The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2

J Biol Chem. 1996 Jan 5;271(1):278-82. doi: 10.1074/jbc.271.1.278.


Binding of interferon alpha (IFN alpha) to its receptor induces activation of the Tyk-2 and Jak-1 tyrosine kinases and tyrosine phosphorylation of multiple downstream signaling elements, including the Stat components of the interferon-stimulated gene factor 3 (ISGF-3). IFN alpha also induces tyrosine phosphorylation of IRS-1, the principle substrate of the insulin receptor. In this study we demonstrate that various Type I IFNs rapidly stimulate tyrosine phosphorylation of IRS-2. This is significant since IRS-2 is the major IRS protein found in hematopoietic cells. The IFN alpha-induced phosphorylated form of IRS-2 associates with the p85 regulatory subunit of the phosphatidylinositol 3'-kinase, suggesting that this kinase participates in an IFN alpha-signaling cascade downstream of IRS-2. We also provide evidence for an interaction of IRS-2 with Tyk-2, suggesting that Tyk-2 is the kinase that phosphorylates this protein during IFN alpha stimulation. A conserved region in the pleckstrin homology domain of IRS-2 may be required for the interaction of IRS-2 with Tyk-2, as shown by the selective binding of glutathione S-transferase (GST) fusion proteins containing the IRS-2-IH1PH or IRS-1-IH1PH domains to Tyk-2 but not other Janus kinases in vitro.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Enzyme Activation
  • Glutathione Transferase / metabolism
  • Humans
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 1
  • Molecular Sequence Data
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • TYK2 Kinase
  • Tumor Cells, Cultured
  • Tyrosine / metabolism*


  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Proteins
  • Receptors, Interferon
  • Recombinant Fusion Proteins
  • Receptor, Interferon alpha-beta
  • Tyrosine
  • Glutathione Transferase
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1
  • TYK2 Kinase
  • TYK2 protein, human