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Interferon-induced nuclear signalling by Jak protein tyrosine kinases

Abstract

INTERFERONS IFN-α/β and IFN-γ act through independent cell-surface receptors, inducing gene expression through tyrosine phosphorylation of cytoplasmic transcription factors1–5. IFN-α 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-α-responsive genes8–10. TFN-γ activates p91 alone2, inducing IFN-γ-responsive genes through a distinct DNA element11,12. Genetic complementation studies implicated the tyrosine kinase Tyk2 in IFN-α signalling13 and, more recently, the related Jak2 kinase in IFN-γ signalling14. We now present biochemical evidence for Jak-family kinase involvement in IFN signal transduction. Jak1 was activated in response to IFN-α and IFN-γ Jak2 responded exclusively to IFN-γ. 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.

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Silvennoinen, O., Ihle, J., Schlessinger, J. et al. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature 366, 583–585 (1993). https://doi.org/10.1038/366583a0

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