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Gene Review

IFNAR2  -  interferon (alpha, beta and omega) receptor 2

Homo sapiens

Synonyms: IFN-R, IFN-R-2, IFN-alpha binding protein, IFN-alpha-REC, IFN-alpha/beta receptor 2, ...
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Disease relevance of IFNAR2

  • IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-beta treatment response [1].
  • The relative endogenous expression levels of the IFNAR2 isoforms influence the cytostatic and pro-apoptotic effect of IFNalpha on pleomorphic sarcoma cells [2].
  • Hence, IFNAR2 expression levels in liver, but not in PBMCs, is predictive of response to IFN treatment in chronic hepatitis C patients [3].
  • Seventeen sustained virologic responders showed lower pretreatment hepatitis C virus (HCV)-RNA levels (P = 0.017) in serum and higher pretreatment levels of IFNAR2 mRNA in liver (P = 0.007), but not in PBMCs, compared with nonsustained virologic responders [3].
  • Initial expression of interferon alpha receptor 2 (IFNAR2) on CD34-positive cells and its down-regulation correlate with clinical response to interferon therapy in chronic myelogenous leukemia [4].

High impact information on IFNAR2

  • Mechanisms underlying down-regulation of the type I interferon receptor consisting of IFNAR1 and IFNAR2 subunits remain largely unknown [5].
  • We have cloned the gene for ifnar2 and show that it produces four different transcripts encoding three different polypeptides that are generated by exon skipping, alternative splicing and differential use of polyadenylation sites [6].
  • Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-lambdas, are associated with viral clearance (haplotype P value = 0.0003), and in vitro assays support functional roles for these variants in receptor signaling [7].
  • The mutual binding sites on IFN-alpha 2 and ifnar2 predicted from the model showed an almost complete superposition with the ones determined from mutagenesis studies [8].
  • We conclude that NF-kappaB activation by IFNalpha/beta is integrated into a signaling pathway through the IFNalpha/beta receptor-1 chain of the type 1 IFN receptor that promotes cell survival in apposition to various apoptotic stimuli [9].

Chemical compound and disease context of IFNAR2


Biological context of IFNAR2

  • In this study, we describe the complementary DNAs for the two known subunits, IFNAR1 and IFNAR2, of this receptor isolated from bovine and ovine endometrial complementary DNA libraries by homology cloning [12].
  • In this report we demonstrate that there are functionally redundant phosphotyrosine-dependent and -independent binding sites for Stat2 in the alpha and beta subunits of the type I IFN-R [13].
  • The serine kinase activity of the PI-3K was activated by human IFNalpha in these cells, suggesting that phosphorylation of the Type I IFN receptor is not essential for PI3K activation [14].
  • Using human-hamster somatic cell hybrids, we mapped the Ifnabr gene, encoding a ligand-binding subunit of the IFN-alpha/beta (type I) receptor, to human chromosome 21 [15].
  • We investigated whether interferon receptor gene (IFNAR1 and IFNAR2 mRNA) expression in the liver before interferon therapy predicts long-term response to therapy in patients with genotype 2a or 2b HCV infection [16].

Anatomical context of IFNAR2


Associations of IFNAR2 with chemical compounds

  • There was a significant correlation between IFNAR2 expression and response to IFN-alpha/5-FU combination therapy in univariate analysis (P = 0.0070) [21].
  • In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit [22].
  • Here, we quantitatively mapped the complete binding region of ifnar2 on interferon (IFN)alpha2 by 35 individual mutations to alanine and isosteric residues [23].
  • In addition, the distal 53 amino acids of the intracellular domain of IFNAR2c are not required for IFN-receptor mediated STAT activation, ISFG3 or SIF complex formation, induction of gene expression, and inhibition of thymidine incorporation [24].
  • They also suggest that the retinoid can bypass IFN/IFN-receptor interactions and induce the expression of IFN-regulated genes [25].

Physical interactions of IFNAR2

  • We generated alanine substitution mutants of hIFNAR2-IgG and determined that regions of hIFNAR2 are important for the binding of these blocking mAbs and hIFN-alpha2/alpha1 [26].
  • Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex [27].
  • We report that Stat5 interacts constitutively with the IFN receptor-associated Tyk-2 kinase, and during IFNalpha stimulation its tyrosine-phosphorylated form acts as a docking site for the SH2 domain of CrkL [28].
  • Abolition of binding to ifnar2-Fc for mutants A2, AB1, AB2, and E established that the ifnar2 binding site on IFN-beta comprises parts of the A helix, the AB loop, and the E helix [29].

Co-localisations of IFNAR2


Regulatory relationships of IFNAR2

  • Interferon alpha (IFN alpha) signaling in cells expressing the variant form of the type I IFN receptor [30].
  • These results demonstrate that the unique IFNbeta induced assembly of type I IFN receptor chains is independent of receptor tyrosine phosphorylation and the recruitment of additional proteins to the receptor by such events [31].
  • The role of CpG-A/TLR9-induced type I IFN in regulating PBMC is determined by blocking with virus-derived soluble type I IFN receptor, B18R [32].
  • Blockade of the type I IFN receptor with a neutralizing antibody blocked retinoic acid induced ISG15 expression and ISG15 conjugation [33].
  • IFNAR2 has antisense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding RNAs with sense Alu elements, and Pol-III transcribed Alus [34].

Other interactions of IFNAR2

  • The ifnar1 component is well characterized and a putative ifnar2 cDNA has recently been identified [6].
  • These findings support the hypothesis that the type I IFNR acts as an adaptor, linking Stat proteins to Jak kinases [35].
  • We report that Stat-2 associates with beta s subunit of the type I IFN receptor in an interferon-dependent manner [35].
  • In this report, we define the role of the type I IFN receptor in STAT3 activation and identify for the first time tyrosine residues present in the cytoplasmic domain of IFNAR2c that are critical for STAT3 activation [36].
  • Mutational analysis of the beta chain of type I interferon receptor (IFNalphaRbetaL/IFNAR2) revealed that Box 1 plays a more significant role in activation than in the association with Jak1 [37].

Analytical, diagnostic and therapeutic context of IFNAR2

  • Gel filtration of a mixture of IFNAR1 and the IFN-beta-1a/IFNAR2 complex indicated that the three proteins formed a stable ternary complex [38].
  • Initial cell-surface IFNAR2 expression at diagnosis assessed by flow cytometry widely distributed but showed overall significantly higher expression in CML patients when compared with normal controls [4].
  • Northern blot analyses show that murine IFNAR 2 is expressed as two transcripts of 4 kilobases encoding the transmembrane isoform and 1.5 kilobases encoding the more abundant soluble isoform [39].
  • Results: As determined by quantitative RT-PCR analysis and immunocytochemistry, H295 and SW13 cells expressed the active type I IFN receptor (IFNAR) mRNA and protein (IFNAR-1 and IFNAR-2c subunits) [40].
  • IFNAR2 expression was examined using immunohistochemistry, in surgically resected tissue samples (20 esophageal, 20 gastric, 20 colorectal, 20 cholangiocarcinoma, and 20 pancreatic samples) [41].


  1. IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-beta treatment response. Leyva, L., Fernández, O., Fedetz, M., Blanco, E., Fernández, V.E., Oliver, B., León, A., Pinto-Medel, M.J., Mayorga, C., Guerrero, M., Luque, G., Alcina, A., Matesanz, F. J. Neuroimmunol. (2005) [Pubmed]
  2. The relative endogenous expression levels of the IFNAR2 isoforms influence the cytostatic and pro-apoptotic effect of IFNalpha on pleomorphic sarcoma cells. Gazziola, C., Cordani, N., Carta, S., De Lorenzo, E., Colombatti, A., Perris, R. Int. J. Oncol. (2005) [Pubmed]
  3. Type I interferon receptor and response to interferon therapy in chronic hepatitis C patients: a prospective study. Fujiwara, D., Hino, K., Yamaguchi, Y., Kubo, Y., Yamashita, S., Uchida, K., Konishi, T., Nakamura, H., Korenaga, M., Okuda, M., Okita, K. J. Viral Hepat. (2004) [Pubmed]
  4. Initial expression of interferon alpha receptor 2 (IFNAR2) on CD34-positive cells and its down-regulation correlate with clinical response to interferon therapy in chronic myelogenous leukemia. Ito, K., Tanaka, H., Ito, T., Sultana, T.A., Kyo, T., Imanaka, F., Ohmoto, Y., Kimura, A. Eur. J. Haematol. (2004) [Pubmed]
  5. SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-alpha receptor. Kumar, K.G., Tang, W., Ravindranath, A.K., Clark, W.A., Croze, E., Fuchs, S.Y. EMBO J. (2003) [Pubmed]
  6. Mutant U5A cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster. Lutfalla, G., Holland, S.J., Cinato, E., Monneron, D., Reboul, J., Rogers, N.C., Smith, J.M., Stark, G.R., Gardiner, K., Mogensen, K.E. EMBO J. (1995) [Pubmed]
  7. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Frodsham, A.J., Zhang, L., Dumpis, U., Taib, N.A., Best, S., Durham, A., Hennig, B.J., Hellier, S., Knapp, S., Wright, M., Chiaramonte, M., Bell, J.I., Graves, M., Whittle, H.C., Thomas, H.C., Thursz, M.R., Hill, A.V. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking. Roisman, L.C., Piehler, J., Trosset, J.Y., Scheraga, H.A., Schreiber, G. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. IFNalpha/beta promotes cell survival by activating NF-kappa B. Yang, C.H., Murti, A., Pfeffer, S.R., Basu, L., Kim, J.G., Pfeffer, L.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  10. Association of mumps virus V protein with RACK1 results in dissociation of STAT-1 from the alpha interferon receptor complex. Kubota, T., Yokosawa, N., Yokota, S., Fujii, N. J. Virol. (2002) [Pubmed]
  11. Is an "a la carte" combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group. Poynard, T., McHutchison, J., Goodman, Z., Ling, M.H., Albrecht, J. Hepatology (2000) [Pubmed]
  12. Molecular cloning of ovine and bovine type I interferon receptor subunits from uteri, and endometrial expression of messenger ribonucleic acid for ovine receptors during the estrous cycle and pregnancy. Han, C.S., Mathialagan, N., Klemann, S.W., Roberts, R.M. Endocrinology (1997) [Pubmed]
  13. The proximal tyrosines of the cytoplasmic domain of the beta chain of the type I interferon receptor are essential for signal transducer and activator of transcription (Stat) 2 activation. Evidence that two Stat2 sites are required to reach a threshold of interferon alpha-induced Stat2 tyrosine phosphorylation that allows normal formation of interferon-stimulated gene factor 3. Nadeau, O.W., Domanski, P., Usacheva, A., Uddin, S., Platanias, L.C., Pitha, P., Raz, R., Levy, D., Majchrzak, B., Fish, E., Colamonici, O.R. J. Biol. Chem. (1999) [Pubmed]
  14. Interferon-dependent activation of the serine kinase PI 3'-kinase requires engagement of the IRS pathway but not the Stat pathway. Uddin, S., Majchrzak, B., Wang, P.C., Modi, S., Khan, M.K., Fish, E.N., Platanias, L.C. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  15. Three distinct loci on human chromosome 21 contribute to interferon-alpha/beta responsiveness. Raz, R., Cheung, K., Ling, L., Levy, D.E. Somat. Cell Mol. Genet. (1995) [Pubmed]
  16. Expression of interferon receptor genes (IFNAR1 and IFNAR2 mRNA) in the liver may predict outcome after interferon therapy in patients with chronic genotype 2a or 2b hepatitis C virus infection. Morita, K., Tanaka, K., Saito, S., Kitamura, T., Kondo, M., Sakaguchi, T., Morimoto, M., Sekihara, H. J. Clin. Gastroenterol. (1998) [Pubmed]
  17. The receptor for type I IFNs is highly expressed on peripheral blood B cells and monocytes and mediates a distinct profile of differentiation and activation of these cells. Pogue, S.L., Preston, B.T., Stalder, J., Bebbington, C.R., Cardarelli, P.M. J. Interferon Cytokine Res. (2004) [Pubmed]
  18. Temporal expression of type I interferon receptor in the peri-implantation ovine extra-embryonic membranes: demonstration that human IFNalpha can bind to this receptor. Imakawa, K., Tamura, K., Lee, R.S., Ji, Y., Kogo, H., Sakai, S., Christenson, R.K. Endocr. J. (2002) [Pubmed]
  19. Inquiring into the differential action of interferons (IFNs): an IFN-alpha2 mutant with enhanced affinity to IFNAR1 is functionally similar to IFN-beta. Jaitin, D.A., Roisman, L.C., Jaks, E., Gavutis, M., Piehler, J., Van der Heyden, J., Uze, G., Schreiber, G. Mol. Cell. Biol. (2006) [Pubmed]
  20. Direct signal transduction via functional interferon-alphabeta receptors in CD34+ hematopoietic stem cells. Giron-Michel, J., Weill, D., Bailly, G., Legras, S., Nardeux, P.C., Azzarone, B., Tovey, M.G., Eid, P. Leukemia (2002) [Pubmed]
  21. Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-alpha and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression. Ota, H., Nagano, H., Sakon, M., Eguchi, H., Kondo, M., Yamamoto, T., Nakamura, M., Damdinsuren, B., Wada, H., Marubashi, S., Miyamoto, A., Dono, K., Umeshita, K., Nakamori, S., Wakasa, K., Monden, M. Br. J. Cancer (2005) [Pubmed]
  22. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Colamonici, O., Yan, H., Domanski, P., Handa, R., Smalley, D., Mullersman, J., Witte, M., Krishnan, K., Krolewski, J. Mol. Cell. Biol. (1994) [Pubmed]
  23. New structural and functional aspects of the type I interferon-receptor interaction revealed by comprehensive mutational analysis of the binding interface. Piehler, J., Roisman, L.C., Schreiber, G. J. Biol. Chem. (2000) [Pubmed]
  24. Role of the intracellular domain of the human type I interferon receptor 2 chain (IFNAR2c) in interferon signaling. Expression of IFNAR2c truncation mutants in U5A cells. Russell-Harde, D., Wagner, T.C., Rani, M.R., Vogel, D., Colamonici, O., Ransohoff, R.M., Majchrzak, B., Fish, E., Perez, H.D., Croze, E. J. Biol. Chem. (2000) [Pubmed]
  25. Stat1 is induced and activated by all-trans retinoic acid in acute promyelocytic leukemia cells. Gianni, M., Terao, M., Fortino, I., LiCalzi, M., Viggiano, V., Barbui, T., Rambaldi, A., Garattini, E. Blood (1997) [Pubmed]
  26. Determination of residues involved in ligand binding and signal transmission in the human IFN-alpha receptor 2. Chuntharapai, A., Gibbs, V., Lu, J., Ow, A., Marsters, S., Ashkenazi, A., De Vos, A., Jin Kim, K. J. Immunol. (1999) [Pubmed]
  27. Identification of critical residues in bovine IFNAR-1 responsible for interferon binding. Cutrone, E.C., Langer, J.A. J. Biol. Chem. (2001) [Pubmed]
  28. Activation of a CrkL-stat5 signaling complex by type I interferons. Fish, E.N., Uddin, S., Korkmaz, M., Majchrzak, B., Druker, B.J., Platanias, L.C. J. Biol. Chem. (1999) [Pubmed]
  29. Systematic mutational mapping of sites on human interferon-beta-1a that are important for receptor binding and functional activity. Runkel, L., deDios, C., Karpusas, M., Betzenhauser, M., Muldowney, C., Zafari, M., Benjamin, C.D., Miller, S., Hochman, P.S., Whitty, A. Biochemistry (2000) [Pubmed]
  30. Interferon alpha (IFN alpha) signaling in cells expressing the variant form of the type I IFN receptor. Colamonici, O.R., Domanski, P., Krolewski, J.J., Fu, X.Y., Reich, N.C., Pfeffer, L.M., Sweet, M.E., Platanias, L.C. J. Biol. Chem. (1994) [Pubmed]
  31. Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation. Russell-Harde, D., Wagner, T.C., Perez, H.D., Croze, E. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  32. Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC. Meyers, J.A., Mangini, A.J., Nagai, T., Roff, C.F., Sehy, D., van Seventer, G.A., van Seventer, J.M. Cytokine (2006) [Pubmed]
  33. Retinoic acid-induced protein ISGylation is dependent on interferon signal transduction. Dao, C.T., Luo, J.K., Zhang, D.E. Blood Cells Mol. Dis. (2006) [Pubmed]
  34. A gene expression restriction network mediated by sense and antisense Alu sequences located on protein-coding messenger RNAs. Liang, K.H., Yeh, C.T. BMC. Genomics. (2013) [Pubmed]
  35. Interaction of the transcriptional activator Stat-2 with the type I interferon receptor. Uddin, S., Chamdin, A., Platanias, L.C. J. Biol. Chem. (1995) [Pubmed]
  36. STAT3 activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c. Activation of multiple STATS proceeds through the redundant usage of two tyrosine residues. Velichko, S., Wagner, T.C., Turkson, J., Jove, R., Croze, E. J. Biol. Chem. (2002) [Pubmed]
  37. Contribution of the Box 1 and Box 2 motifs of cytokine receptors to Jak1 association and activation. Usacheva, A., Sandoval, R., Domanski, P., Kotenko, S.V., Nelms, K., Goldsmith, M.A., Colamonici, O.R. J. Biol. Chem. (2002) [Pubmed]
  38. Characterization of a soluble ternary complex formed between human interferon-beta-1a and its receptor chains. Arduini, R.M., Strauch, K.L., Runkel, L.A., Carlson, M.M., Hronowski, X., Foley, S.F., Young, C.N., Cheng, W., Hochman, P.S., Baker, D.P. Protein Sci. (1999) [Pubmed]
  39. Cloning and characterization of soluble and transmembrane isoforms of a novel component of the murine type I interferon receptor, IFNAR 2. Owczarek, C.M., Hwang, S.Y., Holland, K.A., Gulluyan, L.M., Tavaria, M., Weaver, B., Reich, N.C., Kola, I., Hertzog, P.J. J. Biol. Chem. (1997) [Pubmed]
  40. Potent inhibitory effects of type I interferons on human adrenocortical carcinoma cell growth. van Koetsveld, P.M., Vitale, G., de Herder, W.W., Feelders, R.A., van der Wansem, K., Waaijers, M., van Eijck, C.H., Speel, E.J., Croze, E., van der Lely, A.J., Lamberts, S.W., Hofland, L.J. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  41. Expression of type I interferon receptor as a predictor of clinical response to interferon-alpha therapy of gastrointestinal cancers. Ota, H., Nagano, H., Doki, Y., Sekimoto, M., Kondo, M., Wada, H., Nakamura, M., Noda, T., Damdinsuren, B., Marubashi, S., Miyamoto, A., Takeda, Y., Dono, K., Umeshita, K., Nakamori, S., Wakasa, K., Sakon, M., Monden, M. Oncol. Rep. (2006) [Pubmed]
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