INTERFERON-INDUCED NUCLEAR SIGNALING BY JAK PROTEIN-TYROSINE KINASES

INTERFERONS IFN-alpha/beta and IFN-gamma act through independent cell-surface receptors, inducing gene expression through tyrosine phosphorylation of cytoplasmic transcription factors1-5. IFN-alpha stimulates phosphorylation and nuclear localization of the 84/91K and 113K subunits of latent ISGF3 (interferon-stimulated gene factor 3), which combine with the 48K DNA-binding subunit6,7 to bind regulatory elements of IFN-alpha-responsive genes8-10. IFN-gamma activates p91 alone2, inducing IFN-gamma-responsive genes through a distinct DNA element11,12. Genetic complementation studies implicated the tyrosine kinase Tyk2 in IFN-alpha signalling13 and, more recently, the related Jak2 kinase in IFN-gamma signalling14. We now present biochemical evidence for Jak-family kinase involvement in IFN signal transduction. Jak1 was activated in response to IFN-alpha and IFN-gamma; Jak2 responded exclusively to IFN-gamma. Overexpression of either Jak1 or Jak2 stimulated p91 DNA-binding activity and p91-dependent transcription. Overexpression also activated endogenous Jak kinases, suggesting that interactions between Jak kinases are required during interferon signalling.