THE JAK KINASES DIFFERENTIALLY ASSOCIATE WITH THE ALPHA AND BETA (ACCESSORY FACTOR) CHAINS OF THE INTERFERON-GAMMA RECEPTOR TO FORM A FUNCTIONAL RECEPTOR UNIT CAPABLE OF ACTIVATING STAT TRANSCRIPTION FACTORS

Interferon gamma (IFN gamma) induces the expression of early response genes by tyrosine phosphorylation of Jak kinases and transcription factors referred to as STAT proteins. The topology of the IFN gamma receptor is partially understood and the relationship between the alpha chain that binds the ligand and the beta chain that is required for signal transduction is undefined. In a cell line which expresses only the human alpha chain, we show that these cells did not activate Jak kinases or STAT proteins with human IFN gamma, even though Jak1 co-immunoprecipitated with the alpha chain. In cells unexposed to IFN gamma, Jak1 preferentially associated with the alpha chain, while Jak2 associated with the beta chain. There was evidence for Jak1 kinase activity in untreated cells. For Jak2, kinase activity was IFN gamma-dependent. Although the alpha chain was tyrosine-phosphorylated in response to ligand, we found no evidence for tyrosine phosphorylation of the beta chain. These data are consistent with a model of the IFN gamma receptor in which Jak1 associates with the a chain, whereas Jak2 associates with the beta chain, IFN gamma clusters at least two receptor units which results in the tyrosine phosphorylation of Jak1 and Jak2, the activation of Jak2 kinase activity, and the recruitment of STAT1 alpha resulting in its activation by tyrosine phosphorylation.