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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Apr 12;91(8):3087–3091. doi: 10.1073/pnas.91.8.3087

Dynamics of signal transduction after aggregation of cell-surface receptors: studies on the type I receptor for IgE.

U M Kent 1, S Y Mao 1, C Wofsy 1, B Goldstein 1, S Ross 1, H Metzger 1
PMCID: PMC43520  PMID: 7512721

Abstract

Many ligands stimulate cellular responses by aggregating the cell-surface receptors to which they are bound. We investigated several mechanistic questions related to aggregation of receptors by using the high-affinity receptor for IgE (Fc epsilon RI) on mast cells as a model system. We briefly exposed cells to covalently cross-linked oligomers of IgE and then added excess monomeric IgE to prevent further aggregation. Early events were examined by monitoring the phosphorylation of protein tyrosines; later events were examined by monitoring secretion. We found that aggregated receptors continue to signal both late and early events in the absence of formation of new aggregates. Additional experiments suggested that the clustered receptors undergo a dynamic process of phosphorylation and dephosphorylation. Our findings suggest that for these and related receptors that function by aggregation, the persistence of signal transduction is directly related to the intrinsic affinity of the ligand for the individual receptor.

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Selected References

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  1. Adamczewski M., Paolini R., Kinet J. P. Evidence for two distinct phosphorylation pathways activated by high affinity immunoglobulin E receptors. J Biol Chem. 1992 Sep 5;267(25):18126–18132. [PubMed] [Google Scholar]
  2. Alber G., Kent U. M., Metzger H. Functional comparison of Fc epsilon RI, Fc gamma RII, and Fc gamma RIII in mast cells. J Immunol. 1992 Oct 1;149(7):2428–2436. [PubMed] [Google Scholar]
  3. Bazin H., Querinjean P., Beckers A., Heremans J. F., Dessy F. Transplantable immunoglobulin-secreting tumours in rats. IV. Sixty-three IgE-secreting immunocytoma tumours. Immunology. 1974 Apr;26(4):713–723. [PMC free article] [PubMed] [Google Scholar]
  4. Becker K. E., Ishizaka T., Metzger H., Ishizaka K., Grimley P. M. Surface IgE on human basophils during histamine release. J Exp Med. 1973 Aug 1;138(2):394–409. doi: 10.1084/jem.138.2.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Benhamou M., Gutkind J. S., Robbins K. C., Siraganian R. P. Tyrosine phosphorylation coupled to IgE receptor-mediated signal transduction and histamine release. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5327–5330. doi: 10.1073/pnas.87.14.5327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Benhamou M., Siraganian R. P. Protein-tyrosine phosphorylation: an essential component of Fc epsilon RI signaling. Immunol Today. 1992 Jun;13(6):195–197. doi: 10.1016/0167-5699(92)90152-w. [DOI] [PubMed] [Google Scholar]
  7. De Magistris M. T., Alexander J., Coggeshall M., Altman A., Gaeta F. C., Grey H. M., Sette A. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell. 1992 Feb 21;68(4):625–634. doi: 10.1016/0092-8674(92)90139-4. [DOI] [PubMed] [Google Scholar]
  8. Fantl W. J., Johnson D. E., Williams L. T. Signalling by receptor tyrosine kinases. Annu Rev Biochem. 1993;62:453–481. doi: 10.1146/annurev.bi.62.070193.002321. [DOI] [PubMed] [Google Scholar]
  9. Fewtrell C., Metzger H. Larger oligomers of IgE are more effective than dimers in stimulating rat basophilic leukemia cells. J Immunol. 1980 Aug;125(2):701–710. [PubMed] [Google Scholar]
  10. Hohman R. J. Aggregation of IgE receptors induces degranulation in rat basophilic leukemia cells permeabilized with alpha-toxin from Staphylococcus aureus. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1624–1628. doi: 10.1073/pnas.85.5.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Holowka D., Metzger H. Further characterization of the beta-component of the receptor for immunoglobulin E. Mol Immunol. 1982 Feb;19(2):219–227. doi: 10.1016/0161-5890(82)90334-0. [DOI] [PubMed] [Google Scholar]
  12. ISHIZAKA K., CAMPBELL D. H. Biologic activity of soluble antigen-antibody complexes. IV. The inhibition of the skin reactivity of soluble complexes and the PCA reaction by heterologous complexes. J Immunol. 1959 Aug;83:116–126. [PubMed] [Google Scholar]
  13. Kagey-Sobotka A., MacGlashan D. W., Lichtenstein L. M. Role of receptor aggregation in triggering IgE-mediated reactions. Fed Proc. 1982 Jan;41(1):12–16. [PubMed] [Google Scholar]
  14. Keegan A. D., Paul W. E. Multichain immune recognition receptors: similarities in structure and signaling pathways. Immunol Today. 1992 Feb;13(2):63–68. doi: 10.1016/0167-5699(92)90136-U. [DOI] [PubMed] [Google Scholar]
  15. Kulczycki A., Jr, Metzger H. The interaction of IgE with rat basophilic leukemia cells. II. Quantitative aspects of the binding reaction. J Exp Med. 1974 Dec 1;140(6):1676–1695. doi: 10.1084/jem.140.6.1676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li W., Deanin G. G., Margolis B., Schlessinger J., Oliver J. M. Fc epsilon R1-mediated tyrosine phosphorylation of multiple proteins, including phospholipase C gamma 1 and the receptor beta gamma 2 complex, in RBL-2H3 rat basophilic leukemia cells. Mol Cell Biol. 1992 Jul;12(7):3176–3182. doi: 10.1128/mcb.12.7.3176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Liu F. T., Bohn J. W., Ferry E. L., Yamamoto H., Molinaro C. A., Sherman L. A., Klinman N. R., Katz D. H. Monoclonal dinitrophenyl-specific murine IgE antibody: preparation, isolation, and characterization. J Immunol. 1980 Jun;124(6):2728–2737. [PubMed] [Google Scholar]
  18. Maeyama K., Hohman R. J., Metzger H., Beaven M. A. Quantitative relationships between aggregation of IgE receptors, generation of intracellular signals, and histamine secretion in rat basophilic leukemia (2H3) cells. Enhanced responses with heavy water. J Biol Chem. 1986 Feb 25;261(6):2583–2592. [PubMed] [Google Scholar]
  19. Magro A. M., Alexander A. Histamine release: in vitro studies of the inhibitory region of the dose-response curve. J Immunol. 1974 May;112(5):1762–1765. [PubMed] [Google Scholar]
  20. Mao S. Y., Alber G., Rivera J., Kochan J., Metzger H. Interaction of aggregated native and mutant IgE receptors with the cellular skeleton. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):222–226. doi: 10.1073/pnas.89.1.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McCloskey M. A. Immobilization of Fc epsilon receptors by wheat germ agglutinin. Receptor dynamics in IgE-mediated signal transduction. J Immunol. 1993 Sep 15;151(6):3237–3251. [PubMed] [Google Scholar]
  22. Metzger H. A comment on the 'speculation' of Jarvis and Voss. Mol Immunol. 1982 Aug;19(8):1071–1071. doi: 10.1016/0161-5890(82)90316-9. [DOI] [PubMed] [Google Scholar]
  23. Metzger H. Transmembrane signaling: the joy of aggregation. J Immunol. 1992 Sep 1;149(5):1477–1487. [PubMed] [Google Scholar]
  24. Oliver J. M., Seagrave J., Stump R. F., Pfeiffer J. R., Deanin G. G. Signal transduction and cellular response in RBL-2H3 mast cells. Prog Allergy. 1988;42:185–245. [PubMed] [Google Scholar]
  25. Paolini R., Jouvin M. H., Kinet J. P. Phosphorylation and dephosphorylation of the high-affinity receptor for immunoglobulin E immediately after receptor engagement and disengagement. Nature. 1991 Oct 31;353(6347):855–858. doi: 10.1038/353855a0. [DOI] [PubMed] [Google Scholar]
  26. Pribluda V. S., Metzger H. Transmembrane signaling by the high-affinity IgE receptor on membrane preparations. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11446–11450. doi: 10.1073/pnas.89.23.11446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sarosi G. A., Thomas P. M., Egerton M., Phillips A. F., Kim K. W., Bonvini E., Samelson L. E. Characterization of the T cell antigen receptor--p60fyn protein tyrosine kinase association by chemical cross-linking. Int Immunol. 1992 Nov;4(11):1211–1217. doi: 10.1093/intimm/4.11.1211. [DOI] [PubMed] [Google Scholar]
  28. Schlessinger J. Signal transduction by allosteric receptor oligomerization. Trends Biochem Sci. 1988 Nov;13(11):443–447. doi: 10.1016/0968-0004(88)90219-8. [DOI] [PubMed] [Google Scholar]
  29. Seagrave J. C., Deanin G. G., Martin J. C., Davis B. H., Oliver J. M. DNP-phycobiliproteins, fluorescent antigens to study dynamic properties of antigen-IgE-receptor complexes on RBL-2H3 rat mast cells. Cytometry. 1987 May;8(3):287–295. doi: 10.1002/cyto.990080309. [DOI] [PubMed] [Google Scholar]
  30. Taurog J. D., Mendoza G. R., Hook W. A., Siraganian R. P., Metzger H. Noncytotoxic IgE-mediated release of histamine and serotonin from murine mastocytoma cells. J Immunol. 1977 Nov;119(5):1757–1761. [PubMed] [Google Scholar]
  31. Weetall M., Holowka D., Baird B. Heterologous desensitization of the high affinity receptor for IgE (Fc epsilon R1) on RBL cells. J Immunol. 1993 May 1;150(9):4072–4083. [PubMed] [Google Scholar]
  32. Yu K. T., Lyall R., Jariwala N., Zilberstein A., Haimovich J. Antigen- and ionophore-induced signal transduction in rat basophilic leukemia cells involves protein tyrosine phosphorylation. J Biol Chem. 1991 Nov 25;266(33):22564–22568. [PubMed] [Google Scholar]
  33. Zick Y., Sagi-Eisenberg R. A combination of H2O2 and vanadate concomitantly stimulates protein tyrosine phosphorylation and polyphosphoinositide breakdown in different cell lines. Biochemistry. 1990 Nov 6;29(44):10240–10245. doi: 10.1021/bi00496a013. [DOI] [PubMed] [Google Scholar]

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