STAT3 as an adapter to couple phosphatidylinositol 3-kinase to the IFNAR1 chain of the type I interferon receptor.

STAT (signal transducers and activators of transcription) proteins undergo cytokine-dependent phosphorylation on serine and tyrosine. STAT3, a transcription factor for acute phase response genes, was found to act as an adapter molecule in signal transduction from the type I interferon receptor. STAT3 bound to a conserved sequence in the cytoplasmic tail of the IFNAR1 chain of the receptor and underwent interferon-dependent tyrosine phosphorylation. The p85 regulatory subunit of phosphatidylinositol 3-kinase, which activates a series of serine kinases, bound to phosphorylated STAT3 and subsequently underwent tyrosine phosphorylation. Thus, STAT3 acts as an adapter to couple another signaling pathway to the interferon receptor.

[1]  J. Darnell,et al.  Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors , 1995, Science.

[2]  S. Constantinescu,et al.  Expression and signaling specificity of the IFNAR chain of the type I interferon receptor complex. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  G. Stark,et al.  α-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences , 1985, Nature.

[4]  S. Constantinescu,et al.  Direct Association of STAT3 with the IFNAR-1 Chain of the Human Type I Interferon Receptor (*) , 1996, The Journal of Biological Chemistry.

[5]  J. Krolewski,et al.  Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction , 1996, Molecular and cellular biology.

[6]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[7]  T. Pawson,et al.  SH2 domains recognize specific phosphopeptide sequences , 1993, Cell.

[8]  B. Strulovici,et al.  Interferon-alpha selectively activates the beta isoform of protein kinase C through phosphatidylcholine hydrolysis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L. A. Goldman,et al.  Modifications of vectors pEF-BOS, pcDNA1 and pcDNA3 result in improved convenience and expression. , 1996, BioTechniques.

[10]  J. Blenis,et al.  Requirement of serine phosphorylation for formation of STAT-promoter complexes. , 1995, Science.

[11]  O. Colamonici,et al.  Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase , 1994, Molecular and cellular biology.

[12]  S. Constantinescu,et al.  Role of interferon alpha/beta receptor chain 1 in the structure and transmembrane signaling of the interferon alpha/beta receptor complex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Xin-Yuan Fu A transcription factor with SH2 and SH3 domains is directly activated by an interferon α-induced cytoplasmic protein tyrosine kinase(s) , 1992, Cell.

[14]  M. White,et al.  Interferon-α Engages the Insulin Receptor Substrate-1 to Associate with the Phosphatidylinositol 3′-Kinase (*) , 1995, The Journal of Biological Chemistry.

[15]  G. Lutfalla,et al.  Genetic transfer of a functional human interferon α receptor into mouse cells: Cloning and expression of its c-DNA , 1990, Cell.

[16]  A. Toker,et al.  Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. , 1994, The Journal of biological chemistry.

[17]  J. Darnell,et al.  Transcriptional induction by interferon. New protein(s) determine the extent and length of the induction. , 1986, The Journal of biological chemistry.

[18]  C. Baglioni,et al.  Interaction of interferon with cellular receptors. Internalization and degradation of cell-bound interferon. , 1982, The Journal of biological chemistry.

[19]  Andrius Kazlauskas,et al.  The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase , 1995, Cell.

[20]  O. Colamonici,et al.  Cloning and Expression of a Long Form of the β Subunit of the Interferon αβ Receptor That Is Required for Signaling (*) , 1995, The Journal of Biological Chemistry.

[21]  B. Burgering,et al.  Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction , 1995, Nature.

[22]  L. Pfeffer,et al.  A novel cytoplasmic homology domain in interferon receptors. , 1995, Trends in biochemical sciences.

[23]  J. Darnell,et al.  Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation , 1995, Cell.

[24]  L. Cantley,et al.  Phosphatidylinositol 3‐kinase , 1994, BioEssays : news and reviews in molecular, cellular and developmental biology.