Abstract
Based on the reports of the activation of the transcription factor known as STAT3 (for signal transducers and activators of transcription) or APRF (for acute phase response factor) by various cytokines, we investigated the possible role of STAT3 in type I interferon (IFN) receptor signaling. We show that STAT3 undergoes IFNalpha-dependent tyrosine phosphorylation and IFNalpha treatment induces protein-DNA complexes that contain STAT3. In addition, STAT3 associates with the IFNAR-1 chain of the type I receptor in a tyrosine phosphorylation-dependent manner upon IFNalpha 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. Furthermore, tyrosine-phosphorylated STAT3 bound to the IFNAR-1 chain also undergoes a secondary modification involving serine phosphorylation. This phosphorylation event is apparently mediated by protein kinase C, since it was blocked by low concentrations of the protein kinase inhibitor H-7. The biological relevance of IFN activation of STAT3 is further 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 activated by IFNalpha.
Highlights
Cytokines are multifunctional mediators of the growth and differentiation of hematopoietic, lymphopoietic, and neural systems
Based on the reports of the activation of the transcription factor known as STAT3 or acute phase response factor (APRF) by various cytokines, we investigated the possible role of STAT3 in type I interferon (IFN) receptor signaling
IFN␣ Induction of STAT-related Proteins That Bind to Specific Promoter Elements—Nuclear extracts prepared from IFNsensitive Daudi cells treated with IFN␣ were incubated with a labeled probe for either the high affinity sis-inducible element (SIE) or the IFN stimulus response element (ISRE), and the resultant DNA-protein complexes were analyzed by an electrophoretic mobility shift assay (EMSA)
Summary
Cytokines are multifunctional mediators of the growth and differentiation of hematopoietic, lymphopoietic, and neural systems They exert their effects through specific surface receptors expressed on target cells, triggering biological effects through the activation of specific gene transcription. Central to the type I IFN-activated pathway are two non-receptor protein tyrosine kinases, JAK1 and TYK2, which apparently mediate the tyrosine phosphorylation of IFN receptor chains and STATs [4, 5]. The ligand-induced tyrosine phosphorylation of STAT transcription factors is one of the events most proximal to cytokine-dependent JAK activation [2, 3]. Recent studies indicate that many cytokines, including type I IFNs, induce tyrosine phosphorylation of the STAT3 transcription factor [8, 9], known as the acute phase response factor (APRF) involved in acute phase gene expression. The biological significance of IFN activation of STAT3 is further borne out by the finding that STAT3 is the only signaling molecule in the JAK-STAT pathway not activated by IFN␣ in an IFN␣-resistant cell line
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