Interferon-induced nuclear signalling by Jak protein tyrosine kinases

Nature. 1993 Dec 9;366(6455):583-5. doi: 10.1038/366583a0.

Abstract

Interferons IFN-alpha/beta and IFN-gamma act through independent cell-surface receptors, inducing gene expression through tyrosine phosphorylation of cytoplasmic transcription factors . 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 subunit to bind regulatory elements of IFN-alpha-responsive genes. IFN-gamma activates p91 alone, inducing IFN-gamma-responsive genes through a distinct DNA element. Genetic complementation studies implicated the tyrosine kinase Tyk2 in IFN-alpha signalling and, more recently, the related Jak2 kinase in IFN-gamma signalling. 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.

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

  • 3T3 Cells
  • Animals
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Chickens
  • Enzyme Activation
  • Gene Expression
  • Interferon-alpha / pharmacology*
  • Interferon-gamma / pharmacology*
  • Janus Kinase 1
  • Janus Kinase 2
  • Kinetics
  • Mice
  • Phosphotyrosine
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins*
  • Signal Transduction / drug effects*
  • Transcription, Genetic
  • Transfection
  • Tyrosine / analogs & derivatives
  • Tyrosine / analysis
  • Tyrosine / metabolism

Substances

  • Interferon-alpha
  • Proto-Oncogene Proteins
  • Phosphotyrosine
  • Tyrosine
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • Jak1 protein, mouse
  • Jak2 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 2