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

Binding of interferon α (IFNα) 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). IFNα 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 IFNα-induced phosphorylated form of IRS-2 associates with the p85 regulatory subunit of the phosphatidylinositol 3'-kinase, suggesting that this kinase participates in an IFNα-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 IFNα stimulation. A conserved region in the pleckstrin homology domain of IRS-2 may he 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-IH1(PH) or IRS-1- IH1(PH) domains to Tyk-2 but not other Janus kinases in vitro.