Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein.

Yan, Hai; Krishnan, Kartik G.; Greenlund, Andrew C.; Gupta, Sanjay; Lim, Jin T. E.; Schreiber, Robert D.; Schindler, Christian; Krolewski, John J.

doi:10.1002/j.1460-2075.1996.tb00444.x

Cited by 162 publications

(153 citation statements)

References 49 publications

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“…The chimeric protein in which the amino acid sequence immediately carboxyl-terminal to Tyr 705 in Stat3 was replaced by the corresponding sequence derived from Stat1 was associated with gp130 but not activated, indicating that the SH2 domain is sufficient for Stat3 to bind gp130 but some additional factors are required for the phosphorylation of Stat3. When overexpressed, Jaks equally activate all Stat proteins without ligand stimulation, so the Jak kinase has been regarded as having no specificity for substrate between Stat families (47,48). We also confirm that our recombinant Stat3/1 proteins were all activated by co-expressed Jak1 (data not shown).…”

Section: Discussionsupporting

confidence: 76%

The Amino Acid Residues Immediately Carboxyl-terminal to the Tyrosine Phosphorylation Site Contribute to Interleukin 6-specific Activation of Signal Transducer and Activator of Transcription 3

Inoue

Minami

Matsumoto

et al. 1997

Journal of Biological Chemistry

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Signal transducers and activators of transcription (Stat) proteins play an important role in signaling through a variety of cytokine and growth factor receptors. Each of the Stat proteins is activated in a ligandspecific manner. Only the Src homology 2 (SH2) domains of Stat1 and Stat2 are critical for the ligand-specific activation of interferon signaling. In this study we determined the domains in Stat3 protein that contribute to interleukin 6 (IL-6)-specific phosphorylation. Based on evidence that Stat3, but not Stat1, is activated in the presence of low levels of IL-6 and soluble IL-6 receptor, we constructed various swap mutants between Stat3 and Stat1 and examined their response to IL-6 after their transient expression into COS7 cells. The region upstream of the SH2 domain was exchangeable between Stat1 and Stat3, whereas the region carboxyl-terminal to the SH2 domain of Stat3 was critical to phosphorylation by IL-6. However, unlike Stat1 and Stat2 in interferon signaling, the swap mutant in which 5 amino acid residues just carboxyl-terminal to the tyrosine phosphorylation site (Tyr 705 ) in Stat3 was replaced by the corresponding region derived from Stat1 was not phosphorylated in response to IL-6. Substituting 1 amino acid (Lys 709 ) at position ؉4 relative to Tyr 705 abolished the tyrosine phosporylation of Stat3 in response to IL-6. Co-immunoprecipitation experiments demonstrated that these mutants were associated with gp130 at an extent similar to wild-type Stat3. Taken together, these results show that the amino acid residues immediately carboxyl-terminal to the tyrosine phosphorylation site are involved in IL-6-specific activation of Stat3.Cytokines and growth factors mediate their biological effects through interaction with their receptors. Investigations into the transcriptional response to interferons have identified the Janus kinases (Jak)-signal transducers and activators of transcription (Stat) 1 signaling pathway, which is in fact used by a large number of cytokines and growth factors (1). The Jak family of known nonreceptor protein kinases consists of Jak1, Jak2, Jak3, and Tyk2. The family of Stat proteins constitutes a new class of transcription factors that contains SH2, SH3-like domains, and a carboxyl-terminal tyrosine phosphorylation site (2). Six Stat family members (Stat1-Stat6) have been cloned. Jak kinases associate with the cytoplasmic membrane proximal region of receptors and are catalytically activated after ligand binding. The activated Jak kinases then phosphorylate Stat proteins at their tyrosine residues. Thereafter, the Stat proteins become homodimerized or heterodimerized and translocate to the nucleus to activate transcription by interaction with specific DNA sequences.The Stat proteins are activated in a ligand-specific manner. In in vitro studies, Stat1 and Stat2 are phosphorylated in response to IFN-␣, whereas Stat1, but not Stat2, is phosphorylated in response to IFN-␥. Besides the IFN signaling systems, Stat1 is activated by signaling through various cytokine receptors...

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Section: Discussionsupporting

confidence: 76%

The Amino Acid Residues Immediately Carboxyl-terminal to the Tyrosine Phosphorylation Site Contribute to Interleukin 6-specific Activation of Signal Transducer and Activator of Transcription 3

Inoue

Minami

Matsumoto

et al. 1997

Journal of Biological Chemistry

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“…A membrane-proximal 33 amino acid sequence of the cytoplasmic domain of IFNAR1 physically associated with Tyk2 (Colamonici et al, 1994a,b) (Figure 9A). In response to IFN-a, Jak1 and Tyk2 become activated by phosphorylation resulting in the phosphorylation of tyrosine 466 of IFNAR1, which is utilized as a docking site by the SH2 domain of STAT2 Yan et al, 1996) (Figure 9B). Bound STAT2 to IFNAR1 serves as a substrate of activated Tyk2 resulting in STAT2 phosphorylation on tyrosine 690 , which then provides a docking site for the SH2 domain of STAT1, allowing its tyrosine 701 to become phosphorylated (Greenlund et al, 1994;Improta et al, 1994) (Figure 9B).…”

Section: Discussionmentioning

confidence: 99%

The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α

et al. 1999

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We have examined the e ects of human papilloma virus (HPV) E6 proteins on interferon (IFN) signaling. Here we show that expression of the`malignant' HPV-18 E6 in human HT1080 cells results in inhibition of Jak-STAT activation in response to IFN-a but not IFN-g. This inhibitory e ect is not shared by the`benign' HPV-11 E6. The DNA-binding and transactivation capacities of the transcription factor ISGF3 are diminished in cells expressing HPV-18 E6 after IFN-a treatment as a result of decreased tyrosine phosphorylation of Tyk2, STAT2 and STAT1. However, HPV-18 E6 does not a ect the induction of tyrosine phosphorylation and DNA-binding of STAT1 by IFN-g. In addition, HPV E6 proteins physically interact with Tyk2. This interaction takes place preferably with HPV-18 E6 and to a lesser extent with HPV-11 E6. The E6/Tyk2 interaction requires the JH 6 -JH 7 domains of Tyk2, which are important for Tyk2 binding to the cytoplasmic portion of IFN-a receptor 1 (IFNAR1). These ®ndings demonstrate an inhibitory role of HPV-18 E6 in the IFN-a-induced Jak-STAT pathway, which may be explained, at least in part, by the ability of E6 to interact with and impair Tyk2 activation.

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“…Indeed, it is not known if the intronic (intron 3) IFNAR1-17470 SNP has a functional effect on IFNAR1 gene expression, mRNA stability or mRNA splicing. Similarly, in spite of the fact that several functional domains have been identified within the intracellular part of IFNAR1, 29,30 the functional role of the L168V amino-acid substitution in the extracellular domain of the IFNAR1 is uncertain.…”

Section: Genes and Immunitymentioning

confidence: 99%

Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia

et al. 2003

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The chromosome 21q22.11 cytokine receptor cluster contains four genes that encode subunits of the receptors for the cytokines interleukin-10 and interferon-alpha, -beta and -gamma that may have a role in malaria pathogenesis. A total of 15 polymorphic markers located within these genes were initially genotyped in 190 controls and 190 severe malaria cases from The Gambia. Two interferon-alpha receptor-1 (IFNAR1) gene SNPs (17470 and L168 V) showed evidence for an association with severe malaria phenotypes and were typed in a larger series of samples comprising 538 severe malaria cases, 338 mild malaria cases and 562 controls. Both the 17470-G/G and L168V-G/G genotypes were associated with protection against severe malaria, in general, and cerebral malaria, in particular (P ¼ 0.004 and 0.003, respectively). IFNAR1 diplotypes were then constructed for these two markers using the PHASE software package. The (17470-G L168V-G/17470-G L168V-G) diplotype was found to be associated with a reduced risk of cerebral malaria and the (17470-C L168V-C/17470-G L168V-G) diplotype with an increased risk of cerebral malaria (overall 3 Â 2 w 2 ¼ 12.8, d.f. ¼ 2, P ¼ 0.002 and 3 Â 2 w 2 ¼ 15.2, d.f. ¼ 2, P ¼ 0.0005, respectively). These data suggest a role for the type I interferon pathway in resistance to cerebral malaria.

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Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein.

Cited by 162 publications

References 49 publications

The Amino Acid Residues Immediately Carboxyl-terminal to the Tyrosine Phosphorylation Site Contribute to Interleukin 6-specific Activation of Signal Transducer and Activator of Transcription 3

The Amino Acid Residues Immediately Carboxyl-terminal to the Tyrosine Phosphorylation Site Contribute to Interleukin 6-specific Activation of Signal Transducer and Activator of Transcription 3

The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α

Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia

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