Kinase-negative mutants of JAK1 can sustain interferon-γ-inducible gene expression but not an antiviral state

James Briscoe, Neil C. Rogers, Bruce A. Witthuhn, Diane Watling, Ailsa G. Harpur, Andrew F. Wilks, George R. Stark, James N. Ihle, Ian M. Kerr

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

The receptor-associated protein tyrosine kinases JAK1 and JAK2 are both required for the interferon (IFN)-γ response. The effects of expressing kinase-negative JAK mutant proteins on signal transduction in response to IFN-γ in wild-type cells and in mutant cells lacking either JAK1 or JAK2 have been analysed. In cells lacking endogenous JAK1 the expression of a transfected kinase-negative JAK1 can sustain substantial IFN-γ-inducible gene expression, consistent with a structural as well as an enzymic role for JAK1. Kinase-negative JAK2, expressed in cells lacking endogenous JAK2, cannot sustain IFN-γ-inducible gene expression, despite low level activation of STAT1 DNA binding activity. When expressed in wild-type cells, kinase-negative JAK2 acts as a dominant-negative inhibitor of the IFN-γ response. Further analysis of the JAK/STAT pathway suggests a model for the IFN-γ response in which the initial phosphorylation of JAK1 and JAK2 is mediated by JAK2, whereas phosphorylation of the IFN-γ receptor is normally carried out by JAK1. The efficient phosphorylation of STAT 1 in the receptor-JAK complex may again depend on JAK2. Interestingly, a JAK1-dependent signal, in addition to STAT1 activation, appears to be required for the expression of the antiviral state.

Original languageEnglish (US)
Pages (from-to)799-809
Number of pages11
JournalEMBO Journal
Volume15
Issue number4
DOIs
StatePublished - 1996

Keywords

  • Antiviral
  • Interferons
  • JAKs and STATs
  • Mutants
  • Signal transduction

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