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Ligand-dependent and -independent processes in B-cell-receptor-mediated signaling

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Abstract

The B cell antigen receptor (BCR) is a protein complex expressed on the surface of immature and mature B cells. After ligand-induced aggregation, this complex generates signals that lead to a variety of biological outcomes, including survival, proliferation and differentiation. During B cell development intermediate forms of the BCR are expressed on the surface. The composition of these pro- and preBCR complexes reflects the ordered assembly of the BCR complex and they exist to generate signals for positive selection at defined developmental checkpoints. Because these receptors lack the ability to bind conventional ligands, the pro- and preBCR have been postulated to signal via ligand-independent processes. This ligand-inde-pendent or constitutive signal may also play a role in the survival of peripheral mature B cells. Here we discuss the evidence for ligand-independent functions for the BCR and postulate how it may be regulated and linked to biological processes associated with B cell development and survival.

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References

  1. Alt FW, Yancopoulos GD, Blackwell TK, Wood C, Thomas E, Boss M, Coffman R, Rosenberg N, Tonegawa S, Baltimore D (1984) Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J 3:1209

    PubMed  CAS  Google Scholar 

  2. Aoki Y, Isselbacher KJ, Cherayil BJ, Pilial S (1994) Tyrosine phosphorylation of Blk and Fyn Src homology 2 domain-binding proteins occurs in response to antigen-receptor ligation in B cells and constitutively in pre-B cells. Proc Natl Acad Sci USA 91:4204

    Article  PubMed  CAS  Google Scholar 

  3. Aoki Y, Isselbacher KJ, Pillai S (1994) Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre- B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci USA 91:10606

    Article  PubMed  CAS  Google Scholar 

  4. Bannish G, Fuentes-Panana EM, Cambier JC, Pear WS, Monroe JG. Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis. Exp Med (in press)

  5. Blum JH, Stevens TL, DeFranco AL (1993) Role of the mu immunoglobulin heavy chain transmem-brane and cytoplasmic domains in B cell antigen receptor expression and signal transduction. J Biol Chem 268:27236

    PubMed  CAS  Google Scholar 

  6. Boussiotis VA, Freeman GJ, Berezovskaya A, Barber DL, Nadler LM (1997) Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rapl. Science 278:124

    Article  PubMed  CAS  Google Scholar 

  7. Cambier JC (1995) Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol 155:3281

    PubMed  CAS  Google Scholar 

  8. Chan VW, Lowell CA, DeFranco AL (1998) Defective negative regulation of antigen receptor signaling in Lyn- deficient B lymphocytes. Curr Biol 8:545

    Article  PubMed  CAS  Google Scholar 

  9. Cheng PC, Dykstra ML, Mitchell RN, Pierce SK (1999) A role for lipid rafts in B cell antigen receptor signaling and antigen targeting. J Exp Med 190:1549

    Article  PubMed  CAS  Google Scholar 

  10. Cheng PC, Brown BK, Song W, Pierce SK (2001) Translocation of the B cell antigen receptor into lipid rafts reveals a novel step in signaling. J Immunol 166:3693

    PubMed  CAS  Google Scholar 

  11. Cheng PC, Cherukuri A, Dykstra M, Malapati S, Sproul T, Chen MR, Pierce SK (2001) Floating the raft hypothesis: the roles of lipid rafts in B cell antigen receptor function. Semin Immunol 13:107

    Article  PubMed  CAS  Google Scholar 

  12. Clark MR, Campbell KS, Kazlauskas A, Johnson SA, Hertz M, Potter TA, Pleiman C, Cambier JC (1992) The B cell antigen receptor complex: association of Ig-alpha and Ig-beta with distinct cytoplasmic effectors. Science 258:123

    Article  PubMed  CAS  Google Scholar 

  13. Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC (1998) Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8:497

    Article  PubMed  CAS  Google Scholar 

  14. Cyster JG, Healy JI, Kishihara K, Mak TW, Thomas ML, Goodnow CC (1996) Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381:325

    Article  PubMed  CAS  Google Scholar 

  15. Desiderio S (1997) Role of Btk in B cell development and signaling. Curr Opin Immunol 9:534

    Article  PubMed  CAS  Google Scholar 

  16. Doody GM, Bell SE, Vigorito E, Clayton E, McAdam S, Tooze R, Fernandez C, Lee IJ, Turner M (2001) Signal transduction through Vav-2 participates in humoral immune responses and B cell maturation. Nat Immunol 2:542

    Article  PubMed  CAS  Google Scholar 

  17. Dykstra ML, Cherukuri A, and Pierce SK (2001) Floating the raft hypothesis for immune receptors: access to rafts controls receptor signaling and trafficking. Traffic 2:160

    Article  PubMed  CAS  Google Scholar 

  18. Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF (1995) Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD 19 signal transduction molecule. Immunity 3:39

    Article  PubMed  CAS  Google Scholar 

  19. Fang W, Mueller DL, Pennell CA, Rivard JJ, Li YS, Hardy RR, Schlissel MS, Behreos TW (1996) Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene. Immunity 4:291

    Article  PubMed  CAS  Google Scholar 

  20. Fluckiger AC, Li Z, Kato RM, Wahl MI, Ochs HD, Longnecker R, Kinet JP, Witte ON, Scharenberg AM, Rawlings DJ (1998) Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. EMBO J 17:1973

    Article  PubMed  CAS  Google Scholar 

  21. Gold MR (2000) Intermediary signaling effectors coupling the B-cell receptor to the nucleus. Curr Top Microbiol Immunol 245:77

    PubMed  CAS  Google Scholar 

  22. Gong S, Nussenzweig MC (1996) Regulation of an early developmental checkpoint in the B cell pathway by Ig beta. Science 272:411

    Article  PubMed  CAS  Google Scholar 

  23. Gong S, Sanchez M, Nussenzweig MC (1996) Counterselection against D mu is mediated through immunoglobulin (Ig)alpha-Igbeta. J Exp Med 184:2079

    Article  PubMed  CAS  Google Scholar 

  24. Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ (2000) Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex. Immunity 13:243

    Article  PubMed  CAS  Google Scholar 

  25. Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA, Dunn AR (1995) Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83:301

    Article  PubMed  CAS  Google Scholar 

  26. Hombach J, Tsubata T, Leclercq L, Stappert H, Reth M (1990) Molecular components of the B-cell antigen receptor complex of the IgM class. Nature 343:760

    Article  PubMed  CAS  Google Scholar 

  27. Hutchcroft JE, Harrison ML, Geahlen RL (1992) Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor. J Biol Chem 267:8613

    PubMed  CAS  Google Scholar 

  28. Irving BA, Alt FW, Killeen N (1998) Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 280:905

    Article  PubMed  CAS  Google Scholar 

  29. Jacobs H, Vandeputte D, Tolkamp L, Vries E de, Borst J, Berns A (1994) CD3 components at the surface of pro-T cells can mediate pre-T cell development in vivo. Eur J Immunol 24:934

    Article  PubMed  CAS  Google Scholar 

  30. Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC (1999) The tyrosine kinase negative regulator c-Cbl as a RING-type, E2- dependent ubiquitin-protein ligase. Science 286:309

    Article  PubMed  CAS  Google Scholar 

  31. Justement LB (2000) Signal transduction via the B-cell antigen receptor: the role of protein tyrosine kinases and protein tyrosine phosphatases. Curr Top Microbiol Immunol 245:1

    PubMed  CAS  Google Scholar 

  32. Karasuyama H, Kudo A, Melchers F (1990) The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain. J Exp Med 172: 969

    Article  PubMed  CAS  Google Scholar 

  33. Kishihara K, Penninger J, Wallace VA, Kundig TM, Kawai K, Wakeham A, Timms E, Pfeffer K, Ohashi PS, Thomas ML, et al. (1993) Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74:143

    Article  PubMed  CAS  Google Scholar 

  34. Kitamura D, Kudo A, Schaal S, Muller W, Melchers F, Rajewsky K (1992) A critical role of lambda 5 protein in B cell development. Cell 69:823

    Article  PubMed  CAS  Google Scholar 

  35. Kurosaki T (1999) Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol 17:555

    Article  PubMed  CAS  Google Scholar 

  36. Lam KP, Kuhn R, Rajewsky K (1997) In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death [see comments]. Cell 90:1073

    Article  PubMed  CAS  Google Scholar 

  37. Lee YK, Brewer JW, Hellman R, Hendershot LM (1999) BiP and immunoglobulin light chain cooperate to control the folding of heavy chain and ensure the fidelity of immunoglobulin assembly. Mol Biol Cell 10:2209

    PubMed  CAS  Google Scholar 

  38. Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S, Tarakhovsky A (1996) Immunodeficiency in protein kinase cbeta-deficient mice. Science 273:788

    Article  PubMed  CAS  Google Scholar 

  39. Leo A, Schraven B (2001) Adapters in lymphocyte signalling. Curr Opin Immunol 13:307

    Article  PubMed  CAS  Google Scholar 

  40. Levelt CN, Mombaerts P, Iglesias A, Tonegawa S, Eichmann K (1993) Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon. Proc Natl Acad Sci USA 90:11401

    Article  PubMed  CAS  Google Scholar 

  41. Li YS, Hayakawa K, Hardy RR (1993) The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J Exp Med 178:951

    Article  PubMed  CAS  Google Scholar 

  42. Lutz C, Ledermann B, Kosco-Vilbois MH, Ochsenbein AF, Zinkernagel RM, Kohler G, Brombacher F (1998) IgD can largely substitute for loss of IgM function in B cells. Nature 393:797

    Article  PubMed  CAS  Google Scholar 

  43. Melchers F (1999) Fit for life in the immune system? Surrogate L chain tests H chains that test L chains. Proc Natl Acad Sci USA 96:2571

    Article  PubMed  CAS  Google Scholar 

  44. Michnoff CH, Parikh VS, Lelsz DL, Tucker PW (1994) Mutations within the NH2-terminal trans-membrane domain of membrane immunoglobulin (lg) M alters Ig alpha and Ig beta association and signal transduction. J Biol Chem 269:24237

    PubMed  CAS  Google Scholar 

  45. Monroe JG (2000) B-cell antigen receptor signaling in immature-stage B cells: integrating intrinsic and extrinsic signals. Curr Top Microbiol Immunol 245:1

    PubMed  CAS  Google Scholar 

  46. Monroe JG (2000) Balancing signals for negative selection and activation of developing B lymphocytes. Clin Immunol 95:S8

    Google Scholar 

  47. Myung PS, Boerthe NJ, Koretzky GA (2000) Adapter proteins in lymphocyte antigen-receptor signaling. Curr Opin Immunol 12:256

    Article  PubMed  CAS  Google Scholar 

  48. Nagata K, Nakamura T, Kitamura F, Kuramochi S, Taki S, Campbell KS, Karasuyama H (1997) The Ig alpha/Igbeta heterodimer on mu-negative proB cells is competent for transducing signals to induce early B ceil differentiation. Immunity 7:559

    Article  PubMed  CAS  Google Scholar 

  49. Osmond DG, Rolink A, Melchers F (1998) Murine B lymphopoiesis: towards a unified model. Immunol Today 19:65

    Article  PubMed  CAS  Google Scholar 

  50. Petrie RJ, Schnetkamp PP, Patel KD, Awasthi-Kalia M, Deans JP (2000) Transient translocation of the B cell receptor and Src homology 2 domain-containing inositol phosphatase to lipid rafts: evidence toward a role in calcium regulation. J Immunol 165:1220

    PubMed  CAS  Google Scholar 

  51. Philpott KL, McCarthy MJ, Klippel A, Rubin LL (1997) Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J Cell Biol 139:809

    Article  PubMed  CAS  Google Scholar 

  52. Ray RJ, Stoddart A, Pennycook JL, Huner HO, Furlonger C, Wo GE, Paige CJ (1998) Stromal cell-independent maturation of IL-7-responsive pro-B cells. J Immunol 160:5886

    PubMed  CAS  Google Scholar 

  53. Roth PE, Doglio L, Manz JT, Kim JY, Lo D, Storb U (1993) Immunoglobulin gamma 2b transgenes inhibit heavy chain gene rearrangement, but cannot promote B cell development. J Exp Med 178:2007

    Article  PubMed  CAS  Google Scholar 

  54. Sato S, Miller AS, Inaoki M, Bock CB, Jansen PJ, Tang ML, Tedder TF (1996) CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice. Immunity 5:551

    Article  PubMed  CAS  Google Scholar 

  55. Schamel WW, Refh M (2000) Stability of the B cell antigen receptor complex. Mol Immunol 37:253

    Article  PubMed  CAS  Google Scholar 

  56. Scharenberg AM, Kinet JP (1998) PtdIns-3,4,5-P3: a regulatory nexus between tyrosine kinases and sustained calcium signals. Cell 94:5

    Article  PubMed  CAS  Google Scholar 

  57. Schatzl H, Yakovleva L, Lapin B, Rose D, Inzhiia L, Gaedigk-Nitscnko K, Deinhardt F, Helm K von der (1992) Detection and characterization of T-cell leukemia virus-like proviral sequences in PBL and tissues of baboons by PCR. Leukemia 6:158S

    Google Scholar 

  58. Shaffer AL, Schlissel MS (1997) A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development. J Immunol 159:1265

    PubMed  CAS  Google Scholar 

  59. Shaw AC, Swat W, Ferrini R, Davidson L, Alt FW (1999) Activated Ras signals developmental progression of recombinase- activating gene (RAG)-deficient pro-B lymphocytes. J Exp Med 189:123

    Article  PubMed  CAS  Google Scholar 

  60. Sproul TW, Malapati S, Kim J, Pierce SK (2000) Cutting edge: B cell antigen receptor signaling occurs outside lipid rafts in immature B cells. J Immunol 165:6020

    PubMed  CAS  Google Scholar 

  61. Tedder TF (1998) Introduction: response-regulators of B lymphocyte signaling thresholds provide a context for antigen receptor signal transduction. Semin Immunol 10:259

    Article  PubMed  CAS  Google Scholar 

  62. Tedford K, Nitschke L, Girkontaite I, Charlesworth A, Chan G, Sakk V, Barbacid M, Fischer KD (2001) Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Nat Immunol 2:548

    Article  PubMed  CAS  Google Scholar 

  63. Tsubata T, Reth M (1990) The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface. J Exp Med 172:973

    Article  PubMed  CAS  Google Scholar 

  64. Turner M, Mee PJ, Costello PS, Williams O, Price AA, Duddy LP, Furlong MT, Geahlen RL, Tybulewicz VL (1995) Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378:298

    Article  PubMed  CAS  Google Scholar 

  65. Von Boehmer H, Aifantis I, Feinberg J, Lechner O, Saint-Ruf C, Walter U, Buer J, Azogui O (1999) Pleiotropic changes controlled by the pre-T-cell receptor. Curr Opin Immunol 11:135

    Article  Google Scholar 

  66. Weintraub BC, Jun JE, Bishop AC, Shokat KM, Thomas ML, Goodnow CC (2000) Entry of B cell receptor into signaling domains is inhibited in tolerant B cells. J Exp Med 191:1443

    Article  PubMed  CAS  Google Scholar 

  67. Wienands J, Larbolette O, Reth M (1996) Evidence for a preformed transducer complex organized by the B cell antigen receptor. Proc Natl Acad Sci USA 93:7865

    Article  PubMed  CAS  Google Scholar 

  68. Wiest DL, Burgess WH, McKean D, Kearse KP, Singer A (1995) The molecular chaperone calnexin is expressed on the surface of immature thymocytes in association with clonotype-independent CD3 complexes. EMBO J 14:3425

    PubMed  CAS  Google Scholar 

  69. Williams GT, Venkitaraman AR, Gilmore DJ, Neuberger MS (1990) The sequence of the mu trans-membrane segment determines the tissue specificity of the transport of immunoglobulin M to the cell surface. J Exp Med 171:947

    Article  PubMed  CAS  Google Scholar 

  70. Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cipl. Mol Cell Biol 17:5598

    PubMed  CAS  Google Scholar 

  71. Yamanashi Y, Tamura T, Kanamori T, Yamane H, Nariuchi H, Yamamoto T, Baltimore D (2000) Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling. Genes Dev 14:11

    PubMed  CAS  Google Scholar 

  72. Yao R, Cooper GM (1995) Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267:2003

    Article  PubMed  CAS  Google Scholar 

  73. Zhang Y, Wienands J, Zurn C, Reth M (1998) Induction of the antigen receptor expression on B lymphocytes results in rapid competence for signaling of SLP-65 and Syk. EMBO J 17:7304

    Article  PubMed  CAS  Google Scholar 

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  1. University of Pennsylvania School of Medicine, Room 311 BRBII/III, 421 Curie Blvd., 19104, Philadelphia, PA, USA

    Ezequiel M. Fuentes-Pananá & John G. Monroe

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  1. Ezequiel M. Fuentes-Pananá
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Correspondence to John G. Monroe.

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Fuentes-Pananá, E.M., Monroe, J.G. Ligand-dependent and -independent processes in B-cell-receptor-mediated signaling. Springer Semin Immunopathol 23, 333–350 (2001). https://doi.org/10.1007/s281-001-8163-6

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