• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Sep 1996; 16(9): 4710–4716.
PMCID: PMC231471

A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9.

Abstract

Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor gamma chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines (of other receptors activating STAT3 and STAT5 were observed. Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses.

Full Text

The Full Text of this article is available as a PDF (1.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Coffer PJ, Kruijer W. EGF receptor deletions define a region specifically mediating STAT transcription factor activation. Biochem Biophys Res Commun. 1995 May 5;210(1):74–81. [PubMed]
  • Cohen GB, Ren R, Baltimore D. Modular binding domains in signal transduction proteins. Cell. 1995 Jan 27;80(2):237–248. [PubMed]
  • Damen JE, Wakao H, Miyajima A, Krosl J, Humphries RK, Cutler RL, Krystal G. Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J. 1995 Nov 15;14(22):5557–5568. [PMC free article] [PubMed]
  • De Smet C, Courtois SJ, Faraoni I, Lurquin C, Szikora JP, De Backer O, Boon T. Involvement of two Ets binding sites in the transcriptional activation of the MAGE1 gene. Immunogenetics. 1995;42(4):282–290. [PubMed]
  • Druez C, Coulie P, Uyttenhove C, Van Snick J. Functional and biochemical characterization of mouse P40/IL-9 receptors. J Immunol. 1990 Oct 15;145(8):2494–2499. [PubMed]
  • Fujii H, Nakagawa Y, Schindler U, Kawahara A, Mori H, Gouilleux F, Groner B, Ihle JN, Minami Y, Miyazaki T, et al. 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. [PMC free article] [PubMed]
  • Greenlund AC, Farrar MA, Viviano BL, Schreiber RD. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 1994 Apr 1;13(7):1591–1600. [PMC free article] [PubMed]
  • Gruss HJ, Brach MA, Drexler HG, Bross KJ, Herrmann F. Interleukin 9 is expressed by primary and cultured Hodgkin and Reed-Sternberg cells. Cancer Res. 1992 Feb 15;52(4):1026–1031. [PubMed]
  • 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]
  • Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. [PubMed]
  • Hou J, Schindler U, Henzel WJ, Wong SC, McKnight SL. Identification and purification of human Stat proteins activated in response to interleukin-2. Immunity. 1995 Apr;2(4):321–329. [PubMed]
  • Houssiau FA, Renauld JC, Stevens M, Lehmann F, Lethe B, Coulie PG, Van Snick J. Human T cell lines and clones respond to IL-9. J Immunol. 1993 Apr 1;150(7):2634–2640. [PubMed]
  • Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995 Feb;11(2):69–74. [PubMed]
  • Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE, Jr, Murphy KM. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med. 1995 May 1;181(5):1755–1762. [PMC free article] [PubMed]
  • Keegan AD, Nelms K, Wang LM, Pierce JH, Paul WE. Interleukin 4 receptor: signaling mechanisms. Immunol Today. 1994 Sep;15(9):423–432. [PubMed]
  • 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. [PubMed]
  • Kirken RA, Rui H, Malabarba MG, Howard OM, Kawamura M, O'Shea JJ, Farrar WL. Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor beta-chain. Cytokine. 1995 Oct;7(7):689–700. [PubMed]
  • Lebrun JJ, Ali S, Goffin V, Ullrich A, Kelly PA. A single phosphotyrosine residue of the prolactin receptor is responsible for activation of gene transcription. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):4031–4035. [PMC free article] [PubMed]
  • Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S, et al. 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. [PubMed]
  • Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, Noel H, Kadin M, Mueller-Hermelink HK, Van Snick J, et al. Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma. Blood. 1991 Sep 1;78(5):1311–1317. [PubMed]
  • Mizushima S, Nagata S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 1990 Sep 11;18(17):5322–5322. [PMC free article] [PubMed]
  • Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A. Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. EMBO J. 1996 May 15;15(10):2425–2433. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Palacios R, Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985 Jul;41(3):727–734. [PubMed]
  • Renauld JC, Druez C, Kermouni A, Houssiau F, Uyttenhove C, Van Roost E, Van Snick J. Expression cloning of the murine and human interleukin 9 receptor cDNAs. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5690–5694. [PMC free article] [PubMed]
  • Renauld JC, Houssiau F, Louahed J, Vink A, Van Snick J, Uyttenhove C. Interleukin-9. Adv Immunol. 1993;54:79–97. [PubMed]
  • Renauld JC, Kermouni A, Vink A, Louahed J, Van Snick J. Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis. J Leukoc Biol. 1995 Mar;57(3):353–360. [PubMed]
  • Renauld JC, van der Lugt N, Vink A, van Roon M, Godfraind C, Warnier G, Merz H, Feller A, Berns A, Van Snick J. Thymic lymphomas in interleukin 9 transgenic mice. Oncogene. 1994 May;9(5):1327–1332. [PubMed]
  • Renauld JC, Vink A, Louahed J, Van Snick J. Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood. 1995 Mar 1;85(5):1300–1305. [PubMed]
  • Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O, et al. 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. [PubMed]
  • Schreiber E, Matthias P, Müller MM, Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. [PMC free article] [PubMed]
  • Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE, Jr, Yancopoulos GD. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995 Mar 3;267(5202):1349–1353. [PubMed]
  • Taniguchi T. Cytokine signaling through nonreceptor protein tyrosine kinases. Science. 1995 Apr 14;268(5208):251–255. [PubMed]
  • Uyttenhove C, Simpson RJ, Van Snick J. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6934–6938. [PMC free article] [PubMed]
  • Vink A, Renauld JC, Warnier G, Van Snick J. Interleukin-9 stimulates in vitro growth of mouse thymic lymphomas. Eur J Immunol. 1993 May;23(5):1134–1138. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Yin T, Keller SR, Quelle FW, Witthuhn BA, Tsang ML, Lienhard GE, Ihle JN, Yang YC. Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases. J Biol Chem. 1995 Sep 1;270(35):20497–20502. [PubMed]
  • Yin T, Tsang ML, Yang YC. 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]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM
    OMIM record citing PubMed
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...