References
Query Results -- Details
MGI Accession ID: MGI:4359975
J Number: J:152785
Other Accession IDs:
Title: SOCS-1 binding to tyrosine 441 of IFN-gamma receptor subunit 1 contributes to the attenuation of IFN-gamma signaling in vivo.
Authors: Starr R; Fuchsberger M; Lau LS; Uldrich AP; Goradia A; Willson TA; Verhagen AM; Alexander WS; Smyth MJ
Journal: J Immunol
Volume: 183
Issue: 7
Date: 2009 Oct 1
Year: 2009
Pages: 4537-44
Review Status: Peer Reviewed
Abstract:
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 IFNGR1 in wild-type but not mutant cells. Mutation of Y441 results in impaired negative regulation of IFN-gamma signaling. IFN-gamma-induced STAT1 activation is prolonged in Ifngr1(441F) cells, but not to the extent seen in cells completely lacking 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 IFNGR1 via the recruitment of SOCS-1 to the receptor.
Additional Information:
