Skip to main content
SpringerLink
Log in

Interferon signal transduction

  • Published:
Biotherapy

Abstract

The interferon signal transduction pathway initiates at a cell surface receptor and mediates the activation of target genes in the nucleus. The binding of interferon to a transmembrane receptor stimulates the activation of associated tyrosine kinases of the Janus kinase (JAK) family. Subsequently, latent cytoplasmic transcription factors are activated by tyrosine phosphorylation and function as signal transducers and activators of transcription (STATs). Advances in the field of interferon research have contributed to our understanding of signal transduction induced by many cytokines that also use JAK/STAT signaling pathways to activate early response genes. The specificity of signal activation by distinct cytokines that share these signaling components, and the molecular interaction of the signaling components with each other and their respective cytokine receptors represent major areas of research that are beginning to be elucidated. Signaling molecules other than the JAKs and STATs have also been found to be activated following interferon binding. In addition, the induction of type I interferon stimulated genes by double-stranded RNA in the absence of interferon provides another pathway of specific gene activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. 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; 77: 63–71.

    PubMed  Google Scholar 

  2. Barbieri G, Velazquez L, Cheung K, Ling L, Gauzzi C, Fellous M, Pelligrini S. Structure-function analysis of the protein tyrosine kinase TYK2. J Interferon Res 1994; 14: S49.

    Google Scholar 

  3. Cohen B, Novick D, Rubinstein M. Identification of amino acids of the IFN-α/β receptor that interact with JAK1 and its potential substrates. J Interferon Res 1994; 14: S49.

    Google Scholar 

  4. Colamonici OR, Domanski P, Handa RK, Krolewski J. Interaction of the Type I interferon receptors with the ISGF3α polypeptides and the JAK family of kinases. J Interferon Res 1994; 14: S106.

    Google Scholar 

  5. Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of theα subunit of the Type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol 1994; 14: 8133–42.

    PubMed  Google Scholar 

  6. Dale TC, Ali Iman AM, Kerr IM, Stark GR. Rapid activation by interferon-α of a latent DNA-binding protein present in the cytoplasm of untreated cells. Proc Natl Acad Sci USA 1989; 86: 1203–7.

    PubMed  Google Scholar 

  7. Daly C and Reich NC. Receptor to nucleus signaling via tyrosine phosphorylation of the p91 transcription factor. TEM 1994; 5: 159–64.

    Google Scholar 

  8. Daly C, Reich NC. Double-stranded RNA activates latent DNA-binding factors that induce expression of interferon-α/β-stimulated genes. J Interferon Res 1994; 14: S51.

    Google Scholar 

  9. Daly C, Reich NC. Double-stranded RNA activates novel factors that bind to the interferon-stimulated response element. Mol Cell Biol 1993; 13: 3756–64.

    PubMed  Google Scholar 

  10. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415–21.

    PubMed  Google Scholar 

  11. David M, Larner AC. Activation of transcription factors by interferon-alpha in a cell-free system. Science 1992; 257: 813–5.

    PubMed  Google Scholar 

  12. Decker T, Lew D, Mirkovitch J, Darnell JE Jr. Cytoplasmic activation of GAF, an IFN-γ-regulated DNA-binding factor. EMBO J 1991; 10: 927–32.

    PubMed  Google Scholar 

  13. Diaz MO, Bohlander S, Allen G. Nomenclature of the human interferon genes. J Interferon Res 1993; 13: 61–2.

    PubMed  Google Scholar 

  14. Eilers A, Decker T. Macrophage differentiation-dependent phosphorylation of Stat 1 (P91) on serin residues increases its activatibility by IFN-γ. J Interferon Res 1994; 14: S85.

    Google Scholar 

  15. Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ.tyk2, Prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 1990; 5: 1329–36.

    PubMed  Google Scholar 

  16. Flati V, Haque SJ, Williams BRG. A role for cystolic phospholipase A2 in IFN-α signaling. J Interferon Res 1994; 14: S48.

    Google Scholar 

  17. Fu X-Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferonα-induced cytoplasmic protein tyrosine kinase(s). Cell 1992; 70: 323–35.

    PubMed  Google Scholar 

  18. Fu X-Y, Kessler DS, Veals SA, Levy DE, Darnell JE Jr. The proteins of ISGF-3, the interferonα-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci USA 1992; 89: 7840–3.

    PubMed  Google Scholar 

  19. Gan Y, Fields K, Fang H, Grimley PM. Enhanced signal of IFN-alpha (ISGF3) in differentiated monocytic cells with a depletion of PKC-epsilon J Interferon Res 1994; 14: S113.

    Google Scholar 

  20. Harroch S, Revel M, Chebath J. A 46 kDa protein is present in transcription complexes formed in responses to IL-6 or IFNs on TTCCNNGAA enhancers. J Interferon Res 1994; 14: S80.

    Google Scholar 

  21. Heim MH, Kerr IM, Stark GR, Darnell JE Jr. Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science 1995; 267: 1347–9.

    PubMed  Google Scholar 

  22. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor:IL-4 Stat. Science 1994; 265: 1701–6.

    PubMed  Google Scholar 

  23. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Thierfelder WE, Kreider B, Silvennoinen O. Signaling by the cytokine receptor superfamily: Jaks and stats. TIBS 1994; 19: 222–7.

    PubMed  Google Scholar 

  24. Improta T, Schindler C, Horvath CM, Kerr IM, Stark GR, Darnell JE Jr. Transcription factor ISGF3 formation requires phosphorylated Stat91 protein, but STAT113 protein is phosphorylated independently of Stat91 protein. Proc Natl Acad Sci USA 1994; 91: 4776–80.

    PubMed  Google Scholar 

  25. Johnston JA, Kawamura M, Kirken RA, Chen Y-Q, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. Phosphorylation and activation of the Jak-3 janus kinase in response to interleukin-2. Nature 1994; 370: 151–3.

    PubMed  Google Scholar 

  26. Kamijo R, Huang S, Aguet M, Nagumo M, Vilcek J. Altered production of nitric oxide and cytokines in response to BCG infection in mice lacking a functional IFN-γ receptor. J Interferon Res 1994; 14: S167.

    Google Scholar 

  27. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell 1994; 76: 253–62.

    PubMed  Google Scholar 

  28. Kotanides H, Reich NC. Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science 1993; 262: 1265–7.

    PubMed  Google Scholar 

  29. Kotanides H, Gilmour KC, Reich NC. Receptor to nucleus signaling by interleukin-4, prolactin and interleukin-2 via activation of latent DNA-binding factors. J Interferon Res 1994; 14: S86.

    Google Scholar 

  30. Kumar A, Williams BRG. The role of PKR in DSRNA and interferon signal transduction. J Interferon Res 1994; 14: S50.

    Google Scholar 

  31. Leung S, Qureshi SA, Kerr IM, Darnell JE Jr, Stark GR. Role of STAT2 in the alpha interferon signaling pathway. Mol Cell Biol 1995; 15: 1312–7.

    PubMed  Google Scholar 

  32. Levy DE, Kessler DS, Pine R, Darnell JE Jr. Cytoplasmic activation of ISGF3, the positive regulator of interferon-α-stimulated transcription, reconstitutedin vitro. Genes Dev 1989; 3: 1362–71.

    PubMed  Google Scholar 

  33. Levy DE, Kessler D, Pine R, Reich N, Darnell JE Jr. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev 1988; 2: 383–93.

    PubMed  Google Scholar 

  34. Lew DJ, Decker T, Strehlow I, Darnell JE Jr. Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferon. Mol Cell Biol 1991; 11: 182–91.

    PubMed  Google Scholar 

  35. Lewis JA. Suppression of responses to interferon-γ by inhibitors of endosomal function. J Interferon Res 1994; 14: S84.

    Google Scholar 

  36. Maran A, Maitra RK, Kumar A, Dong B, Xiao W, Li G, Williams BRG, Torrence PF, Silverman RH. Blockage of NFkB signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. Science 1994; 265: 789–92.

    PubMed  Google Scholar 

  37. Maran A, Maitra RK, Dong B, Xiao W, Li G, Torrence PF, Silverman RH. Selective ablation of PKR mRNA and activity by 2-5A-antisense chimeras. J Interferon Res 1994; 14: S114.

    Google Scholar 

  38. Müller MJ, Briscoe C, Laxton D, Guschin A, Ziemiecki O, Silvennoinen AG, Harpur G, Barbieri BA, Witthuhn C, Schindler S, Pellegrini AF, Wilks JN, Ihle GR, Stark GR, Kerr IMet al. The protein tyrosine kinase JAK1 complements defects in interferon-α/β and -γ signal transduction. Nature 1993; 366: 129–35.

    PubMed  Google Scholar 

  39. 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 USA 1991; 88: 11349–53.

    PubMed  Google Scholar 

  40. Novick D, Cohen B, Rubinstein M. The human interferonα/β receptor: Characterization and molecular cloning. Cell 1994; 77: 391–400.

    PubMed  Google Scholar 

  41. Oh JW, Revel M, Chebath J. IL-6 binding and signal transduction capacities of soluble forms of IL-6 receptors differing at their C-terminal ends. J Interferon Res 1994; 14: S107.

    Google Scholar 

  42. Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Ann Rev Biochem 1987; 56: 727–77.

    PubMed  Google Scholar 

  43. Pine R. Mechanism of ISGF2/IRF-1 induction by tumor necrosis factor. J Interferon Res 1994; 14: S79.

    Google Scholar 

  44. Porter ACG, Chernajovsky Y, Dale TC, Gilbert CS, Stark GR, Kerr IM. Interferon response element of the human gene 6–16. EMBO J 1988; 7: 85–92.

    PubMed  Google Scholar 

  45. Premecz G, Markovits A, Nagy J, Bagi G, Földes I. IFN-α stimulates a biphasic intracellular calcium response in human amnion cells. J Interferon Res 1994; 14: S83.

    Google Scholar 

  46. Raz R, Durbin J, Levy DE. Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons and growth factors. J Biol Chem 1994; 269: 24391–5.

    PubMed  Google Scholar 

  47. Raz R, Durbin JE, Levy DE. Cloning of the acute phase response factor, an ISGF3 homologue that integrates the diverse signals from interferons, cytokines and growth factors. J Interferon Res 1994; 14: S50.

    Google Scholar 

  48. Reich NC, Evans B, Levy D, Fahey D, Knight E, Darnell JE Jr. Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci USA 1987; 8: 6394–8.

    Google Scholar 

  49. Revel M, Harroch S, Abramovich C, Chebath J. Various cytokines signaling through the JAK-stat pathway: Specific and common effects of IL-6, IFN-γ and IFN-β on genes. J Interferon Res 1994; 14: S48.

    Google Scholar 

  50. Schindler C, Shuai K, Prezioso VR, Darnell JE Jr. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 1992; 257: 809–13.

    PubMed  Google Scholar 

  51. Schindler C, Fu X, Improta T, Aebersold R, Darnell JE Jr. Proteins of transcription factor ISGF-3: One gene encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferonα. Proc Natl Acad Sci USA 1992; 89: 7836–9.

    PubMed  Google Scholar 

  52. Shuai K, Schindler C, Prezioso VR, Darnell JE Jr. Activation of transcription by IFN-γ: Tyrosine phosphorylation of a 91-kD DNA binding protein. Science 1992; 258: 1808–12.

    PubMed  Google Scholar 

  53. Uzé G, Uzé G, Lutfalla G, Gresser I. Genetic transfer of a functional human interferon a receptor into mouse cells: Cloning and expression of its cDNA. Cell 1990; 60: 225–34.

    PubMed  Google Scholar 

  54. Veals SA, Schindler C, Leonard D, Fu X, Aebersold R, Darnell JE Jr, Levy DE. Subunit of an alpha-interferon responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol Cell Biol 1992; 12: 3315–24.

    PubMed  Google Scholar 

  55. Velazquez L, Fellows M, Stark GR, Pellegrini S. A protein tyrosine kinase in the interferonα/β signaling pathway. Cell 1992; 70: 313–22.

    PubMed  Google Scholar 

  56. Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine transcription factor gene family and confers the prolactin response. EMBO J 1994; 13: 2182–91.

    PubMed  Google Scholar 

  57. Watling D, Guschin D, Muller M, Silvennoinen O, Witthuhn BAF, Quelle W, Rogers NC, Schindler C, Stark GR, Kerr IM. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-γ signal transduction pathway. Nature 1993; 366: 166–70.

    PubMed  Google Scholar 

  58. Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol 1991; 11: 2057–65.

    PubMed  Google Scholar 

  59. Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C, Liu ET, Ihle JN. Involvement of the Jak-3 janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 1994; 370: 153–7.

    PubMed  Google Scholar 

  60. Zhong Z, Wen Z, Darnell JE Jr. Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994; 264: 95–8.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cytokine Biology, Center for Biologics Evaluation and Research, 8800 Rockville Pike, 20892, Bethesda, MD, USA

    Andrew Larner

  2. Department of Pathology, Basic Sciences T-9, State University of New York, 11794, Stonybrook, NY, USA

    Nancy C. Reich

Authors
  1. Andrew Larner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy C. Reich
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larner, A., Reich, N.C. Interferon signal transduction. Biotherapy 8, 175–181 (1996). https://doi.org/10.1007/BF01877202

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01877202

Key words

Search

Navigation