Skip to main content
NCBI 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
. 1995 Sep 12;92(19):8705–8709. doi: 10.1073/pnas.92.19.8705

Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.

J A Johnston 1, C M Bacon 1, D S Finbloom 1, R C Rees 1, D Kaplan 1, K Shibuya 1, J R Ortaldo 1, S Gupta 1, Y Q Chen 1, J D Giri 1, et al.
PMCID: PMC41035  PMID: 7568001

Abstract

The cytokines interleukin 2 (IL-2) and IL-15 have similar biological effects on T cells and bind common hematopoietin receptor subunits. Pathways that involve Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to be important for hematopoietin receptor signaling. In this study we identify the STAT proteins activated by IL-2 and IL-15 in human T cells. IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5, and DNA-binding complexes containing STAT3 and STAT5 were rapidly activated by these cytokines in T cells. IL-4 induced tyrosine phosphorylation and activation of STAT3 but not STAT5. JAK1 and JAK3 were tyrosine-phosphorylated in response to IL-2 and IL-15. Hence, the JAK and STAT molecules that are activated in response to IL-2 and IL-15 are similar but differ from those induced by IL-4. These observations identify the STAT proteins activated by IL-2 and IL-15 and therefore define signaling pathways by which these T-cell growth factors may regulate gene transcription.

Full text

PDF
8705

Images in this article

8706Fig. 1
on p.8706
8707Fig. 2
on p.8707
8708Fig. 3
on p.8708

Selected References

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

  1. Bacon C. M., McVicar D. W., Ortaldo J. R., Rees R. C., O'Shea J. J., Johnston J. A. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med. 1995 Jan 1;181(1):399–404. doi: 10.1084/jem.181.1.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bacon C. M., Petricoin E. F., 3rd, Ortaldo J. R., Rees R. C., Larner A. C., Johnston J. A., O'Shea J. J. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7307–7311. doi: 10.1073/pnas.92.16.7307. [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. Burdon T. G., Demmer J., Clark A. J., Watson C. J. The mammary factor MPBF is a prolactin-induced transcriptional regulator which binds to STAT factor recognition sites. FEBS Lett. 1994 Aug 22;350(2-3):177–182. doi: 10.1016/0014-5793(94)00757-8. [DOI] [PubMed] [Google Scholar]
  5. Carson W. E., Giri J. G., Lindemann M. J., Linett M. L., Ahdieh M., Paxton R., Anderson D., Eisenmann J., Grabstein K., Caligiuri M. A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994 Oct 1;180(4):1395–1403. doi: 10.1084/jem.180.4.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  7. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  8. Dorsch M., Hock H., Diamantstein T. Gene transfer of the interleukin (IL)-2 receptor beta chain into an IL-7-dependent pre-B cell line permits IL-2-driven proliferation: tyrosine phosphorylation of Shc is induced by IL-2 but not IL-7. Eur J Immunol. 1994 Sep;24(9):2049–2054. doi: 10.1002/eji.1830240917. [DOI] [PubMed] [Google Scholar]
  9. Finbloom D. S., Petricoin E. F., 3rd, Hackett R. H., David M., Feldman G. M., Igarashi K., Fibach E., Weber M. J., Thorner M. O., Silva C. M. Growth hormone and erythropoietin differentially activate DNA-binding proteins by tyrosine phosphorylation. Mol Cell Biol. 1994 Mar;14(3):2113–2118. doi: 10.1128/mcb.14.3.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. 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]
  13. Gouilleux F., Wakao H., Mundt M., Groner B. Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. EMBO J. 1994 Sep 15;13(18):4361–4369. doi: 10.1002/j.1460-2075.1994.tb06756.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Ihle J. N., Kerr I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995 Feb;11(2):69–74. doi: 10.1016/s0168-9525(00)89000-9. [DOI] [PubMed] [Google Scholar]
  18. Improta T., Schindler C., Horvath C. M., Kerr I. M., Stark G. R., Darnell J. E., Jr Transcription factor ISGF-3 formation requires phosphorylated Stat91 protein, but Stat113 protein is phosphorylated independently of Stat91 protein. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4776–4780. doi: 10.1073/pnas.91.11.4776. [DOI] [PMC free article] [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. Kawamura M., McVicar D. W., Johnston J. A., Blake T. B., Chen Y. Q., Lal B. K., Lloyd A. R., Kelvin D. J., Staples J. E., Ortaldo J. R. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6374–6378. doi: 10.1073/pnas.91.14.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Larner A. C., David M., Feldman G. M., Igarashi K., Hackett R. H., Webb D. S., Sweitzer S. M., Petricoin E. F., 3rd, Finbloom D. S. Tyrosine phosphorylation of DNA binding proteins by multiple cytokines. Science. 1993 Sep 24;261(5129):1730–1733. doi: 10.1126/science.8378773. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Müller M., Laxton C., Briscoe J., Schindler C., Improta T., Darnell J. E., Jr, Stark G. R., Kerr I. M. Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways. EMBO J. 1993 Nov;12(11):4221–4228. doi: 10.1002/j.1460-2075.1993.tb06106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  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. Pearse R. N., Feinman R., Ravetch J. V. Characterization of the promoter of the human gene encoding the high-affinity IgG receptor: transcriptional induction by gamma-interferon is mediated through common DNA response elements. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11305–11309. doi: 10.1073/pnas.88.24.11305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pine R., Canova A., Schindler C. Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF-1 promoter to mediate induction by IFN alpha and IFN gamma, and is likely to autoregulate the p91 gene. EMBO J. 1994 Jan 1;13(1):158–167. doi: 10.1002/j.1460-2075.1994.tb06245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rothman P., Kreider B., Azam M., Levy D., Wegenka U., Eilers A., Decker T., Horn F., Kashleva H., Ihle J. Cytokines and growth factors signal through tyrosine phosphorylation of a family of related transcription factors. Immunity. 1994 Sep;1(6):457–468. doi: 10.1016/1074-7613(94)90088-4. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. 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]
  32. Schindler C., Shuai K., Prezioso V. R., Darnell J. E., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. doi: 10.1126/science.1496401. [DOI] [PubMed] [Google Scholar]
  33. Stahl N., Farruggella T. J., Boulton T. G., Zhong Z., Darnell J. E., Jr, Yancopoulos G. D. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995 Mar 3;267(5202):1349–1353. doi: 10.1126/science.7871433. [DOI] [PubMed] [Google Scholar]
  34. Takahashi T., Shirasawa T. Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases. FEBS Lett. 1994 Apr 4;342(2):124–128. doi: 10.1016/0014-5793(94)80485-0. [DOI] [PubMed] [Google Scholar]
  35. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Welham M. J., Duronio V., Leslie K. B., Bowtell D., Schrader J. W. Multiple hemopoietins, with the exception of interleukin-4, induce modification of Shc and mSos1, but not their translocation. J Biol Chem. 1994 Aug 19;269(33):21165–21176. [PubMed] [Google Scholar]
  38. 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]
  39. Zhong Z., Wen Z., Darnell J. E., Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994 Apr 1;264(5155):95–98. doi: 10.1126/science.8140422. [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