatively regulating BCR signaling. Among the three previously identified ITIMs, Both ITIMs containing tyrosine residues at position 843 (Tyr843) and 863 (Tyr863), respectively, are shown to Be required for CD22 to recruit SHP-1 and regulate BCR signaling upon BCR ligation By anti-Ig antiBody (AB), indicating that CD22 has the SHP-1-Binding domain at the region containing Tyr843 and Tyr863. Here we address the requirement of CD22 for SHP-1 recruitment and BCR regulation upon BCR ligation By Antigen, which induces much stronger CD22 phosphorylation than anti-Ig AB does. We demonstrate that the CD22 mutant in which Both Tyr843 and Tyr863 are replaced By phenylalanine (CD22F5/6) recruits SHP-1 and regulates BCR signaling upon stimulation with Antigen But not anti-Ig AB. This result strongly suggests that CD22 contains another SHP-1 Binding domain that is specifically activated upon stimulation with Antigen. Both of the flanking sequences of Tyr783 and Tyr817 fit the consensus sequence of ITIM, and the CD22F5/6 mutant requires these tyrosine residues for SHP-1 Binding and BCR regulation. Thus, these ITIMs constitute a novel conditional SHP-1-Binding site of CD22 that is activated upon BCR ligation By Antigen But not By anti-Ig AB.

  • CD22 Forms a Quaternary Complex with SHIP, GrB2, and Shc A PATHWAY FOR REGULATION OF B Lymphocyte Antigen RECEPTOR-INDUCED CALCIUM FLUX
    Journal of Biological Chemistry, 2000
    Co-Authors: Jonathan C. Poe, Manabu Fujimoto, Ann S. Miller, Paul J. Jansen, Thomas F. Tedder
    Abstract:

    CD22 is a cell surface molecule that regulates signal transduction in B Lymphocytes. Tyrosine-phosphorylated CD22 recruits numerous cytoplasmic effector molecules including SHP-1, a potent phosphotyrosine phosphatase that down-regulates B cell Antigen receptor (BCR)- and CD19-generated signals. Paradoxically, B cells from CD22-deficient mice generate augmented intracellular calcium responses following BCR ligation, yet proliferation is decreased. To understand further the mechanisms through which CD22 regulates BCR-dependent calcium flux and proliferation, interactions Between CD22 and effector molecules involved in these processes were assessed. The adapter proteins GrB2 and Shc were found to interact with distinct and specific regions of the CD22 cytoplasmic domain. Src homology-2 domain-containing inositol polyphosphate-5'-phosphatase (SHIP) also Bound phosphorylated CD22, But Binding required an intact CD22 cytoplasmic domain. All three molecules were Bound to CD22 when isolated from BCR-stimulated splenic B cells, indicating the formation of a CD22.GrB2.Shc.SHIP quaternary complex. Therefore, SHIP associating with CD22 may Be important for SHIP recruitment to the cell surface where it negatively regulates calcium influx. Although augmented calcium responses in CD22-deficient mice should facilitate enhanced c-Jun N-terminal kinase (JNK) activation, BCR ligation did not induce JNK activation in CD22-deficient B cells. These data demonstrate that CD22 functions as a molecular "scaffold" that specifically coordinates the docking of multiple effector molecules, in addition to SHP-1, in a context necessary for BCR-dependent SHIP activity and JNK stimulation.

  • modulation of B Lymphocyte Antigen receptor signal transduction By a cd19 cd22 regulatory loop
    Immunity, 1999
    Co-Authors: Manabu Fujimoto, Alice P. Bradney, Jonathan C. Poe, Douglas A. Steeber, Thomas F. Tedder
    Abstract:

    CD19 and CD22 are B Lymphocyte cell-surface molecules that positively and negatively regulate Antigen receptor signal transduction, respectively. Biochemical studies with B cells from CD19-deficient and CD22-deficient mice indicated that these two regulatory molecules influenced each other's functions: CD22 expression negatively regulated CD19 tyrosine phosphorylation, while optimal CD22 function was dependent on CD19 expression. Functional CD19 and CD22 interactions were also assessed in vivo By generating CD19/CD22 douBle-deficient mice. RemarkaBly, the CD19 mutation was dominant to the CD22 mutation in most instances. B Lymphocytes from CD19/CD22-deficient and CD19-deficient mice were functionally equivalent despite the negative influence normally provided By CD22 expression. These data collectively suggest that CD19 activates the CD22/SHP1 inhiBitory pathway that then acts primarily on CD19.

Marcus R. Clark - One of the best experts on this subject based on the ideXlab platform.

  • Cutting Edge: Signals from the B Lymphocyte Antigen Receptor Regulate MHC Class II Containing Late Endosomes
    Journal of immunology (Baltimore Md. : 1950), 1998
    Co-Authors: Karyn Siemasko, Bartholomew J. Eisfelder, Edward K. Williamson, Shara Kabak, Marcus R. Clark
    Abstract:

    The B Lymphocyte response to protein Ag is dependent upon the successful presentation to T cells of Ag-derived, MHC class II-restricted peptides. The B cell Ag receptor (BCR) facilitates this process By internalizing ligand and delivering it to specialized compartment(s) (MHC class II peptide-loading compartments (MIIC)) where it is processed into peptides and loaded onto MHC class II. In addition to efficiently targeting Ag, the BCR can provide tyrosine kinase-dependent signals that augment the presentation of Ag, possiBly By enhancing the generation of immunogenic peptides. However, the mechanism By which this occurs is unclear. Herein, we report that the BCR signals a reorganization, fusion, and acidification of an MHC-like compartment into an invariant chain- and MHC class II-rich complex of large vesicles. This complex Becomes the primary target for endocytosed receptors. These data suggest that signals generated By the BCR regulate the site of Ag processing.

  • signal transduction By the B cell Antigen receptor and its coreceptors
    Annual Review of Immunology, 1994
    Co-Authors: John C. Cambier, Christopher M Pleiman, Marcus R. Clark
    Abstract:

    B Lymphocyte Antigen receptors, memBrane immunogloBulins (mIg), function in focusing and internalization of Antigen for suBsequent presentation to T cells and in transmemBrane transduction of signals leading to cell activation, anergy, or deletion. Until quite recently, the aBility of this receptor to transduce signals in spite of a virtual lack of cytoplasmic structure, left a significant gap in our understanding of how it is coupled to cytoplasmic signal propagators. Studies conducted during the past five years have defined a mIg-associated protein complex homologous to the CD3 complex associated with the T cell Antigen receptor. Components of this disulfide linked heterodimeric complex, Ig-alpha and Ig-Beta, contain an approximately 26 residue sequence motif termed ARH1, also known as TAM, which Binds to cytoplasmic effectors, including src-family tyrosine kinases, and contains all structural information needed for signal transduction. Receptor associated src-family kinases which are activated following receptor cross-linking, also associate with downstream effectors, including phospholipase C gamma (PLC gamma), p21ras. GTPase activating protein (GAP), phosphatidylinositol 3-kinase (PI3-k) and microtuBule associate protein kinase (MAPk2). In some cases, these associations are induced By receptor cross-linking and lead directly to effector activation. The current literature indicates that these interactions may occur in sequence and culminate in the activation of three major pathways of signal propagation including those mediated By PLC gamma, p21ras and PI3-k. This chapter reviews various molecular aspects of the B cell Antigen receptor complex, including extended structure of the complex, and receptor-effector interactions and their Biologic consequences. Finally, an integrated model of Antigen receptor signaling is presented.