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Originally published In Press as doi:10.1074/jbc.M108928200 on October 26, 2001

J. Biol. Chem., Vol. 277, Issue 2, 1493-1499, January 11, 2002
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Interferon Signaling Is Dependent on Specific Tyrosines Located within the Intracellular Domain of IFNAR2c
EXPRESSION OF IFNAR2c TYROSINE MUTANTS IN U5A CELLS*

T. Charis WagnerDagger , Sharlene VelichkoDagger , David VogelDagger , M. R. Sandhya Rani§, Stewart LeungDagger , Richard M. Ransohoff§, George R. Stark§, H. Daniel PerezDagger , and Ed CrozeDagger

From the Dagger  Berlex Biosciences Inc., Richmond, California 94804 and the § Cleveland Clinic Foundation, Cleveland, Ohio 44195

Type I interferons (IFNs) are cytokines that play a central role in mediating antiviral, antiproliferative, and immunomodulatory activities in virtually all cells. These activities are entirely dependent on the interaction of IFNs with their particular cell surface receptor. In this report, we identify two specific tyrosine residues located within the cytoplasmic domain of IFNAR2c that are obligatory for IFN-dependent signaling. Various IFNAR2c tyrosine mutants were expressed in a human lung fibroscarcoma cell line lacking IFNAR2c (U5A). Stable clones expressing these mutants were analyzed for their ability to induce STAT1 and STAT2 activation, ISGF3 transcriptional complex formation, gene expression, and cell growth regulation in response to stimulation with type I IFNs. The replacement of all seven cytoplasmic tyrosine residues of IFNAR2c with phenylalanine resulted in a receptor unable to respond to IFN stimulation. Substitution of single tyrosines at amino acid residue 269, 316, 318, 337, or 512 with phenylalanine had no effect on IFN-dependent signaling, suggesting that no single tyrosine is essential for IFN receptor-mediated signaling. In addition, IFNAR2c retaining five proximal tyrosines residues (269, 306, 316, 318, and 337) or either two distal tyrosine residues (411 or 512) continued to be responsive to IFN stimulation. Surprisingly, the presence of only a single tyrosine at either position 337 or 512 was sufficient to restore a complete IFN response. These results indicate that IFN-dependent signaling proceeds through the redundant usage of two tyrosine residues in the cytoplasmic domain of IFNAR2c.

* This work was supported in part by National Cancer Institute Grant POI 62220 (to G. R. S.) and by a grant (project 3) to R. M. R.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. Immunology, Berlex Biosciences, 15049 San Pablo Ave., Richmond, CA 94804. Tel.: 510-669-4043; Fax: 510-669-4246; E-mail: ed_croze@berlex.com.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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