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J. Biol. Chem., Vol. 280, Issue 3, 1849-1853, January 21, 2005

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Role of Tyrosine 441 of Interferon- Receptor Subunit 1 in SOCS-1-mediated Attenuation of STAT1 Activation^*

Yulan Qing, Ana P. Costa-Pereira¶, Diane Watling¶, and George R. Stark||

From the Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and ^¶Cancer Research UK, London Research Institute, Lincoln's Inn Laboratories, London WC2A 3PX, United Kingdom

Suppressor of cytokine signaling (SOCS)-1, the key negative regulator of interferon (IFN)--dependent signaling, is induced in response to IFN. SOCS-1 binds to and inhibits the IFN receptor-associated kinase Janus-activated kinase (JAK) 2 and inhibits its function in vitro, but the mechanism by which SOCS-1 inhibits IFN-dependent signaling in vivo is not clear. Upon stimulation, mouse IFN receptor subunit 1 (IFNGR1) is phosphorylated on several cytoplasmic tyrosine residues, and Tyr⁴¹⁹ is required for signal transducer and activator of transcription (STAT) 1 activation in mouse embryo fibroblasts. However, the functions of the other three cytoplasmic tyrosine residues are not known. Here we show that Tyr⁴⁴¹ is required to attenuate STAT1 activation in response to IFN. Several tyrosine to phenylalanine mutants of IFNGR1, expressed at normal levels in stable pools of IFNGR1-null cells, were analyzed for the phosphorylation of STAT1 during a 48-h period, and antiviral activity in response to IFN was also measured. Stronger activation of STAT1 was observed in cells expressing all IFNGR1 variants mutated at Tyr⁴⁴¹, and, consistently, stronger antiviral activity was also observed in these cells. Furthermore, constitutive overexpression of SOCS-1 inhibited IFN-dependent signaling only in cells expressing IFNGR1 variants that included the Tyr⁴⁴¹ mutation. Mutation of Tyr⁴⁴¹ also blocked the ability of SOCS-1 to bind to IFNGR1 and JAK2 in response to IFN and the normal down-regulation of STAT1 activation and antiviral activity. These results, together with data from the literature, suggest a model in which, in response to IFN, phosphorylation of Tyr⁴⁴¹ creates a docking site for SOCS-1, which then binds to JAK2 within the receptor-JAK complex to partially inhibit JAK2 phosphorylation. Furthermore, the virtually complete blockade of STAT1 phosphorylation by overexpressed SOCS-1 in this experiment suggests that the binding of SOCS-1 to Tyr⁴⁴¹ also blocks the access of STAT1 to Tyr⁴¹⁹ and that this effect may be the principal mechanism of inhibition of downstream signaling.

Received for publication, August 26, 2004 , and in revised form, October 27, 2004.

^* This work was supported by National Institutes of Health Grant PO1 CA62220 (to G. R. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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. of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-6062; Fax: 216-444-3279; E-mail: starkg{at}ccf.org.

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