Binding of interferon- (IFN) to the multisubunit type I IFN receptor (IFNR) induces activation of the Tyk-2 and Jak-1 kinases and tyrosine phosphorylation of multiple signaling elements, including the Stat proteins that form the ISGF3 complex. Although Jak kinases are required for IFN-dependent activation of Stats, the mechanisms by which Stats interact with these kinases are not known. We report that Stat-2 associates with subunit of the type I IFN receptor in an interferon-dependent manner. This association is rapid, occurring within 1 min of interferon treatment of cells, and is inducible by various type I (, , ) but not type II () IFNs. The kinetics of Stat-2-IFNR association are similar to the kinetics of phosphorylation of Stat-2, suggesting that during its binding to the type I IFNR, Stat-2 acts as a substrate for interferon-dependent tyrosine kinase activity. These findings support the hypothesis that the type I IFNR acts as an adaptor, linking Stat proteins to Jak kinases. Interaction of Stat-2 with the subunit of the type I IFNR may be a critical signaling event, required for the formation of the ISGF3 complex and downstream transcription of interferon-stimulated genes.

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