DIRECT ASSOCIATION OF STAT3 WITH THE IFNAR-1 CHAIN OF THE HUMAN TYPE-I INTERFERON RECEPTOR

Based on the reports of the activation of the transcription factor kno wn as STAT3 (for signal transducers and activators of transcription) o r APRF (for acute phase response factor) by various cytokines, we inve stigated the possible role of STAT3 in type I interferon (IFN) recepto r signaling. We show that STAT3 undergoes IFN alpha-dependent tyrosine phosphorylation and IFN alpha treatment induces protein-DNA complexes that contain STAT3. In addition, STAT3 associates with the IFNAR-1 ch ain of the type I receptor in a tyrosine phosphorylation-dependent man ner upon IFN alpha addition. The binding of STAT3 to the IFNAR-1 chain occurs through a direct interaction between the SH2 domain-containing portion of STAT3 and the tyrosine-phosphorylated IFNAR-1 chain. Furth ermore, tyrosine-phosphorylated STAT3 bound to the IFNAR-1 chain also undergoes a secondary modification involving serine phosphorylation. T his phosphorylation event is apparently mediated by protein kinase C, since it was blocked by low concentrations of the protein kinase inhib itor H-7. The biological relevance of IFN activation of STAT3 is furth er illustrated by the finding that STAT3 is not activated by IFN in a cell line resistant to the antiviral and antiproliferative actions of IFN alpha but in which other components of the JAK-STAT pathway are ac tivated by IFN alpha.