Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis (original) (raw)

Abstract

By searching a database of expressed sequences, we identified a member of the signal transducers and activators of transcription (Stat) family of proteins. Human and murine full-length cDNA clones were obtained and sequenced. The sequence of the human cDNA was identical to the recently published sequence for interleukin-4 (IL-4)-Stat (J. Hou, U. Schindler, W.J. Henzel, T.C. Ho, M. Brasseur, and S. L. McKnight, Science 265:1701-1706, 1994), while the murine Stat6 amino acid and nucleotide sequences were 83 and 84% identical to the human sequences, respectively. Using Stat6-specific antiserum, we demonstrated that Stat6 is rapidly tyrosine phosphorylated following stimulation of appropriate cell lines with IL-4 or IL-3 but is not detectably phosphorylated following stimulation with IL-2, IL-12, or erythropoietin. In contrast, IL-2, IL-3, and erythropoietin induce the tyrosine phosphorylation of Stat5 while IL-12 uniquely induces the tyrosine phosphorylation of Stat4. Inducible tyrosine phosphorylation of Stat6 requires the membrane-distal region of the IL-4 receptor alpha chain. This region of the receptor is not required for cell growth, demonstrating that Stat6 tyrosine phosphorylation does not contribute to mitogenesis.

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  1. Adams M. D., Kelley J. M., Gocayne J. D., Dubnick M., Polymeropoulos M. H., Xiao H., Merril C. R., Wu A., Olde B., Moreno R. F. Complementary DNA sequencing: expressed sequence tags and human genome project. Science. 1991 Jun 21;252(5013):1651–1656. doi: 10.1126/science.2047873. [DOI] [PubMed] [Google Scholar]
  2. Akira S., Nishio Y., Inoue M., Wang X. J., Wei S., Matsusaka T., Yoshida K., Sudo T., Naruto M., Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994 Apr 8;77(1):63–71. doi: 10.1016/0092-8674(94)90235-6. [DOI] [PubMed] [Google Scholar]
  3. Arai K. I., Lee F., Miyajima A., Miyatake S., Arai N., Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem. 1990;59:783–836. doi: 10.1146/annurev.bi.59.070190.004031. [DOI] [PubMed] [Google Scholar]
  4. Askew D. S., Bartholomew C., Buchberg A. M., Valentine M. B., Jenkins N. A., Copeland N. G., Ihle J. N. His-1 and His-2: identification and chromosomal mapping of two commonly rearranged sites of viral integration in a myeloid leukemia. Oncogene. 1991 Nov;6(11):2041–2047. [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  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. Eilers A., Baccarini M., Horn F., Hipskind R. A., Schindler C., Decker T. A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. Mol Cell Biol. 1994 Feb;14(2):1364–1373. doi: 10.1128/mcb.14.2.1364. [DOI] [PMC free article] [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. 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]
  11. 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]
  12. Graves J. D., Downward J., Izquierdo-Pastor M., Rayter S., Warne P. H., Cantrell D. A. The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes. J Immunol. 1992 Apr 15;148(8):2417–2422. [PubMed] [Google Scholar]
  13. Harada N., Yang G., Miyajima A., Howard M. Identification of an essential region for growth signal transduction in the cytoplasmic domain of the human interleukin-4 receptor. J Biol Chem. 1992 Nov 15;267(32):22752–22758. [PubMed] [Google Scholar]
  14. Hori T., Uchiyama T., Tsudo M., Umadome H., Ohno H., Fukuhara S., Kita K., Uchino H. Establishment of an interleukin 2-dependent human T cell line from a patient with T cell chronic lymphocytic leukemia who is not infected with human T cell leukemia/lymphoma virus. Blood. 1987 Oct;70(4):1069–1072. [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. Ihle J. N. Interleukin-3 and hematopoiesis. Chem Immunol. 1992;51:65–106. doi: 10.1159/000420755. [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. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Silvennoinen O. Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol. 1995;13:369–398. doi: 10.1146/annurev.iy.13.040195.002101. [DOI] [PubMed] [Google Scholar]
  19. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Thierfelder W. E., Kreider B., Silvennoinen O. Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends Biochem Sci. 1994 May;19(5):222–227. doi: 10.1016/0968-0004(94)90026-4. [DOI] [PubMed] [Google Scholar]
  20. Ihle J. N., Witthuhn B., Tang B., Yi T., Quelle F. W. Cytokine receptors and signal transduction. Baillieres Clin Haematol. 1994 Mar;7(1):17–48. doi: 10.1016/s0950-3536(05)80005-8. [DOI] [PubMed] [Google Scholar]
  21. 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]
  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. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989 May 4;339(6219):27–30. doi: 10.1038/339027a0. [DOI] [PubMed] [Google Scholar]
  25. Meyer D. J., Campbell G. S., Cochran B. H., Argetsinger L. S., Larner A. C., Finbloom D. S., Carter-Su C., Schwartz J. Growth hormone induces a DNA binding factor related to the interferon-stimulated 91-kDa transcription factor. J Biol Chem. 1994 Feb 18;269(7):4701–4704. [PubMed] [Google Scholar]
  26. Miura O., D'Andrea A., Kabat D., Ihle J. N. Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis. Mol Cell Biol. 1991 Oct;11(10):4895–4902. doi: 10.1128/mcb.11.10.4895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Morstyn G., Burgess A. W. Hemopoietic growth factors: a review. Cancer Res. 1988 Oct 15;48(20):5624–5637. [PubMed] [Google Scholar]
  30. Pignata C., Sanghera J. S., Cossette L., Pelech S. L., Ritz J. Interleukin-12 induces tyrosine phosphorylation and activation of 44-kD mitogen-activated protein kinase in human T cells. Blood. 1994 Jan 1;83(1):184–190. [PubMed] [Google Scholar]
  31. Quelle F. W., Sato N., Witthuhn B. A., Inhorn R. C., Eder M., Miyajima A., Griffin J. D., Ihle J. N. JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol. 1994 Jul;14(7):4335–4341. doi: 10.1128/mcb.14.7.4335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Rothman P., Li S. C., Gorham B., Glimcher L., Alt F., Boothby M. Identification of a conserved lipopolysaccharide-plus-interleukin-4-responsive element located at the promoter of germ line epsilon transcripts. Mol Cell Biol. 1991 Nov;11(11):5551–5561. doi: 10.1128/mcb.11.11.5551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Satoh T., Nakafuku M., Miyajima A., Kaziro Y. Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3314–3318. doi: 10.1073/pnas.88.8.3314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schindler C., Kashleva H., Pernis A., Pine R., Rothman P. STF-IL-4: a novel IL-4-induced signal transducing factor. EMBO J. 1994 Mar 15;13(6):1350–1356. doi: 10.1002/j.1460-2075.1994.tb06388.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Seldin D. C., Leder P. Mutational analysis of a critical signaling domain of the human interleukin 4 receptor. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2140–2144. doi: 10.1073/pnas.91.6.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Shuai K., Horvath C. M., Huang L. H., Qureshi S. A., Cowburn D., Darnell J. E., Jr Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 1994 Mar 11;76(5):821–828. doi: 10.1016/0092-8674(94)90357-3. [DOI] [PubMed] [Google Scholar]
  41. Shuai K., Stark G. R., Kerr I. M., Darnell J. E., Jr A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. 1993 Sep 24;261(5129):1744–1746. doi: 10.1126/science.7690989. [DOI] [PubMed] [Google Scholar]
  42. Taniguchi T., Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993 Apr 9;73(1):5–8. doi: 10.1016/0092-8674(93)90152-g. [DOI] [PubMed] [Google Scholar]
  43. Tian S. S., Lamb P., Seidel H. M., Stein R. B., Rosen J. Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. Blood. 1994 Sep 15;84(6):1760–1764. [PubMed] [Google Scholar]
  44. Wakao H., Gouilleux F., Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 1994 May 1;13(9):2182–2191. doi: 10.1002/j.1460-2075.1994.tb06495.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wang L. M., Keegan A. D., Paul W. E., Heidaran M. A., Gutkind J. S., Pierce J. H. IL-4 activates a distinct signal transduction cascade from IL-3 in factor-dependent myeloid cells. EMBO J. 1992 Dec;11(13):4899–4908. doi: 10.1002/j.1460-2075.1992.tb05596.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wang L. M., Myers M. G., Jr, Sun X. J., Aaronson S. A., White M., Pierce J. H. IRS-1: essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells. Science. 1993 Sep 17;261(5128):1591–1594. doi: 10.1126/science.8372354. [DOI] [PubMed] [Google Scholar]
  47. Welham M. J., Dechert U., Leslie K. B., Jirik F., Schrader J. W. Interleukin (IL)-3 and granulocyte/macrophage colony-stimulating factor, but not IL-4, induce tyrosine phosphorylation, activation, and association of SHPTP2 with Grb2 and phosphatidylinositol 3'-kinase. J Biol Chem. 1994 Sep 23;269(38):23764–23768. [PubMed] [Google Scholar]
  48. Welham M. J., Duronio V., Schrader J. W. Interleukin-4-dependent proliferation dissociates p44erk-1, p42erk-2, and p21ras activation from cell growth. J Biol Chem. 1994 Feb 25;269(8):5865–5873. [PubMed] [Google Scholar]
  49. Witthuhn B. A., Quelle F. W., Silvennoinen O., Yi T., Tang B., Miura O., Ihle J. N. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. doi: 10.1016/0092-8674(93)90414-l. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Yamamoto K., Quelle F. W., Thierfelder W. E., Kreider B. L., Gilbert D. J., Jenkins N. A., Copeland N. G., Silvennoinen O., Ihle J. N. Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. Mol Cell Biol. 1994 Jul;14(7):4342–4349. doi: 10.1128/mcb.14.7.4342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Zhong Z., Wen Z., Darnell J. E., Jr Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4806–4810. doi: 10.1073/pnas.91.11.4806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. 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]