Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of B-cell signal transduction by adaptor proteins

Nature Reviews Immunology volume 2, pages 354–363 (2002)Cite this article

Key Points

  • Adaptor molecules are crucial for B-cell function and development.

  • By using protein–protein interaction domains, such as SRC-homology 2 (SH2) and SH3 domains, adaptor molecules make intermolecular complexes, thereby contributing to the selective partitioning of binding partners into discrete subcellular locations.

  • The subcellular location of adaptors by themselves, such as exclusion or inclusion, in lipid rafts is also crucial for B-cell signal transduction.

  • Adaptor molecules can induce intramolecular conformational changes in their binding partners, thereby regulating their intrinsic enzymatic activities.

  • Because they have multiple binding partners (such as kinases and substrates), adaptor molecules can accelerate interactions between these partners.

  • Co-receptors, such as paired immunoglobulin-like receptor B (PIRB) and FcγRIIB, can be viewed also as adaptor molecules, as the tyrosine phosphorylation status of their cytoplasmic tails regulates the partitioning of protein- and lipid-phosphatases in the vicinity of the B-cell receptor signalling complex.

  • Adaptor molecules and co-receptors participate in establishing negative or positive regulatory loops, thereby fine-tuning B-cell responses.

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Signalling molecules that are found in B cells illustrated to highlight their modular structures and protein–protein interaction domains.
Figure 2: Raft translocation of the BCR by ligand binding.
Figure 3: Models of negative-feedback regulatory loops for LYN and BTK.
Figure 4: Phosphoinositide metabolism mediated by PI3K, SHIP, PTEN and PLCγ2.
Figure 5: Two-step models for PLCγ2 and PI3K activation.
Figure 6: Negative-regulatory loops mediated by inhibitory receptors on B cells.

Similar content being viewed by others

References

  1. Leo, A. & Schraven, B. Adapters in lymphocyte signalling. Curr. Opin. Immunol. 13, 307–316 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Campbell, K. S. Signal transduction from the B-cell antigen-receptor. Curr. Opin. Immunol. 11, 256–264 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Kelly, M. E. & Chan, A. C. Regulation of B-cell function by linker proteins. Curr. Opin. Immunol. 12, 267–275 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Annaiah, C. & Pillai, S. Antigen-dependent B-cell development. Curr. Opin. Immunol. 14, 241–249 (2002).

    Article  Google Scholar 

  5. Fruman, D. A., Satterthwaite, A. B. & Witte, O. N. Xid-like phenotypes: a B-cell signalosome takes shape. Immunity 13, 1–3 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Kurosaki, T. Regulation of B-cell fates by BCR signaling components. Curr. Opin. Immunol. (in the press).

  7. Pierce, S. K. Lipid rafts and B-cell activation. Nature Rev. Immunol. 2, 96–105 (2002).

    Article  CAS  Google Scholar 

  8. DeFranco, A. L. The complexity of signaling pathways activated by the BCR. Curr. Opin. Immunol. 9, 296–308 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Kurosaki, T. Molecular mechanisms in B-cell antigen-receptor signaling. Curr. Opin. Immunol. 9, 309–318 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Reth, M. & Wienands, J. Initiation and processing of signals from the B-cell antigen receptor. Annu. Rev. Immunol. 15, 453–479 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Tamir, I. & Cambier, J. C. Antigen-receptor signaling: integration of protein tyrosine kinase functions. Oncogene 17, 1353–1364 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nature Rev. Mol. Cell Biol. 1, 31–39 (2000).

    Article  CAS  Google Scholar 

  13. Cherukuri, A., Dykstra, M. & Pierce, S. K. Floating the raft hypothesis: lipid rafts play a role in immune-cell activation. Immunity 14, 657–660 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Cheng, P. C., Dykstra, M. L., Mitchell, R. N. & Pierce, S. K. A role for lipid rafts in B-cell antigen receptor signaling and antigen targeting. J. Exp. Med. 190, 1549–1560 (1999).This study shows that BCR components, after BCR crosslinking, enter into rafts, which include LYN, but not CD45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guo, B., Kato, R. M., Garcia-Lloret, M., Wahl, M. I. & Rawlings, D. J. Engagement of the human pre-B-cell receptor generates a lipid raft-dependent calcium signaling complex. Immunity 13, 243–253 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Chung, J. B., Baumeister, M. A. & Monroe, J. G. Cutting edge: differential sequestration of plasma membrane-associated B-cell antigen receptor in mature and immature B cells into glycosphingolipid-enriched domains. J. Immunol. 166, 736–740 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Sproul, T. W., Malapati, S., Kim, J. & Pierce, S. K. Cutting edge: B-cell antigen receptor signaling occurs outside lipid rafts in immature B cells. J. Immunol. 165, 6020–6023 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Weintraub, B. C. et al. Entry of B-cell receptor into signaling domains is inhibited in tolerant B cells. J. Exp. Med. 191, 1443–1448 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cherukuri, A., Cheng, P. C., Sohn, H. W. & Pierce, S. K. The CD19/CD21 complex functions to prolong B-cell antigen receptor signaling from lipid rafts. Immunity 14, 169–179 (2001).This study shows that co-ligation of BCR and CD19–CD21 enhances the residency of both of these receptors in lipid rafts and retards the internalization and degradation of the BCR.

    Article  CAS  PubMed  Google Scholar 

  20. Dykstra, M. L., Longnecker, R. & Pierce, S. K. Epstein–Barr virus coopts lipid rafts to block the signaling and antigen-transport functions of the BCR. Immunity 14, 57–67 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Kurosaki, T. Genetic analysis of B-cell antigen-receptor signaling. Annu. Rev. Immunol. 17, 555–592 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Cooper, J. A. & Howell, B. The when and how of Src regulation. Cell 73, 1051–1054 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Hata, A., Sabe, H., Kurosaki, T., Takata, M. & Hanafusa, H. Functional analysis of Csk in signal transduction through the B-cell antigen receptor. Mol. Cell Biol. 14, 7306–7313 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Yanagi, S. et al. CD45 modulates phosphorylation of both autophosphorylation and negative regulatory tyrosines of Lyn in B cells. J. Biol. Chem. 271, 30487–30492 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Kawabuchi, M. et al. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999–1003 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Brdicka, T. et al. Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase Csk and is involved in regulation of T-cell activation. J. Exp. Med. 191, 1591–1604 (2000).References 25 and 26 describe the purification and molecular cloning of a novel raft-associated adaptor protein that recruits the tyrosine kinase Csk to the plasma membrane.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takeuchi, S., Takayama, Y., Ogawa, A., Tamura, K. & Okada, M. Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk. J. Biol. Chem. 275, 29183–29186 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Harder, K. W. et al. Gain- and loss-of-function Lyn-mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity 15, 603–615 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Hakak, Y. & Martin, G. S. Ubiquitin-dependent degradation of active Src. Curr. Biol. 9, 1039–1042 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Harris, K. F. et al. Ubiquitin-mediated degradation of active Src tyrosine kinase. Proc. Natl Acad. Sci. USA 96, 13738–13743 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fruman, D. A., Satterthwaite, A. B. & Witte, O. N. Xid-like phenotypes: a B-cell signalosome takes shape. Immunity 13, 1–3 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Rawlings, D. J. Bruton's tyrosine kinase controls a sustained calcium signal essential for B-lineage development and function. Clin. Immunol. 91, 243–253 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Takata, M. & Kurosaki, T. A role for Bruton's tyrosine kinase in B-cell antigen receptor-mediated activation of phospholipase C-γ2. J. Exp. Med. 184, 31–40 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Kang, S. W. et al. PKCβ modulates antigen receptor signaling via regulation of Btk membrane localization. EMBO J. 20, 5692–5702 (2001).This study describes the identification of Ser180, a Pkcβ target, in a short linker within the TH domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk. This result led the authors to propose that Pkcβ, once activated by the Btk–Plcγ2 pathway, acts as a feedback-loop inhibitor of Btk activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, W. et al. Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein. Nature Immunol. 2, 939–946 (2001).

    Article  CAS  Google Scholar 

  36. Yamadori, T. et al. Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein. Proc. Natl Acad. Sci. USA 96, 6341–6346 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, D. et al. Phospholipase Cγ2 is essential in the functions of B-cell and several Fc receptors. Immunity 13, 25–35 (2000).

    Article  PubMed  Google Scholar 

  38. Hashimoto, A. et al. Cutting edge: essential role of phospholipase Cγ2 in B-cell development and function. J. Immunol. 165, 1738–1742 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Suzuki, H. et al. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase. Science 283, 390–392 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Fruman, D. A. et al. Impaired B-cell development and proliferation in absence of phosphoinositide 3-kinase p85α. Science 283, 393–397 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Liu, Q. et al. The inositol polyphosphate 5-phosphatase SHIP is a crucial negative regulator of B-cell antigen-receptor signaling. J. Exp. Med. 188, 1333–1342 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Helgason, C. D. et al. A dual role for Src homology 2 domain-containing inositol-5-phosphatase (SHIP) in immunity: aberrant development and enhanced function of B lymphocytes in SHIP−/− mice. J. Exp. Med. 191, 781–794 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pike, L. J. & Miller, J. M. Cholesterol depletion delocalizes phosphatidylinositol bisphosphate and inhibits hormone-stimulated phosphatidylinositol turnover. J. Biol. Chem. 273, 22298–22304 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Aman, M. J. & Ravichandran, K. S. A requirement for lipid rafts in B-cell receptor-induced Ca2+ flux. Curr. Biol. 10, 393–396 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Richards, J. D., Gold, M. R., Hourihane, S. L., DeFranco, A. L. & Matsuuchi, L. Reconstitution of B-cell antigen receptor-induced signaling events in a nonlymphoid cell line by expressing the Syk protein-tyrosine kinase. J. Biol. Chem. 271, 6458–6466 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Wienands, J. et al. SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation. J. Exp. Med. 188, 791–795 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fu, C., Turck, C. W., Kurosaki, T. & Chan, A. C. BLNK: a central linker protein in B-cell activation. Immunity 9, 93–103 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Goitsuka, R. et al. BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius. J. Immunol. 161, 5804–5808 (1998).

    CAS  PubMed  Google Scholar 

  49. Gangi-Peterson, L. et al. Bca: an activation-related B-cell gene. Mol. Immunol. 35, 55–63 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Ishiai, M., Sugawara, H., Kurosaki, M. & Kurosaki, T. Cutting edge: association of phospholipase C-γ2 Src homology 2 domains with BLNK is critical for B-cell antigen receptor signaling. J. Immunol. 163, 1746–1749 (1999).

    CAS  PubMed  Google Scholar 

  51. Ishiai, M. et al. BLNK required for coupling Syk to PLCγ2 and Rac1–JNK in B cells. Immunity 10, 117–125 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P. & Samelson, L. E. LAT: the ZAP-70 tyrosine kinase substrate that links T-cell receptor to cellular activation. Cell 92, 83–92 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Zhang, W., Trible, R. P. & Samelson, L. E. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T-cell activation. Immunity 9, 239–246 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Ishiai, M. et al. Involvement of LAT, Gads and Grb2 in compartmentation of SLP-76 to the plasma membrane. J. Exp. Med. 192, 847–856 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Boerth, N. J. et al. Recruitment of SLP-76 to the membrane and glycolipid-enriched membrane microdomains replaces the requirement for linker for activation of T cells in T-cell receptor signaling. J. Exp. Med. 192, 1047–1058 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Engels, N., Wollscheid, B. & Wienands, J. Association of SLP-65/BLNK with the B-cell antigen receptor through a non-ITAM tyrosine of Ig-α. Eur. J. Immunol. 31, 2126–2134 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Hashimoto, S. et al. Identification of the SH2-domain-binding protein of Bruton's tyrosine kinase as BLNK: functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling. Blood 94, 2357–2364 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Su, Y. W. et al. Interaction of SLP adaptors with the SH2 domain of Tec family kinases. Eur. J. Immunol. 29, 3702–3711 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Baba, Y. et al. BLNK mediates Syk-dependent Btk activation. Proc. Natl Acad. Sci. USA 98, 2582–2586 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yablonski, D., Kadlecek, T. & Weiss, A. Identification of a phospholipase C-γ (PLC-γ) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-γ and NFAT. Mol. Cell. Biol. 21, 4208–4218 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pappu, R. et al. Requirement for B-cell linker protein (BLNK) in B-cell development. Science 286, 1949–1954 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Jumaa, H. et al. Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 11, 547–554 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Otero, D. C., Omori, S. A. & Rickert, R. C. CD19-dependent activation of Akt kinase in B lymphocytes. J. Biol. Chem. 276, 1474–1478 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Buhl, A. M. & Cambier, J. C. Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B-cell antigen receptor-mediated activation of Bruton's tyrosine kinase. J. Immunol. 162, 4438–4446 (1999).

    CAS  PubMed  Google Scholar 

  65. Hippen, K. L. et al. FcγRIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation. Immunity 7, 49–58 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Hayami, K. et al. Molecular cloning of a novel murine cell-surface glycoprotein homologous to killer-cell inhibitory receptors. J. Biol. Chem. 272, 7320–7327 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Kubagawa, H., Burrows, P. D. & Cooper, M. D. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc. Natl Acad. Sci. USA 94, 5261–5266 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Blery, M. et al. The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc. Natl Acad. Sci. USA 95, 2446–2451 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Maeda, A., Kurosaki, M., Ono, M., Takai, T. & Kurosaki, T. Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal. J. Exp. Med. 187, 1355–1360 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Maeda, A. et al. Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1. Oncogene 18, 2291–2297 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Ho, L. H., Uehara, T., Chen, C. C., Kubagawa, H. & Cooper, M. D. Constitutive tyrosine phosphorylation of the inhibitory paired Ig-like receptor PIR-B. Proc. Natl Acad. Sci. USA 96, 15086–15090 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tsui, F. W. & Tsui, H. W. Molecular basis of the motheaten phenotype. Immunol. Rev. 138, 185–206 (1994).

    Article  CAS  PubMed  Google Scholar 

  73. Cyster, J. G. & Goodnow, C. C. Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity 2, 13–24 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. Fearon, D. T. & Carroll, M. C. Regulation of B-lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu. Rev. Immunol. 18, 393–422 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Fujimoto, M. et al. CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity 13, 47–57 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Otero, D. C., Omori, S. A. & Rickert, R. C. CD19-dependent activation of Akt kinase in B lymphocytes. J. Biol. Chem. 276, 1474–1478 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Engel, P. et al. Abnormal B-lymphocyte development, activation and differentiation in mice that lack or overexpress the CD19 signal-transduction molecule. Immunity 3, 39–50 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. Rickert, R. C., Rajewsky, K. & Roes, J. Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376, 352–355 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Okada, T., Maeda, A., Iwamatsu, A., Gotoh, K. & Kurosaki, T. BCAP: the tyrosine kinase substrate that connects B-cell receptor to phosphoinositide 3-kinase activation. Immunity 13, 817–827 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Ingham, R. J., Holgado-Madruga, M., Siu, C., Wong, A. J. & Gold, M. R. The Gab1 protein is a docking site for multiple proteins involved in signaling by the B-cell antigen receptor. J. Biol. Chem. 273, 30630–30637 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Gu, H. et al. Essential role for Gab2 in the allergic response. Nature 412, 186–190 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Pike, L. J. & Miller, J. M. Cholesterol depletion delocalizes phosphatidylinositol bisphosphate and inhibits hormone-stimulated phosphatidylinositol turnover. J. Biol. Chem. 273, 22298–22304 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Manetz, T. S. et al. Vav1 regulates phospholipase Cγ activation and calcium responses in mast cells. Mol. Cell. Biol. 21, 3763–3774 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Inabe, K. et al. Vav3 modulates B-cell receptor responses by regulating phosphoinositide 3-kinase activation. J. Exp. Med. 195, 189–200 (2002).References 83 and 84 describe how loss of Vav-family proteins leads to insufficient PI3K activation in the context of FcɛRI, BCR and TCR signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zheng, Y., Bagrodia, S. & Cerione, R. A. Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J. Biol. Chem. 269, 18727–18730 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Bokoch, G. M., Vlahos, C. J., Wang, Y., Knaus, U. G. & Traynor-Kaplan, A. E. Rac GTPase interacts specifically with phosphatidylinositol 3-kinase. Biochem. J. 315, 775–779 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bustelo, X. R. Regulatory and signaling properties of the Vav family. Mol. Cell. Biol. 20, 1461–1477 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bolland, S., Pearse, R. N., Kurosaki, T. & Ravetch, J. V. SHIP modulates immune receptor responses by regulating membrane association of Btk. Immunity 8, 509–516 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Ono, M., Bolland, S., Tempst, P. & Ravetch, J. V. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIB. Nature 383, 263–266 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Ono, M. et al. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 90, 293–301 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Okada, H. et al. Role of the inositol phosphatase SHIP in B-cell receptor-induced Ca2+ oscillatory response. J. Immunol. 161, 5129–5132 (1998).

    CAS  PubMed  Google Scholar 

  92. Petrie, R. J., Schnetkamp, P. P., Patel, K. D., Awasthi-Kalia, M. & Deans, J. P. 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, 1220–1227 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Tamir, I. et al. The RasGAP-binding protein p62dok is a mediator of inhibitory FcγRIIB signals in B cells. Immunity 12, 347–358 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Yamanashi, Y. et al. Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B-cell receptor-mediated signaling. Genes Dev. 14, 11–16 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Suzuki, A. et al. T-cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Torres, J. & Pulido, R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C-terminus. Implications for PTEN stability to proteasome-mediated degradation. J. Biol. Chem. 276, 993–998 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Shieh, B. H. & Zhu, M. Y. Regulation of the TRP Ca2+ channel by INAD in Drosophila photoreceptors. Neuron 16, 991–998 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Tsunoda, S. et al. A multivalent PDZ-domain protein assembles signalling complexes in a G-protein-coupled cascade. Nature 388, 243–249 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Kabak, S. et al. The direct recruitment of BLNK to immunoglobulin α couples the B-cell antigen receptor to distal signaling pathway. Mol. Cell Biol. 22, 2524–2535 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yamazaki, T. et al. Essential immunoregulatory role for BCAP in B-cell development and function. J. Exp. Med. 195, 535–545 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Reynolds, L. F. et al. Vav1 transduces T-cell receptor signals to the activation of phospolipase Cγ via phosphoinositide-3-kinase-dependent and -independent pathways. J. Exp. Med. (in the press).

Download references

Acknowledgements

Work in my laboratory was supported by grants from the Ministry of Education, Science, Sports and Culture in Japan, the Toray Science Foundation and the Human Frontier Science Program. I thank V. Tybulewicz for communicating his preprint and the members of my laboratory for their contribution to both the work that is cited and the writing of this manuscript.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, and Laboratory for Lymphocyte Differentiation, RIKEN Research Centre for Allergy and Immunology, Moriguchi, 570-8506, Japan

    Tomohiro Kurosaki

Authors
  1. Tomohiro Kurosaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Entrez

EBV

LMP2A

InterPro

ITAM

PDZ domain

PH domain

PTB domain

SH2

SH3

TH domain

LocusLink

AKT

Akt

BCAP

Bcap

BLK

BLNK

Blnk

BTK

Btk

CD19

CD21

CD22

CD45

CD79A

CD79B

CD81

CK2

CSK

DOK1

Dok1

DOK2

ERK

Erk

FcɛRI (human)

FcɛRI (mouse)

FcγRIIB

FYN

GAB1

GAB2

IBTK

inaD

LAT

LEU13

LYN

Lyn

PAG

PI3K (human)

PI3K (mouse)

PI5K

PIRB

Prkcβ

PLCγ1

PLCγ2

Plcγ2

PTEN

RAC1

SAB

Sab

SHC

SHIP

Ship

SHP1

Shp1

SLP76

SRC

Src

SYK

TEC

trp

VAV

Vav1

Vav2

Vav3

OMIM

XLA

FURTHER INFORMATION

Alliance for Cellular Signalling

RIKEN

Glossary

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several activating receptors, such as the BCR. The motif has the form Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins containing SH2 domains.

SIGNALOSOME

A putative, stable signalling complex, which consists of BTK, BLNK, BCAP, VAV1/2, PLCγ2 and PI3K, that is proposed to regulate intracellular calcium and subsequent downstream events.

PLCγ2–CALCIUM–PKCβ PATHWAY

Activated phospholipase Cγ2 (PLCγ2), presumably tyrosine phosphorylated by Bruton's tyrosine kinase (BTK), converts phosphatidylinositol-4,5-bisphosphate (PtdInsP2) into two second messengers, diacylglycerol (DAG) and InsP3. DAG activates protein kinase Cβ (PKCβ), and InsP3 causes the release of calcium from the endoplasmic reticulum through its binding to InsP3 receptors.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

(ITIM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several inhibitory receptors, such as FcγRIIB and PIRB. The prototype six-amino-acid sequence is (Ile/Val/Leu/Ser)-Xaa-Tyr-Xaa-Xaa-Leu/Val. Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases that have an SH2 domain.

B1 B CELLS

In the mouse, the B1 B-cell subset is found primarily in the peritoneal and pleural cavities. B1 B cells form a self-renewing subset with a restricted repertoire of B-cell receptors that respond to common bacterial antigens and might have a role in autoimmunity.

TI-II RESPONSE

Thymus-independent type II (TI-II) antigens, which are derived typically from polysaccharides, consist of complex repeating units that drive B-cell responses by extensive crosslinking. Both B1 and marginal-zone B cells are thought to be responsible for TI-II antibody responses.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). Proteins fused to cyan, yellow or red fluorescent proteins are expressed and assessed for interaction by measuring the energy transfer between fluors, which can only occur if proteins physically interact. This is used to measure protein–protein interactions microscopically or by a FACS-based method.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurosaki, T. Regulation of B-cell signal transduction by adaptor proteins. Nat Rev Immunol 2, 354–363 (2002). https://doi.org/10.1038/nri801

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri801

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing