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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
. 1993 May 1;90(9):4201–4205. doi: 10.1073/pnas.90.9.4201

Functional coupling of the src-family protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: implications for redundancy and pleiotropism in cytokine signal transduction.

N Kobayashi 1, T Kono 1, M Hatakeyama 1, Y Minami 1, T Miyazaki 1, R M Perlmutter 1, T Taniguchi 1
PMCID: PMC46474  PMID: 8483935

Abstract

The binding of interleukin 2 (IL-2) to the IL-2 receptor (IL-2R) induces a rapid increase in tyrosine phosphorylation of cellular proteins. In a previous study, we have shown that p56lck (lck), a src-family protein tyrosine kinase (src-PTK), physically and functionally associates with the IL-2R beta chain (IL-2R beta). To further investigate a role of src-PTKs in IL-2 signaling, we analyzed a mouse pro-B-cell line, in which lck is not expressed detectably. We observed that in this cell line, IL-2 induces activation of at least two src-PTKs, p59fyn (fyn) and p53/56lyn (lyn). Interestingly, stimulation of this cell line with IL-3 also induces activation of src-PTKs. The activation of fyn or lyn seems to be selective for stimulation with IL-2 or IL-3 since stimulation with IL-6 fails to activate them. Furthermore, we provide evidence for the physical association of fyn with IL-2R beta. Taken together with previous results, our current study suggests that different src-PTKs, each of which is expressed in a cell-type-specific manner, can participate in the IL-2 signal transduction.

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Selected References

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  1. Augustine J. A., Sutor S. L., Abraham R. T. Interleukin 2- and polyomavirus middle T antigen-induced modification of phosphatidylinositol 3-kinase activity in activated T lymphocytes. Mol Cell Biol. 1991 Sep;11(9):4431–4440. doi: 10.1128/mcb.11.9.4431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cooke M. P., Perlmutter R. M. Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol. 1989 Oct;1(1):66–74. [PubMed] [Google Scholar]
  3. Cooper J. A., Sefton B. M., Hunter T. Detection and quantification of phosphotyrosine in proteins. Methods Enzymol. 1983;99:387–402. doi: 10.1016/0076-6879(83)99075-4. [DOI] [PubMed] [Google Scholar]
  4. Cosman D., Cerretti D. P., Larsen A., Park L., March C., Dower S., Gillis S., Urdal D. Cloning, sequence and expression of human interleukin-2 receptor. Nature. 1984 Dec 20;312(5996):768–771. doi: 10.1038/312768a0. [DOI] [PubMed] [Google Scholar]
  5. Doi T., Hatakeyama M., Minamoto S., Kono T., Mori H., Taniguchi T. Human interleukin 2 (IL 2) receptor beta chain allows transduction of IL 2-induced proliferation signal(s) in a murine cell line. Eur J Immunol. 1989 Dec;19(12):2375–2378. doi: 10.1002/eji.1830191229. [DOI] [PubMed] [Google Scholar]
  6. Dymecki S. M., Niederhuber J. E., Desiderio S. V. Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells. Science. 1990 Jan 19;247(4940):332–336. doi: 10.1126/science.2404338. [DOI] [PubMed] [Google Scholar]
  7. Ferris D. K., Willette-Brown J., Ortaldo J. R., Farrar W. L. IL-2 regulation of tyrosine kinase activity is mediated through the p70-75 beta-subunit of the IL-2 receptor. J Immunol. 1989 Aug 1;143(3):870–876. [PubMed] [Google Scholar]
  8. Fung M. R., Scearce R. M., Hoffman J. A., Peffer N. J., Hammes S. R., Hosking J. B., Schmandt R., Kuziel W. A., Haynes B. F., Mills G. B. A tyrosine kinase physically associates with the beta-subunit of the human IL-2 receptor. J Immunol. 1991 Aug 15;147(4):1253–1260. [PubMed] [Google Scholar]
  9. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  10. Hanks S. K., Quinn A. M., Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. doi: 10.1126/science.3291115. [DOI] [PubMed] [Google Scholar]
  11. Hatakeyama M., Kono T., Kobayashi N., Kawahara A., Levin S. D., Perlmutter R. M., Taniguchi T. Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science. 1991 Jun 14;252(5012):1523–1528. doi: 10.1126/science.2047859. [DOI] [PubMed] [Google Scholar]
  12. Hatakeyama M., Mori H., Doi T., Taniguchi T. A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization. Cell. 1989 Dec 1;59(5):837–845. doi: 10.1016/0092-8674(89)90607-7. [DOI] [PubMed] [Google Scholar]
  13. Hatakeyama M., Tsudo M., Minamoto S., Kono T., Doi T., Miyata T., Miyasaka M., Taniguchi T. Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. Science. 1989 May 5;244(4904):551–556. doi: 10.1126/science.2785715. [DOI] [PubMed] [Google Scholar]
  14. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar]
  15. Horak I. D., Gress R. E., Lucas P. J., Horak E. M., Waldmann T. A., Bolen J. B. T-lymphocyte interleukin 2-dependent tyrosine protein kinase signal transduction involves the activation of p56lck. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1996–2000. doi: 10.1073/pnas.88.5.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hsi E. D., Siegel J. N., Minami Y., Luong E. T., Klausner R. D., Samelson L. E. T cell activation induces rapid tyrosine phosphorylation of a limited number of cellular substrates. J Biol Chem. 1989 Jun 25;264(18):10836–10842. [PubMed] [Google Scholar]
  17. Kawakami T., Kawakami Y., Aaronson S. A., Robbins K. C. Acquisition of transforming properties by FYN, a normal SRC-related human gene. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3870–3874. doi: 10.1073/pnas.85.11.3870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kono T., Doi T., Yamada G., Hatakeyama M., Minamoto S., Tsudo M., Miyasaka M., Miyata T., Taniguchi T. Murine interleukin 2 receptor beta chain: dysregulated gene expression in lymphoma line EL-4 caused by a promoter insertion. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1806–1810. doi: 10.1073/pnas.87.5.1806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Koyasu S., Tojo A., Miyajima A., Akiyama T., Kasuga M., Urabe A., Schreurs J., Arai K., Takaku F., Yahara I. Interleukin 3-specific tyrosine phosphorylation of a membrane glycoprotein of Mr 150,000 in multi-factor-dependent myeloid cell lines. EMBO J. 1987 Dec 20;6(13):3979–3984. doi: 10.1002/j.1460-2075.1987.tb02740.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Leonard W. J., Depper J. M., Crabtree G. R., Rudikoff S., Pumphrey J., Robb R. J., Krönke M., Svetlik P. B., Peffer N. J., Waldmann T. A. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):626–631. doi: 10.1038/311626a0. [DOI] [PubMed] [Google Scholar]
  21. Louie R. R., King C. S., MacAuley A., Marth J. D., Perlmutter R. M., Eckhart W., Cooper J. A. p56lck protein-tyrosine kinase is cytoskeletal and does not bind to polyomavirus middle T antigen. J Virol. 1988 Dec;62(12):4673–4679. doi: 10.1128/jvi.62.12.4673-4679.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Marth J. D., Peet R., Krebs E. G., Perlmutter R. M. A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA. Cell. 1985 Dec;43(2 Pt 1):393–404. doi: 10.1016/0092-8674(85)90169-2. [DOI] [PubMed] [Google Scholar]
  23. Merida I., Gaulton G. N. Protein tyrosine phosphorylation associated with activation of the interleukin 2 receptor. J Biol Chem. 1990 Apr 5;265(10):5690–5694. [PubMed] [Google Scholar]
  24. Minami Y., Kono T., Yamada K., Kobayashi N., Kawahara A., Perlmutter R. M., Taniguchi T. Association of p56lck with IL-2 receptor beta chain is critical for the IL-2-induced activation of p56lck. EMBO J. 1993 Feb;12(2):759–768. doi: 10.1002/j.1460-2075.1993.tb05710.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Murakami M., Narazaki M., Hibi M., Yawata H., Yasukawa K., Hamaguchi M., Taga T., Kishimoto T. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11349–11353. doi: 10.1073/pnas.88.24.11349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nikaido T., Shimizu A., Ishida N., Sabe H., Teshigawara K., Maeda M., Uchiyama T., Yodoi J., Honjo T. Molecular cloning of cDNA encoding human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):631–635. doi: 10.1038/311631a0. [DOI] [PubMed] [Google Scholar]
  27. Okamoto Y., Minamoto S., Shimizu K., Mogami H., Taniguchi T. Interleukin 2 receptor beta chain expressed in an oligodendroglioma line binds interleukin 2 and delivers growth signal. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6584–6588. doi: 10.1073/pnas.87.17.6584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Otani H., Siegel J. P., Erdos M., Gnarra J. R., Toledano M. B., Sharon M., Mostowski H., Feinberg M. B., Pierce J. H., Leonard W. J. Interleukin (IL)-2 and IL-3 induce distinct but overlapping responses in murine IL-3-dependent 32D cells transduced with human IL-2 receptor beta chain: involvement of tyrosine kinase(s) other than p56lck. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2789–2793. doi: 10.1073/pnas.89.7.2789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Perlmutter R. M., Marth J. D., Ziegler S. F., Garvin A. M., Pawar S., Cooke M. P., Abraham K. M. Specialized protein tyrosine kinase proto-oncogenes in hematopoietic cells. Biochim Biophys Acta. 1989 Feb;948(3):245–262. doi: 10.1016/0304-419x(89)90001-2. [DOI] [PubMed] [Google Scholar]
  30. Sabe H., Kuno J., Koromilas A., Saito Y., Kinashi T., Ueda M., Takamatsu T., Hamaguchi M., Kawakami T., Honjo T. Comparison of protein tyrosine phosphorylation and morphological changes induced by IL-2 and IL-3. Int Immunol. 1991 Nov;3(11):1137–1148. doi: 10.1093/intimm/3.11.1137. [DOI] [PubMed] [Google Scholar]
  31. Saltzman E. M., Thom R. R., Casnellie J. E. Activation of a tyrosine protein kinase is an early event in the stimulation of T lymphocytes by interleukin-2. J Biol Chem. 1988 May 25;263(15):6956–6959. [PubMed] [Google Scholar]
  32. Shibuya H., Yoneyama M., Ninomiya-Tsuji J., Matsumoto K., Taniguchi T. IL-2 and EGF receptors stimulate the hematopoietic cell cycle via different signaling pathways: demonstration of a novel role for c-myc. Cell. 1992 Jul 10;70(1):57–67. doi: 10.1016/0092-8674(92)90533-i. [DOI] [PubMed] [Google Scholar]
  33. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  34. Takeshita T., Asao H., Ohtani K., Ishii N., Kumaki S., Tanaka N., Munakata H., Nakamura M., Sugamura K. Cloning of the gamma chain of the human IL-2 receptor. Science. 1992 Jul 17;257(5068):379–382. doi: 10.1126/science.1631559. [DOI] [PubMed] [Google Scholar]
  35. Takeshita T., Goto Y., Tada K., Nagata K., Asao H., Sugamura K. Monoclonal antibody defining a molecule possibly identical to the p75 subunit of interleukin 2 receptor. J Exp Med. 1989 Apr 1;169(4):1323–1332. doi: 10.1084/jem.169.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Taniguchi T., Matsui H., Fujita T., Hatakeyama M., Kashima N., Fuse A., Hamuro J., Nishi-Takaoka C., Yamada G. Molecular analysis of the interleukin-2 system. Immunol Rev. 1986 Aug;92:121–133. doi: 10.1111/j.1600-065x.1986.tb01497.x. [DOI] [PubMed] [Google Scholar]
  37. Torigoe T., Saragovi H. U., Reed J. C. Interleukin 2 regulates the activity of the lyn protein-tyrosine kinase in a B-cell line. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2674–2678. doi: 10.1073/pnas.89.7.2674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tsudo M., Kitamura F., Miyasaka M. Characterization of the interleukin 2 receptor beta chain using three distinct monoclonal antibodies. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1982–1986. doi: 10.1073/pnas.86.6.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Veillette A., Horak I. D., Bolen J. B. Post-translational alterations of the tyrosine kinase p56lck in response to activators of protein kinase C. Oncogene Res. 1988 May;2(4):385–401. [PubMed] [Google Scholar]
  40. Veillette A., Horak I. D., Horak E. M., Bookman M. A., Bolen J. B. Alterations of the lymphocyte-specific protein tyrosine kinase (p56lck) during T-cell activation. Mol Cell Biol. 1988 Oct;8(10):4353–4361. doi: 10.1128/mcb.8.10.4353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Voronova A. F., Sefton B. M. Expression of a new tyrosine protein kinase is stimulated by retrovirus promoter insertion. Nature. 1986 Feb 20;319(6055):682–685. doi: 10.1038/319682a0. [DOI] [PubMed] [Google Scholar]
  42. Waldmann T. A. The multi-subunit interleukin-2 receptor. Annu Rev Biochem. 1989;58:875–911. doi: 10.1146/annurev.bi.58.070189.004303. [DOI] [PubMed] [Google Scholar]
  43. Wang J. Y. Isolation of antibodies for phosphotyrosine by immunization with a v-abl oncogene-encoded protein. Mol Cell Biol. 1985 Dec;5(12):3640–3643. doi: 10.1128/mcb.5.12.3640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yamanashi Y., Fukui Y., Wongsasant B., Kinoshita Y., Ichimori Y., Toyoshima K., Yamamoto T. Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1118–1122. doi: 10.1073/pnas.89.3.1118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yi T. L., Bolen J. B., Ihle J. N. Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino terminus. Mol Cell Biol. 1991 May;11(5):2391–2398. doi: 10.1128/mcb.11.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]

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