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. 1996 May 1;315(Pt 3):767–774. doi: 10.1042/bj3150767

Growth inhibition signalled through the interleukin-4/interleukin-13 receptor complex is associated with tyrosine phosphorylation of insulin receptor substrate-1.

B Schnyder 1, H Lahm 1, G Woerly 1, N Odartchenko 1, B Ryffel 1, B D Car 1
PMCID: PMC1217273  PMID: 8645156

Abstract

Induction of growth inhibition in human colorectal carcinoma cell lines by interleukin (IL)-4 and IL-13 was associated with the neophosphorylation of a 170 kDa cellular protein, identified as insulin receptor substrate-1 (IRS-1) by immunoprecipitation. Tyrosine phosphorylation of IRS-I was also induced by insulin and insulin-like growth factor I. Sublines of colorectal carcinoma cells unresponsive to growth modulation by IL-4, IL-13 or insulin-like growth factor I-induced growth did not phosphorylate IRS-1. A functional, multimeric IL-4 receptor complex was present on all carcinoma cell lines with a subunit composition of 65 kDa, 75 kDa and the previously characterized 130 kDa band as demonstrated by affinity cross-link with 126I labelled IL-4. The 65 kDa subunit is novel whereas the 75 kDa band represents the common IL-2 receptor gama-chain the novel 65 kDa receptor was present as a double band and bound primarily 125I-labelled IL-13. The present study demonstrates the involvement of a novel chain other than the gama-chain in the receptor complexes of IL-4 and IL-13 and and post-receptor tyrosine phosphorylation of IRS-1. The association of IRS-1 with growth inhibitory signals in carcinoma cells suggests a novel mechanism of tumour growth control.

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Selected References

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  1. Araki E., Lipes M. A., Patti M. E., Brüning J. C., Haag B., 3rd, Johnson R. S., Kahn C. R. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994 Nov 10;372(6502):186–190. doi: 10.1038/372186a0. [DOI] [PubMed] [Google Scholar]
  2. Boussiotis V. A., Barber D. L., Nakarai T., Freeman G. J., Gribben J. G., Bernstein G. M., D'Andrea A. D., Ritz J., Nadler L. M. Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor. Science. 1994 Nov 11;266(5187):1039–1042. doi: 10.1126/science.7973657. [DOI] [PubMed] [Google Scholar]
  3. DiSanto J. P., Müller W., Guy-Grand D., Fischer A., Rajewsky K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):377–381. doi: 10.1073/pnas.92.2.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Estes M. L., Iwasaki K., Jacobs B. S., Barna B. P. Interleukin-4 down-regulates adult human astrocyte DNA synthesis and proliferation. Am J Pathol. 1993 Aug;143(2):337–341. [PMC free article] [PubMed] [Google Scholar]
  5. Foxwell B. M., Woerly G., Ryffel B. Identification of interleukin 4 receptor-associated proteins and expression of both high- and low-affinity binding on human lymphoid cells. Eur J Immunol. 1989 Sep;19(9):1637–1641. doi: 10.1002/eji.1830190918. [DOI] [PubMed] [Google Scholar]
  6. Galizzi J. P., Castle B., Djossou O., Harada N., Cabrillat H., Yahia S. A., Barrett R., Howard M., Banchereau J. Purification of a 130-kDa T cell glycoprotein that binds human interleukin 4 with high affinity. J Biol Chem. 1990 Jan 5;265(1):439–444. [PubMed] [Google Scholar]
  7. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hou J., Schindler U., Henzel W. J., Ho T. C., Brasseur M., McKnight S. L. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. doi: 10.1126/science.8085155. [DOI] [PubMed] [Google Scholar]
  9. Keegan A. D., Johnston J. A., Tortolani P. J., McReynolds L. J., Kinzer C., O'Shea J. J., Paul W. E. Similarities and differences in signal transduction by interleukin 4 and interleukin 13: analysis of Janus kinase activation. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7681–7685. doi: 10.1073/pnas.92.17.7681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Keegan A. D., Nelms K., Wang L. M., Pierce J. H., Paul W. E. Interleukin 4 receptor: signaling mechanisms. Immunol Today. 1994 Sep;15(9):423–432. doi: 10.1016/0167-5699(94)90272-0. [DOI] [PubMed] [Google Scholar]
  11. Keegan A. D., Nelms K., White M., Wang L. M., Pierce J. H., Paul W. E. An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell. 1994 Mar 11;76(5):811–820. doi: 10.1016/0092-8674(94)90356-5. [DOI] [PubMed] [Google Scholar]
  12. Keegan A. D., Pierce J. H. The interleukin-4 receptor: signal transduction by a hematopoietin receptor. J Leukoc Biol. 1994 Feb;55(2):272–279. doi: 10.1002/jlb.55.2.272. [DOI] [PubMed] [Google Scholar]
  13. Kotanides H., Reich N. C. Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science. 1993 Nov 19;262(5137):1265–1267. doi: 10.1126/science.7694370. [DOI] [PubMed] [Google Scholar]
  14. Kuhné M. R., Zhao Z., Rowles J., Lavan B. E., Shen S. H., Fischer E. H., Lienhard G. E. Dephosphorylation of insulin receptor substrate 1 by the tyrosine phosphatase PTP2C. J Biol Chem. 1994 Jun 3;269(22):15833–15837. [PubMed] [Google Scholar]
  15. Lahm H., Amstad P., Wyniger J., Yilmaz A., Fischer J. R., Schreyer M., Givel J. C. Blockade of the insulin-like growth-factor-I receptor inhibits growth of human colorectal cancer cells: evidence of a functional IGF-II-mediated autocrine loop. Int J Cancer. 1994 Aug 1;58(3):452–459. doi: 10.1002/ijc.2910580325. [DOI] [PubMed] [Google Scholar]
  16. Lahm H., Schnyder B., Wyniger J., Borbenyi Z., Yilmaz A., Car B. D., Fischer J. R., Givel J. C., Ryffel B. Growth inhibition of human colorectal-carcinoma cells by interleukin-4 and expression of functional interleukin-4 receptors. Int J Cancer. 1994 Nov 1;59(3):440–447. doi: 10.1002/ijc.2910590325. [DOI] [PubMed] [Google Scholar]
  17. Lahm H., Suardet L., Laurent P. L., Fischer J. R., Ceyhan A., Givel J. C., Odartchenko N. Growth regulation and co-stimulation of human colorectal cancer cell lines by insulin-like growth factor I, II and transforming growth factor alpha. Br J Cancer. 1992 Mar;65(3):341–346. doi: 10.1038/bjc.1992.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lee F., Yokota T., Otsuka T., Meyerson P., Villaret D., Coffman R., Mosmann T., Rennick D., Roehm N., Smith C. Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2061–2065. doi: 10.1073/pnas.83.7.2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Malabarba M. G., Kirken R. A., Rui H., Koettnitz K., Kawamura M., O'Shea J. J., Kalthoff F. S., Farrar W. L. Activation of JAK3, but not JAK1, is critical to interleukin-4 (IL4) stimulated proliferation and requires a membrane-proximal region of IL4 receptor alpha. J Biol Chem. 1995 Apr 21;270(16):9630–9637. doi: 10.1074/jbc.270.16.9630. [DOI] [PubMed] [Google Scholar]
  20. Minty A., Chalon P., Derocq J. M., Dumont X., Guillemot J. C., Kaghad M., Labit C., Leplatois P., Liauzun P., Miloux B. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993 Mar 18;362(6417):248–250. doi: 10.1038/362248a0. [DOI] [PubMed] [Google Scholar]
  21. Mire-Sluis A. R., Thorpe R. Interleukin-4 proliferative signal transduction involves the activation of a tyrosine-specific phosphatase and the dephosphorylation of an 80-kDa protein. J Biol Chem. 1991 Sep 25;266(27):18113–18118. [PubMed] [Google Scholar]
  22. Miyajima A., Kitamura T., Harada N., Yokota T., Arai K. Cytokine receptors and signal transduction. Annu Rev Immunol. 1992;10:295–331. doi: 10.1146/annurev.iy.10.040192.001455. [DOI] [PubMed] [Google Scholar]
  23. Morla A. O., Schreurs J., Miyajima A., Wang J. Y. Hematopoietic growth factors activate the tyrosine phosphorylation of distinct sets of proteins in interleukin-3-dependent murine cell lines. Mol Cell Biol. 1988 May;8(5):2214–2218. doi: 10.1128/mcb.8.5.2214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morrone G., Bond H. M., Cuomo C., Agosti V., Petrella A., Pagnano A. M., Della Corte A., Marasco O., Venuta S. Differential regulation of the expression of interleukin-2 receptor gamma-chain during the in vitro differentiation of human myeloid cells. Biochem J. 1995 Jun 15;308(Pt 3):909–914. doi: 10.1042/bj3080909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moser R., Fehr J., Bruijnzeel P. L. IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals. J Immunol. 1992 Aug 15;149(4):1432–1438. [PubMed] [Google Scholar]
  26. Noguchi M., Yi H., Rosenblatt H. M., Filipovich A. H., Adelstein S., Modi W. S., McBride O. W., Leonard W. J. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147–157. doi: 10.1016/0092-8674(93)90167-o. [DOI] [PubMed] [Google Scholar]
  27. Obiri N. I., Debinski W., Leonard W. J., Puri R. K. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common gamma chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J Biol Chem. 1995 Apr 14;270(15):8797–8804. doi: 10.1074/jbc.270.15.8797. [DOI] [PubMed] [Google Scholar]
  28. Obiri N. I., Hillman G. G., Haas G. P., Sud S., Puri R. K. Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. J Clin Invest. 1993 Jan;91(1):88–93. doi: 10.1172/JCI116205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Russell S. M., Johnston J. A., Noguchi M., Kawamura M., Bacon C. M., Friedmann M., Berg M., McVicar D. W., Witthuhn B. A., Silvennoinen O. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994 Nov 11;266(5187):1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  30. Russell S. M., Keegan A. D., Harada N., Nakamura Y., Noguchi M., Leland P., Friedmann M. C., Miyajima A., Puri R. K., Paul W. E. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880–1883. doi: 10.1126/science.8266078. [DOI] [PubMed] [Google Scholar]
  31. Schleimer R. P., Sterbinsky S. A., Kaiser J., Bickel C. A., Klunk D. A., Tomioka K., Newman W., Luscinskas F. W., Gimbrone M. A., Jr, McIntyre B. W. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J Immunol. 1992 Feb 15;148(4):1086–1092. [PubMed] [Google Scholar]
  32. Smerz-Bertling C., Duschl A. Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor. J Biol Chem. 1995 Jan 13;270(2):966–970. doi: 10.1074/jbc.270.2.966. [DOI] [PubMed] [Google Scholar]
  33. Sun X. J., Miralpeix M., Myers M. G., Jr, Glasheen E. M., Backer J. M., Kahn C. R., White M. F. Expression and function of IRS-1 in insulin signal transmission. J Biol Chem. 1992 Nov 5;267(31):22662–22672. [PubMed] [Google Scholar]
  34. Sun X. J., Wang L. M., Zhang Y., Yenush L., Myers M. G., Jr, Glasheen E., Lane W. S., Pierce J. H., White M. F. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 14;377(6545):173–177. doi: 10.1038/377173a0. [DOI] [PubMed] [Google Scholar]
  35. Tamemoto H., Kadowaki T., Tobe K., Yagi T., Sakura H., Hayakawa T., Terauchi Y., Ueki K., Kaburagi Y., Satoh S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994 Nov 10;372(6502):182–186. doi: 10.1038/372182a0. [DOI] [PubMed] [Google Scholar]
  36. Toi M., Harris A. L., Bicknell R. Interleukin-4 is a potent mitogen for capillary endothelium. Biochem Biophys Res Commun. 1991 Feb 14;174(3):1287–1293. doi: 10.1016/0006-291x(91)91561-p. [DOI] [PubMed] [Google Scholar]
  37. Totpal K., Aggarwal B. B. Interleukin 4 potentiates the antiproliferative effects of tumor necrosis factor on various tumor cell lines. Cancer Res. 1991 Aug 15;51(16):4266–4270. [PubMed] [Google Scholar]
  38. Vita N., Lefort S., Laurent P., Caput D., Ferrara P. Characterization and comparison of the interleukin 13 receptor with the interleukin 4 receptor on several cell types. J Biol Chem. 1995 Feb 24;270(8):3512–3517. doi: 10.1074/jbc.270.8.3512. [DOI] [PubMed] [Google Scholar]
  39. Wang L. M., Keegan A. D., Li W., Lienhard G. E., Pacini S., Gutkind J. S., Myers M. G., Jr, Sun X. J., White M. F., Aaronson S. A. Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4032–4036. doi: 10.1073/pnas.90.9.4032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Welham M. J., Learmonth L., Bone H., Schrader J. W. Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. J Biol Chem. 1995 May 19;270(20):12286–12296. doi: 10.1074/jbc.270.20.12286. [DOI] [PubMed] [Google Scholar]
  41. Yin T., Tsang M. L., Yang Y. C. JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes. J Biol Chem. 1994 Oct 28;269(43):26614–26617. [PubMed] [Google Scholar]
  42. Zurawski S. M., Chomarat P., Djossou O., Bidaud C., McKenzie A. N., Miossec P., Banchereau J., Zurawski G. The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J Biol Chem. 1995 Jun 9;270(23):13869–13878. doi: 10.1074/jbc.270.23.13869. [DOI] [PubMed] [Google Scholar]
  43. Zurawski S. M., Vega F., Jr, Huyghe B., Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 1993 Jul;12(7):2663–2670. doi: 10.1002/j.1460-2075.1993.tb05927.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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