The proximal tyrosines of the cytoplasmic domain of the β 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 α-induced Stat2 tyrosine phosphorylation that allows normal formation of interferon-stimulated gene factor 3

Owen W. Nadeau, Paul Domanski, Anna Usacheva, Shahab Uddin, Leonidas C. Platanias, Paula Pitha, Regina Raz, David Levy, Beata Majchrzak, Eleanor Fish, Oscar R. Colamonici*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The precise role of the different subunits (α/IFNAR1 and β(L)/IFNAR2) of the type I interferon receptor (IFN-R) in the activation of signal transducer and activator of transcription (Stat) 1, Stat2, and Stat3 has not yet been established. In this report we demonstrate that there are functionally redundant phosphotyrosine-dependent and -independent binding sites for Stat2 in the α and β subunits of the type I IFN-R. Expression of a type I IFN-R containing only the constitutive Stat2 site or the proximal tyrosines of β(L), but not the docking site on the a chain (Tyr466 and Tyr481), supported low levels of Stat2 activation. However, the presence of only one intact Stat2 site did not lead to induction of interferon- stimulated gene factor 3 (ISGF3) or an antiviral state. Normal levels of Stat2 tyrosine phosphorylation, induction of ISGF3, and an antiviral effect always required the proximal tyrosines of β(L) and at least one of the other Stat2 sites (Tyr(α466,481) or β(L404-462)). These data suggest that a threshold of Star2 tyrosine phosphorylation is required for complete activation of ISGF3. Interestingly, a receptor in which all tyrosines were mutated to phenylalanine shows normal Stat3 phosphorylation and low levels of activation of Stat1.

Original languageEnglish (US)
Pages (from-to)4045-4052
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number7
DOIs
StatePublished - Feb 12 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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