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

• Published in: The Journal of biological chemistry Vol. 274; no. 7; p. 4045
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 12.02.1999
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.7.4045

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 α chain (Tyr 466 and Tyr 481 ), 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 Stat2 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.