PHOSPHORYLATED INTERFERON-ALPHA RECEPTOR-1 SUBUNIT (IFNAR1) ACTS AS ADOCKING SITE FOR THE LATENT FORM OF THE 113 KDA STAT2 PROTEIN

Interferon-alpha (IFN alpha) induces rapid tyrosine phosphorylation of its receptors, two JAK kinases and three STAT transcription factors, One kinase, p135(tyk2), is complexed with the IFNaR1 receptor, and may catalyze some of these phosphorylation events, We demonstrate that, i n vitro, p135(tyk2) phosphorylates two tyrosines on IFNaR1, A phosphop eptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH2-dependent manner, Furthermore, only la tent, non-phosphorylated STAT2 interacts with this phosphopeptide, Whe n this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked, Fin ally, mutant versions of IFNaR1, in which Tyr466 is changed to phenyla lanine, can act in a dominant negative manner to inhibit phosphorylati on of STAT2, These observations are consistent with a model in which I FNaR1 mediates the interaction between JAK kinases and the STAT transc ription factors.