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SOCS-1 Binding to Tyrosine 441 of IFN-gamma Receptor Subunit 1 Contributes to the Attenuation of IFN-gamma Signaling In Vivo


Starr, R; Fuchsberger, M; Lau, LS; Uldrich, AP; Goradia, A; Willson, TA; Verhagen, AM; Alexander, WS; Smyth, MJ
2009-10-01
JOURNAL OF IMMUNOLOGY
Journal Article
183
7
4537-4544
Suppressor of cytokine signaling (SOCS)-1 is a critical inhibitor of IFN-gamma signal transduction in vivo, but the precise biochemical mechanism of action of SOCS-1 is unclear. Studies in vitro have shown that SOCS-1 binds to Jaks and inhibits their catalytic activity, but recent studies indicate SOCS-1 may act in a similar manner to SOCS-3 by firstly interacting with cytokine receptors and then inhibiting Jak activity. Here, we have generated mice, termed Ifngr1(441F), in which a putative SOCS-1 binding site, tyrosine 441 (Y441), on the IFN-gamma receptor subunit 1 (IFNGR1) is mutated. We confirm that SOCS-1 binds to IFNGRI in wild-type but not mutant cells. Mutation of Y441 results in impaired negative regulation of IFN-gamma signaling. IFN-gamma-induced STATI activation is prolonged in Ifngr1(441F) cells, but not to the extent seen in cells completely SOCS-1, suggesting that SOCS-1 maintains activity to modulate IFN-gamma signaling via other mechanisms. Despite this, we show that hypersensitivity to IFN-gamma results in enhanced innate tumor protection in Ifngr1(441F) mice in vivo, and unregulated expression of an IFN-gamma-dependent chemokine, monokine-induced by IFN-gamma. Collectively, these data indicate that Y441 contributes to the regulation of signaling through IFNGRI via the recruitment of SOCS-1 to the receptor. The Journal of Immunology, 2009, 183: 4537-4544.
AMER ASSOC IMMUNOLOGISTS
INTERFERON-GAMMA; CYTOKINE SIGNALING-1; SH2 DOMAIN; T-CELLS; SUPPRESSOR; MICE; ACTIVATION; GP130; GENE; TRANSDUCTION
10.4049/jimmunol.0901010
Refer to copyright notice on published article.

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Creation Date 2009-10-01 12:00:00