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. 1992 May 1;175(5):1381–1390. doi: 10.1084/jem.175.5.1381

Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain

PMCID: PMC2119196  PMID: 1314888

Abstract

To determine the functional role of the two isoforms of Fc gamma RIII (CD16) (IIIA, IIIB), the signal transduction capabilities of wild-type and mutant forms of these receptors were analyzed in transfected lymphoid, myeloid, and fibroblastic cell lines. Functional reconstitution of receptor signalling was observed in hematopoietic T and mast cells, and was absent in nonhematopoietic (CHO) cells. Fc gamma RIIIA, a hetero-oligomeric receptor composed of a ligand-binding subunit alpha and dimeric gamma chains, generated both proximal and distal responses in Jurkat and P815 cells, typical of what is seen in natural killer cells and macrophages upon receptor activation. In contrast, Fc gamma RIIIB, which is normally attached to the cell surface via a glycosyl-phosphatidylinositol anchor, was incapable of transducing signals. After crosslinking, Fc gamma RIIIA signalling was dependent only upon the gamma chain. Fc gamma RIIIA chimeras in which the alpha subunit transmembrane and cytoplasmic domains were substituted with the corresponding gamma chain sequences functioned as well as wild-type hetero-oligomeric receptors. These data indicate that the ability of the Fc gamma RIIIA complex to activate the appropriate pathways for cell activation is cell-type restricted and independent of the transmembrane and cytoplasmic domains of the alpha subunit. The presence of the gamma chain is responsible for the assembly of, as well as the signal transduction by, the functional cell surface complex.

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Selected References

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  1. Alber G., Miller L., Jelsema C. L., Varin-Blank N., Metzger H. Structure-function relationships in the mast cell high affinity receptor for IgE. Role of the cytoplasmic domains and of the beta subunit. J Biol Chem. 1991 Nov 25;266(33):22613–22620. [PubMed] [Google Scholar]
  2. Anderson P., Caligiuri M., O'Brien C., Manley T., Ritz J., Schlossman S. F. Fc gamma receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2274–2278. doi: 10.1073/pnas.87.6.2274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anegón I., Cuturi M. C., Trinchieri G., Perussia B. Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. J Exp Med. 1988 Feb 1;167(2):452–472. doi: 10.1084/jem.167.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Berridge M. J., Dawson R. M., Downes C. P., Heslop J. P., Irvine R. F. Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J. 1983 May 15;212(2):473–482. doi: 10.1042/bj2120473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blank U., Ra C., Miller L., White K., Metzger H., Kinet J. P. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature. 1989 Jan 12;337(6203):187–189. doi: 10.1038/337187a0. [DOI] [PubMed] [Google Scholar]
  7. Cassatella M. A., Anegón I., Cuturi M. C., Griskey P., Trinchieri G., Perussia B. Fc gamma R(CD16) interaction with ligand induces Ca2+ mobilization and phosphoinositide turnover in human natural killer cells. Role of Ca2+ in Fc gamma R(CD16)-induced transcription and expression of lymphokine genes. J Exp Med. 1989 Feb 1;169(2):549–567. doi: 10.1084/jem.169.2.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Einspahr K. J., Abraham R. T., Binstadt B. A., Uehara Y., Leibson P. J. Tyrosine phosphorylation provides an early and requisite signal for the activation of natural killer cell cytotoxic function. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6279–6283. doi: 10.1073/pnas.88.14.6279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fleit H. B., Wright S. D., Unkeless J. C. Human neutrophil Fc gamma receptor distribution and structure. Proc Natl Acad Sci U S A. 1982 May;79(10):3275–3279. doi: 10.1073/pnas.79.10.3275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Frank S. J., Niklinska B. B., Orloff D. G., Merćep M., Ashwell J. D., Klausner R. D. Structural mutations of the T cell receptor zeta chain and its role in T cell activation. Science. 1990 Jul 13;249(4965):174–177. doi: 10.1126/science.2371564. [DOI] [PubMed] [Google Scholar]
  11. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  12. Gunter K. C., Germain R. N., Kroczek R. A., Saito T., Yokoyama W. M., Chan C., Weiss A., Shevach E. M. Thy-1-mediated T-cell activation requires co-expression of CD3/Ti complex. Nature. 1987 Apr 2;326(6112):505–507. doi: 10.1038/326505a0. [DOI] [PubMed] [Google Scholar]
  13. Hibbs M. L., Selvaraj P., Carpén O., Springer T. A., Kuster H., Jouvin M. H., Kinet J. P. Mechanisms for regulating expression of membrane isoforms of Fc gamma RIII (CD16). Science. 1989 Dec 22;246(4937):1608–1611. doi: 10.1126/science.2531918. [DOI] [PubMed] [Google Scholar]
  14. Huizinga T. W., van der Schoot C. E., Jost C., Klaassen R., Kleijer M., von dem Borne A. E., Roos D., Tetteroo P. A. The PI-linked receptor FcRIII is released on stimulation of neutrophils. Nature. 1988 Jun 16;333(6174):667–669. doi: 10.1038/333667a0. [DOI] [PubMed] [Google Scholar]
  15. Irving B. A., Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991 Mar 8;64(5):891–901. doi: 10.1016/0092-8674(91)90314-o. [DOI] [PubMed] [Google Scholar]
  16. Kimberly R. P., Ahlstrom J. W., Click M. E., Edberg J. C. The glycosyl phosphatidylinositol-linked Fc gamma RIIIPMN mediates transmembrane signaling events distinct from Fc gamma RII. J Exp Med. 1990 Apr 1;171(4):1239–1255. doi: 10.1084/jem.171.4.1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Klausner R. D., Samelson L. E. T cell antigen receptor activation pathways: the tyrosine kinase connection. Cell. 1991 Mar 8;64(5):875–878. doi: 10.1016/0092-8674(91)90310-u. [DOI] [PubMed] [Google Scholar]
  18. Kurosaki T., Gander I., Ravetch J. V. A subunit common to an IgG Fc receptor and the T-cell receptor mediates assembly through different interactions. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3837–3841. doi: 10.1073/pnas.88.9.3837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kurosaki T., Gander I., Wirthmueller U., Ravetch J. V. The beta subunit of the Fc epsilon RI is associated with the Fc gamma RIII on mast cells. J Exp Med. 1992 Feb 1;175(2):447–451. doi: 10.1084/jem.175.2.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kurosaki T., Ravetch J. V. A single amino acid in the glycosyl phosphatidylinositol attachment domain determines the membrane topology of Fc gamma RIII. Nature. 1989 Dec 14;342(6251):805–807. doi: 10.1038/342805a0. [DOI] [PubMed] [Google Scholar]
  21. Lanier L. L., Yu G., Phillips J. H. Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature. 1989 Dec 14;342(6251):803–805. doi: 10.1038/342803a0. [DOI] [PubMed] [Google Scholar]
  22. Letourneur F., Klausner R. D. T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8905–8909. doi: 10.1073/pnas.88.20.8905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miller J., Germain R. N. Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain. J Exp Med. 1986 Nov 1;164(5):1478–1489. doi: 10.1084/jem.164.5.1478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miller L., Alber G., Varin-Blank N., Ludowyke R., Metzger H. Transmembrane signaling in P815 mastocytoma cells by transfected IgE receptors. J Biol Chem. 1990 Jul 25;265(21):12444–12453. [PubMed] [Google Scholar]
  25. Orloff D. G., Ra C. S., Frank S. J., Klausner R. D., Kinet J. P. Family of disulphide-linked dimers containing the zeta and eta chains of the T-cell receptor and the gamma chain of Fc receptors. Nature. 1990 Sep 13;347(6289):189–191. doi: 10.1038/347189a0. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Perussia B., Ravetch J. V. Fc gamma RIII (CD16) on human macrophages is a functional product of the Fc gamma RIII-2 gene. Eur J Immunol. 1991 Feb;21(2):425–429. doi: 10.1002/eji.1830210226. [DOI] [PubMed] [Google Scholar]
  28. Perussia B., Tutt M. M., Qiu W. Q., Kuziel W. A., Tucker P. W., Trinchieri G., Bennett M., Ravetch J. V., Kumar V. Murine natural killer cells express functional Fc gamma receptor II encoded by the Fc gamma R alpha gene. J Exp Med. 1989 Jul 1;170(1):73–86. doi: 10.1084/jem.170.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ra C., Jouvin M. H., Blank U., Kinet J. P. A macrophage Fc gamma receptor and the mast cell receptor for IgE share an identical subunit. Nature. 1989 Oct 26;341(6244):752–754. doi: 10.1038/341752a0. [DOI] [PubMed] [Google Scholar]
  30. Ravetch J. V., Kinet J. P. Fc receptors. Annu Rev Immunol. 1991;9:457–492. doi: 10.1146/annurev.iy.09.040191.002325. [DOI] [PubMed] [Google Scholar]
  31. Ravetch J. V., Perussia B. Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. J Exp Med. 1989 Aug 1;170(2):481–497. doi: 10.1084/jem.170.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Romeo C., Amiot M., Seed B. Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor zeta chain. Cell. 1992 Mar 6;68(5):889–897. doi: 10.1016/0092-8674(92)90032-8. [DOI] [PubMed] [Google Scholar]
  33. Romeo C., Seed B. Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell. 1991 Mar 8;64(5):1037–1046. doi: 10.1016/0092-8674(91)90327-u. [DOI] [PubMed] [Google Scholar]
  34. Saito T., Weiss A., Miller J., Norcross M. A., Germain R. N. Specific antigen-Ia activation of transfected human T cells expressing murine Ti alpha beta-human T3 receptor complexes. Nature. 1987 Jan 8;325(7000):125–130. doi: 10.1038/325125a0. [DOI] [PubMed] [Google Scholar]
  35. Salmon J. E., Kapur S., Kimberly R. P. Opsonin-independent ligation of Fc gamma receptors. The 3G8-bearing receptors on neutrophils mediate the phagocytosis of concanavalin A-treated erythrocytes and nonopsonized Escherichia coli. J Exp Med. 1987 Dec 1;166(6):1798–1813. doi: 10.1084/jem.166.6.1798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scallon B. J., Scigliano E., Freedman V. H., Miedel M. C., Pan Y. C., Unkeless J. C., Kochan J. P. A human immunoglobulin G receptor exists in both polypeptide-anchored and phosphatidylinositol-glycan-anchored forms. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5079–5083. doi: 10.1073/pnas.86.13.5079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Selvaraj P., Rosse W. F., Silber R., Springer T. A. The major Fc receptor in blood has a phosphatidylinositol anchor and is deficient in paroxysmal nocturnal haemoglobinuria. Nature. 1988 Jun 9;333(6173):565–567. doi: 10.1038/333565a0. [DOI] [PubMed] [Google Scholar]
  38. Simmons D., Seed B. The Fc gamma receptor of natural killer cells is a phospholipid-linked membrane protein. Nature. 1988 Jun 9;333(6173):568–570. doi: 10.1038/333568a0. [DOI] [PubMed] [Google Scholar]
  39. Spruyt L. L., Glennie M. J., Beyers A. D., Williams A. F. Signal transduction by the CD2 antigen in T cells and natural killer cells: requirement for expression of a functional T cell receptor or binding of antibody Fc to the Fc receptor, Fc gamma RIIIA (CD16). J Exp Med. 1991 Dec 1;174(6):1407–1415. doi: 10.1084/jem.174.6.1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Stefanová I., Horejsí V., Ansotegui I. J., Knapp W., Stockinger H. GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science. 1991 Nov 15;254(5034):1016–1019. doi: 10.1126/science.1719635. [DOI] [PubMed] [Google Scholar]
  41. Unkeless J. C., Scigliano E., Freedman V. H. Structure and function of human and murine receptors for IgG. Annu Rev Immunol. 1988;6:251–281. doi: 10.1146/annurev.iy.06.040188.001343. [DOI] [PubMed] [Google Scholar]
  42. Weissman A. M., Baniyash M., Hou D., Samelson L. E., Burgess W. H., Klausner R. D. Molecular cloning of the zeta chain of the T cell antigen receptor. Science. 1988 Feb 26;239(4843):1018–1021. doi: 10.1126/science.3278377. [DOI] [PubMed] [Google Scholar]

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