JANUS KINASE-DEPENDENT ACTIVATION OF INSULIN-RECEPTOR-SUBSTRATE-1 IN RESPONSE TO INTERLEUKIN-4, ONCOSTATIN-M, AND THE INTERFERONS

In addition to a role in response to insulin and insulinlike growth fa ctors, insulin receptor substrate 1 (IRS-1) is phosphorylated in respo nse to IL-4, the interferons (IFNs) and oncostatin M (OSM). Here mutan t cell lines lacking JAK1, JAK2, or Tyk2 were used to determine the ro le(s) of the Janus kinase (JAK) family of protein-tyrosine kinases in IRS-1 phophorylation. 32D cells, which do not express IRS proteins, we re analyzed for any requirement for these proteins in response to the IFNs. For the mutant human fibrosarcoma cell lines, phospho rylation o f IRS-1 through the insulin-like growth factor receptor is independent of JAK1, JAK2, or Tyk2. In contrast, phosphorylation of IRS-1 mediate d by the Type I IFNs, IL-4, and OSM is JAK-dependent. For the alpha be ta-IFNs, activation of IRS-1 is dependent on JAK1 and Tyk2, consistent with the interdependence of these kinases in the IFN-alpha beta respo nse. Neither IRS-1 nor IRS-2 was detectably activated by IFN-gamma. Co nsistent with this, activation of neither IRS proteins appears to be a n absolute requirement for an antiproliferative or an antiviral respon se to the IFNs. For IL-4 and OSM phosphorylation of IRS-1 in the human fibrosarcoma cells is largely dependent on JAK1 but can also be media ted through Tyk2 or JAK2. Activation of phosphatidylinositol 3'-kinase in response to IL-4 and OSM, at least, was also JAK-dependent. The JA Ks are, therefore, required not only for STAT activation but also for the activation through a variety of different types of cytokine recept or, of an additional signaling pathway(s) through IRS-1 and phosphatid ylinositol S'-kinase.