Skip to main content
PMC home page
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
. 1996 Mar 5;93(5):2077–2082. doi: 10.1073/pnas.93.5.2077

Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation.

M C Friedmann 1, T S Migone 1, S M Russell 1, W J Leonard 1
PMCID: PMC39912  PMID: 8700888

Abstract

One of the earliest events induced by interleukin 2 (IL-2) is tyrosine phosphorylation of cellular proteins, including the IL-2 receptor beta chain (IL-2Rbeta). Simultaneous mutation of three tyrosines (Y338, Y392, and Y510) in the IL-2Rbeta cytoplasmic domain abrogated IL-2-induced proliferation, whereas mutation of only Y338 or of Y392 and Y510 inhibited proliferation only partially. While Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. Thus, activation of both Jak-STAT and Shc-coupled signaling pathways requires specific IL-2Rbeta tyrosines that together act in concert to mediate maximal proliferation. In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510, suggesting that the role for this Jak kinase may extend beyond the Jak-STAT pathway.

Full text

PDF
2077

Images in this article

2078Fig. 1
on p.2078
2079Fig. 2
on p.2079
2080Fig. 3
on p.2080
2081Fig. 4
on p.2081

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Asao H., Takeshita T., Nakamura M., Nagata K., Sugamura K. Interleukin 2 (IL-2)-induced tyrosine phosphorylation of IL-2 receptor p75. J Exp Med. 1990 Mar 1;171(3):637–644. doi: 10.1084/jem.171.3.637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bamford R. N., Grant A. J., Burton J. D., Peters C., Kurys G., Goldman C. K., Brennan J., Roessler E., Waldmann T. A. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4940–4944. doi: 10.1073/pnas.91.11.4940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beadling C., Guschin D., Witthuhn B. A., Ziemiecki A., Ihle J. N., Kerr I. M., Cantrell D. A. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J. 1994 Dec 1;13(23):5605–5615. doi: 10.1002/j.1460-2075.1994.tb06898.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Burns L. A., Karnitz L. M., Sutor S. L., Abraham R. T. Interleukin-2-induced tyrosine phosphorylation of p52shc in T lymphocytes. J Biol Chem. 1993 Aug 25;268(24):17659–17661. [PubMed] [Google Scholar]
  6. Danial N. N., Pernis A., Rothman P. B. Jak-STAT signaling induced by the v-abl oncogene. Science. 1995 Sep 29;269(5232):1875–1877. doi: 10.1126/science.7569929. [DOI] [PubMed] [Google Scholar]
  7. Fujii H., Nakagawa Y., Schindler U., Kawahara A., Mori H., Gouilleux F., Groner B., Ihle J. N., Minami Y., Miyazaki T. Activation of Stat5 by interleukin 2 requires a carboxyl-terminal region of the interleukin 2 receptor beta chain but is not essential for the proliferative signal transmission. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5482–5486. doi: 10.1073/pnas.92.12.5482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gaffen S. L., Lai S. Y., Xu W., Gouilleux F., Groner B., Goldsmith M. A., Greene W. C. Signaling through the interleukin 2 receptor beta chain activates a STAT-5-like DNA-binding activity. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7192–7196. doi: 10.1073/pnas.92.16.7192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gilmour K. C., Reich N. C. Receptor to nucleus signaling by prolactin and interleukin 2 via activation of latent DNA-binding factors. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6850–6854. doi: 10.1073/pnas.91.15.6850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Goldsmith M. A., Lai S. Y., Xu W., Amaral M. C., Kuczek E. S., Parent L. J., Mills G. B., Tarr K. L., Longmore G. D., Greene W. C. Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the beta chain and non-tyrosine residues of the gamma c chain. J Biol Chem. 1995 Sep 15;270(37):21729–21737. doi: 10.1074/jbc.270.37.21729. [DOI] [PubMed] [Google Scholar]
  12. Hakimi J., Ha V. C., Lin P., Campbell E., Gately M. K., Tsudo M., Payne P. W., Waldmann T. A., Grant A. J., Tsien W. H. Humanized Mik beta 1, a humanized antibody to the IL-2 receptor beta-chain that acts synergistically with humanized anti-TAC. J Immunol. 1993 Jul 15;151(2):1075–1085. [PubMed] [Google Scholar]
  13. 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]
  14. Heldin C. H. Dimerization of cell surface receptors in signal transduction. Cell. 1995 Jan 27;80(2):213–223. doi: 10.1016/0092-8674(95)90404-2. [DOI] [PubMed] [Google Scholar]
  15. Hou J., Schindler U., Henzel W. J., Wong S. C., McKnight S. L. Identification and purification of human Stat proteins activated in response to interleukin-2. Immunity. 1995 Apr;2(4):321–329. doi: 10.1016/1074-7613(95)90140-x. [DOI] [PubMed] [Google Scholar]
  16. Howe L. R., Weiss A. Multiple kinases mediate T-cell-receptor signaling. Trends Biochem Sci. 1995 Feb;20(2):59–64. doi: 10.1016/s0968-0004(00)88958-6. [DOI] [PubMed] [Google Scholar]
  17. Izquierdo Pastor M., Reif K., Cantrell D. The regulation and function of p21ras during T-cell activation and growth. Immunol Today. 1995 Mar;16(3):159–164. doi: 10.1016/0167-5699(95)80134-0. [DOI] [PubMed] [Google Scholar]
  18. Izquierdo M., Downward J., Otani H., Leonard W. J., Cantrell D. A. Interleukin (IL)-2 activation of p21ras in murine myeloid cells transfected with human IL-2 receptor beta chain. Eur J Immunol. 1992 Mar;22(3):817–821. doi: 10.1002/eji.1830220328. [DOI] [PubMed] [Google Scholar]
  19. Johnston J. A., Kawamura M., Kirken R. A., Chen Y. Q., Blake T. B., Shibuya K., Ortaldo J. R., McVicar D. W., O'Shea J. J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151–153. doi: 10.1038/370151a0. [DOI] [PubMed] [Google Scholar]
  20. Kimura Y., Takeshita T., Kondo M., Ishii N., Nakamura M., Van Snick J., Sugamura K. Sharing of the IL-2 receptor gamma chain with the functional IL-9 receptor complex. Int Immunol. 1995 Jan;7(1):115–120. doi: 10.1093/intimm/7.1.115. [DOI] [PubMed] [Google Scholar]
  21. Kondo M., Takeshita T., Higuchi M., Nakamura M., Sudo T., Nishikawa S., Sugamura K. Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes. Science. 1994 Mar 11;263(5152):1453–1454. doi: 10.1126/science.8128231. [DOI] [PubMed] [Google Scholar]
  22. Kondo M., Takeshita T., Ishii N., Nakamura M., Watanabe S., Arai K., Sugamura K. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993 Dec 17;262(5141):1874–1877. doi: 10.1126/science.8266076. [DOI] [PubMed] [Google Scholar]
  23. Leonard W. J., Noguchi M., Russell S. M., McBride O. W. The molecular basis of X-linked severe combined immunodeficiency: the role of the interleukin-2 receptor gamma chain as a common gamma chain, gamma c. Immunol Rev. 1994 Apr;138:61–86. doi: 10.1111/j.1600-065x.1994.tb00847.x. [DOI] [PubMed] [Google Scholar]
  24. Leonard W. J. The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling. Annu Rev Med. 1996;47:229–239. doi: 10.1146/annurev.med.47.1.229. [DOI] [PubMed] [Google Scholar]
  25. Lin J. X., Migone T. S., Tsang M., Friedmann M., Weatherbee J. A., Zhou L., Yamauchi A., Bloom E. T., Mietz J., John S. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995 Apr;2(4):331–339. doi: 10.1016/1074-7613(95)90141-8. [DOI] [PubMed] [Google Scholar]
  26. Mathews L. S., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991 Jun 14;65(6):973–982. doi: 10.1016/0092-8674(91)90549-e. [DOI] [PubMed] [Google Scholar]
  27. Migone T. S., Lin J. X., Cereseto A., Mulloy J. C., O'Shea J. J., Franchini G., Leonard W. J. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science. 1995 Jul 7;269(5220):79–81. doi: 10.1126/science.7604283. [DOI] [PubMed] [Google Scholar]
  28. Mills G. B., May C., McGill M., Fung M., Baker M., Sutherland R., Greene W. C. Interleukin 2-induced tyrosine phosphorylation. Interleukin 2 receptor beta is tyrosine phosphorylated. J Biol Chem. 1990 Feb 25;265(6):3561–3567. [PubMed] [Google Scholar]
  29. Miyazaki T., Kawahara A., Fujii H., Nakagawa Y., Minami Y., Liu Z. J., Oishi I., Silvennoinen O., Witthuhn B. A., Ihle J. N. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994 Nov 11;266(5187):1045–1047. doi: 10.1126/science.7973659. [DOI] [PubMed] [Google Scholar]
  30. Nakamura Y., Russell S. M., Mess S. A., Friedmann M., Erdos M., Francois C., Jacques Y., Adelstein S., Leonard W. J. Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling. Nature. 1994 May 26;369(6478):330–333. doi: 10.1038/369330a0. [DOI] [PubMed] [Google Scholar]
  31. Nelson B. H., Lord J. D., Greenberg P. D. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature. 1994 May 26;369(6478):333–336. doi: 10.1038/369333a0. [DOI] [PubMed] [Google Scholar]
  32. Nielsen M., Svejgaard A., Skov S., Odum N. Interleukin-2 induces tyrosine phosphorylation and nuclear translocation of stat3 in human T lymphocytes. Eur J Immunol. 1994 Dec;24(12):3082–3086. doi: 10.1002/eji.1830241225. [DOI] [PubMed] [Google Scholar]
  33. Noguchi M., Nakamura Y., Russell S. M., Ziegler S. F., Tsang M., Cao X., Leonard W. J. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993 Dec 17;262(5141):1877–1880. doi: 10.1126/science.8266077. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Otani H., Erdos M., Leonard W. J. Tyrosine kinase(s) regulate apoptosis and bcl-2 expression in a growth factor-dependent cell line. J Biol Chem. 1993 Oct 25;268(30):22733–22736. [PubMed] [Google Scholar]
  36. 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]
  37. Ravichandran K. S., Burakoff S. J. The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J Biol Chem. 1994 Jan 21;269(3):1599–1602. [PubMed] [Google Scholar]
  38. Remillard B., Petrillo R., Maslinski W., Tsudo M., Strom T. B., Cantley L., Varticovski L. Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem. 1991 Aug 5;266(22):14167–14170. [PubMed] [Google Scholar]
  39. 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]
  40. 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]
  41. Russell S. M., Tayebi N., Nakajima H., Riedy M. C., Roberts J. L., Aman M. J., Migone T. S., Noguchi M., Markert M. L., Buckley R. H. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995 Nov 3;270(5237):797–800. doi: 10.1126/science.270.5237.797. [DOI] [PubMed] [Google Scholar]
  42. Satoh T., Minami Y., Kono T., Yamada K., Kawahara A., Taniguchi T., Kaziro Y. Interleukin 2-induced activation of Ras requires two domains of interleukin 2 receptor beta subunit, the essential region for growth stimulation and Lck-binding domain. J Biol Chem. 1992 Dec 15;267(35):25423–25427. [PubMed] [Google Scholar]
  43. Shackelford D. A., Trowbridge I. S. Ligand-stimulated tyrosine phosphorylation of the IL-2 receptor beta chain and receptor-associated proteins. Cell Regul. 1991 Jan;2(1):73–85. doi: 10.1091/mbc.2.1.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sharon M., Gnarra J. R., Leonard W. J. The beta-chain of the IL-2 receptor (p70) is tyrosine-phosphorylated on YT and HUT-102B2 cells. J Immunol. 1989 Oct 15;143(8):2530–2533. [PubMed] [Google Scholar]
  45. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. 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]
  47. Taniguchi T. Cytokine signaling through nonreceptor protein tyrosine kinases. Science. 1995 Apr 14;268(5208):251–255. doi: 10.1126/science.7716517. [DOI] [PubMed] [Google Scholar]
  48. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  49. Yu C. L., Meyer D. J., Campbell G. S., Larner A. C., Carter-Su C., Schwartz J., Jove R. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science. 1995 Jul 7;269(5220):81–83. doi: 10.1126/science.7541555. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES