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Signalling through the high-affinity IgE receptor FcεRI

Nature volume 402, pages 24–30 (1999)Cite this article

Abstract

The FcεRI complex forms a high-affinity cell-surface receptor for the Fc region of antigen-specific immunoglobulin E (IgE) molecules. FcεRI is multimeric and is a member of a family of related antigen/Fc receptors which have conserved structural features and similar roles in initiating intracellular signalling cascades. In humans, FcεRI controls the activation of mast cells and basophils, and participates in IgE-mediated antigen presentation. Multivalent antigens bind and crosslink IgE molecules held at the cell surface by FcεRI. Receptor aggregation induces multiple signalling pathways that control diverse effector responses. These include the secretion of allergic mediators and induction of cytokine gene transcription, resulting in secretion of molecules such as interleukin-4, interleukin-6, tumour-necrosis factor-α and granulocyte-macrophage colony-stimulating factor. FcεRI is therefore central to the induction and maintenance of an allergic response and may confer physiological protection in parasitic infections.

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Figure 1: ITAM-containing immunoreceptors.
Figure 2: Structural relationship of FcεRIα and its ligand, IgE.
Figure 3: FcεRI activation induces complex networks of signalling events.

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Notes

  1. *Terms in italic are defined in the glossary on p. 39.

References

  1. Kinet, J. P. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu. Rev. Immunol. 17, 931– 972 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263– 274 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Cambier, J. Antigen and Fc receptor signalling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J. Immunol. 155, 3281–3285 (1995).

    CAS  PubMed  Google Scholar 

  4. Reth, M. Antigen receptor tail clue. Nature 338, 383– 384 (1989).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Keown, M. B., Henry, A. J., Ghirlando, R., Sutton, B. J. & Gould, H. J. Thermodynamics of the interaction of human immunoglobulin E with its high-affinity receptor Fc epsilon RI. Biochemistry 37, 8863–8869 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Presta, L. et al. The binding site on human immunoglobulin E for its high affinity receptor. J. Biol. Chem. 269, 26368– 26373 (1994).

    CAS  PubMed  Google Scholar 

  7. Henry, A. J. et al. Participation of the N-terminal region of Cepsilon3 in the binding of human IgE to its high-affinity receptor FcepsilonRI. Biochemistry 36, 15568–15578 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Robertson, M. W. Phage and Escherichia coli expression of the human high affinity immunoglobulin E receptor alpha-subunit ectodomain. Domain localization of the IgE-binding site. J. Biol. Chem. 268, 12736– 12743 (1993).

    CAS  PubMed  Google Scholar 

  9. Letourneur, O., Sechi, S., Willette Brown, J., Robertson, M. W. & Kinet, J. P. Glycosylation of human truncated Fc epsilon RI alpha chain is necessary for efficient folding in the endoplasmic reticulum. J. Biol. Chem. 270, 8249 –8256 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Garman, S. C., Kinet, J. P. & Jardetzky, T. S. Crystal structure of the human high-affinity IgE receptor. Cell 95, 951– 961 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Alber, G., Miller, L., Jelsema, C. L., Varin-Blank, N. & Metzger, H. Structure function relationships in mast cell high affinity receptor for IgE. J. Biol. Chem. 266, 22613–22620 (1991).

    CAS  PubMed  Google Scholar 

  12. Daeron, M. Fc receptor biology. Annu. Rev. Immunol. 15, 203–234 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Cohen, G. B., Ren, R. & Baltimore, D. Modular binding domains in signal transduction proteins. Cell 80, 237–248 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Scharenberg, A. M., Lin, S., Cuenod, B., Yamamura, H. & Kinet, J. P. Reconstitution of interactions between tyrosine kinases and the high affinity IgE receptor which are controlled by receptor clustering. EMBO J. 14, 3385–3394 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jouvin, M. H. et al. Differential control of the tyrosine kinases Lyn and Syk by the two signaling chains of the high affinity immunoglobulin E receptor. J. Biol. Chem. 269, 5918–5925 (1994).

    CAS  PubMed  Google Scholar 

  16. Nishizumi, H. & Yamamoto, T. Impaired tyrosine phosphorylation and Ca2+ mobilization, but not degranulation, in lyn-deficient bone marrow-derived mast cells. J. Immunol. 158, 2350–2355 (1997).

    CAS  PubMed  Google Scholar 

  17. Costello, P. S. et al. Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells. Oncogene 13, 2595–2605 (1996).

    CAS  PubMed  Google Scholar 

  18. Zhang, J., Berenstein, E. H., Evans, R. L. & Siraganian, R. P. Transfection of Syk protein tyrosine kinase reconstitutes high affinity IgE receptor-mediated degranulation in a Syk-negative variant of rat basophilic leukemia RBL-2H3 cells. J. Exp. Med. 184, 71–79 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Vonakis, B. M., Chen, H., Haleem-Smith, H. & Metzger, H. The unique domain as the site on Lyn kinase for its constitutive association with the high affinity receptor for IgE. J. Biol. Chem. 272, 24072–24080 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Pribluda, V. S., Pribluda, C. & Metzger, H. Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation. Proc. Natl Acad. Sci. USA 91, 11246–11250 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. El-Hillal, O., Kurosaki, T., Yamamura, H., Kinet, J. P. & Scharenberg, A. M. syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction. Proc. Natl Acad. Sci. USA 94, 1919– 1924 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Honda, Z. et al. Roles of C-terminal Src kinase in the initiation and the termination of the high affinity IgE receptor-mediated signaling. J. Biol. Chem. 272, 25753–25760 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  23. Moarefi, I. et al. Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature 385, 650– 653 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Thomas, M. L. The regulation of antigen-receptor signaling by protein tyrosine phosphatases: a hole in the story. Curr. Opin. Immunol. 11, 270–276 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Sheets, E. D., Holowka, D. & Baird, B. Membrane organization in immunoglobulin E receptor signaling. Curr. Opin. Chem. Biol. 3, 95– 99 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Finco, T. S., Kadlecek, T., Zhang, W., Samelson, L. E. & Weiss, A. LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity 9, 617– 626 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Facchetti, F. et al. Linker for activation of T cells (LAT), a novel immunohistochemical marker for T cells, NK cells, mast cells, and megakaryocytes: evaluation in normal and pathological conditions. Am. J. Pathol. 154, 1037–1046 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Salim, K. et al. Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase. EMBO J. 15, 6241–6250 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rameh, L. E. et al. A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains. J. Biol. Chem. 272, 22059–22066 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Rawlings, D. J. et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 271, 822– 825 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  32. Scharenberg, A. M. & Kinet, J. P. PtdIns-3,4,5-P3: a regulatory nexus between tyrosine kinases and sustained calcium signals. Cell 94, 5–8 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Vanhaesebroeck, B., Leevers, S. J., Panayotou, G. & Waterfield, M. D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem. Sci. 22, 267–272 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Turner, H., Reif, K., Rivera, J. & Cantrell, D. A. Regulation of the adapter molecule Grb2 by the FceR1 in the mast cell line RBL2H3. J. Biol. Chem. 270, 9500–9506 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Chen, R., Corbalan-Garcia, S. & Bar-Sagi, D. The role of the PH domain in the signal dependent membrane targeting of Sos. EMBO J. 16, 1351– 1359 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nimnual, A. S., Yatsula, B. A. & Bar-Sagi, D. Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. Science 279, 560– 563 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Marshall, C. J. Ras effectors. Curr. Opin. Cell. Biol. 8, 197–204 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Tuosto, L., Michel, F. & Acuto, O. p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells. J. Exp. Med. 184, 1161–1166 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Crespo, P., Schuebel, K. E., Ostrom, A. A., Gutkind, J. S. & Bustelo, X. R. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product. Nature 385, 169–172 ( 1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Liu, S. K., Fang, N., Koretzky, G. A. & McGlade, C. J. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr. Biol. 9, 67–75 (1999 ).

    Article  CAS  PubMed  Google Scholar 

  41. Turner, H. & Cantrell, D. A. Distinct Ras effector pathways are involved in FcεR1 regulation of the transcriptional activity of Elk-1 and NFAT in mast cells. J. Exp. Med. 185, 43–57 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Turner, H., Gomez, M., Mckenzie, E., Kirchem, A., Lennard, A. & Cantrell, D. Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to FcεR1 stimulation of mast cells. J. Exp. Med. 188, 527–537 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Roa, M., Paumet, F., Le Mao, J., David, B. & Blank, U. Involvement of the ras-like GTPase rab3d in RBL-2H3 mast cell exocytosis following stimulation via high affinity IgE receptors (Fc epsilonRI). J. Immunol. 159, 2815– 2823 (1997).

    CAS  PubMed  Google Scholar 

  44. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279 , 509–514 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Hutchinson, L. & McCloskey, M. Fcε R1 mediated induction of nuclear factor of activated T cells. J. Biol. Chem. 270, 16333–16338 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  46. Rao, A., Luo, C. & Hogan, P. Transcription factors of the NFAT family. Annu. Rev. Immunol. 15, 707–748 (1997).

    CAS  PubMed  Google Scholar 

  47. Putney, J. W. Jr & McKay, R. R. Capacitative calcium entry channels. BioEssays 21, 38 –46 (1999).

    Article  PubMed  Google Scholar 

  48. Parekh, A. B. & Penner, R. Store depletion and calcium influx. Physiol. Rev. 77, 901– 930 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Hoth, M. & Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355, 353–356 (1992).

    Article  ADS  CAS  PubMed  Google Scholar 

  50. Paolini, R., Jouvin, M. H. & Kinet, J. P. Phosphorylation and dephosphorylation of the high affinity receptor for IgE immediately after receptor engagement and disengagement. Nature 353, 855–858 (1991).

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Kimura, T. et al. Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor. J. Immunol. 159, 4426– 4434 (1997).

    CAS  PubMed  Google Scholar 

  52. Kimura, T., Sakamoto, H., Appella, E. & Siraganian, R. P. The negative signaling molecule SH2 domain-containing inositol- polyphosphate 5-phosphatase (SHIP) binds to the tyrosine-phosphorylated beta subunit of the high affinity IgE receptor. J. Biol. Chem. 272, 13991–13996 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Ottinger, E. A., Botfield, M. C. & Shoelson, S. E. Tandem SH2 domains confer high specificity in tyrosine kinase signaling. J. Biol. Chem. 273, 729 –735 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Lin, S., Cicala, C., Scharenberg, A. M. & Kinet, J. P. The Fc(epsilon)RIbeta subunit functions as an amplifier of Fc(epsilon)RIgamma-mediated cell activation signals. Cell 85, 985– 995 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Dombrowicz, D. et al. Allergy-associated FcRbeta is a molecular amplifier of IgE- and IgG-mediated in vivo responses. Immunity 8, 517–529 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Sandford, A. J. et al. Localisation of atopy and beta subunit of high-affinity IgE receptor (Fc epsilon RI) on chromosome 11q. Lancet 341, 332–334 (1993).

    Article  CAS  PubMed  Google Scholar 

  57. Adra, C. et al. Chromosome 11q13 and atopic asthma. Clin. Genet. 55, 431–437 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Shirakawa, T. et al. Association between atopy and variants of the β subunit of the high-affinity immunoglobulin E receptor. Nature Genet. 7, 125–129 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Hill, M. R. et al. Fc epsilon RI-beta polymorphism and risk of atopy in a general population sample. Br. Med. J. 311, 776– 779 (1995).

    Article  CAS  Google Scholar 

  60. Yamaguchi, M. et al. IgE enhances mouse mast cell Fc(epsilon)RI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. J. Exp. Med. 185, 663– 672 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Takizawa, F., Adamczewski, M. & Kinet, J. P. Identification of the low affinity receptor for immunoglobulin E on mouse mast cells and macrophages as Fc gamma RII and Fc gamma RIII. J. Exp. Med. 176, 469–475 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Blank, U., Ra, C. S. & Kinet, J. P. Characterization of truncated alpha chain products from human, rat, and mouse high affinity receptor for immunoglobulin E. J. Biol. Chem. 266, 2639–2646 (1991).

    CAS  PubMed  Google Scholar 

  63. Maurer, D. et al. Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J. Exp. Med. 179, 745–750 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  64. Maurer, D. et al. The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation. J. Immunol. 154, 6285–6290 (1995).

    CAS  PubMed  Google Scholar 

  65. Oettgen, H. C. et al. Active anaphylaxis in IgE-deficient mice. Nature 370, 367–370 ( 1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  66. Ujike, A. et al. Modulation of immunoglobulin (Ig)E-mediated systemic anaphylaxis by low-affinity Fc receptors for IgG. J. Exp. Med. 189, 1573–1579 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M.-H. Jouvin and other members of our laboratory for helpful advice and discussions. H.T. is an International Prize Travelling Fellow of the Wellcome Trust.

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  1. Department of Pathology, Laboratory of Allergy and Immunology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Helen Turner & Jean-Pierre Kinet

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Turner, H., Kinet, JP. Signalling through the high-affinity IgE receptor FcεRI. Nature 402 (Suppl 6760), 24–30 (1999). https://doi.org/10.1038/35037021

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