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

EMBO J. 1996 Feb 15;15(4):799-809.

Abstract

The receptor-associated protein tyrosine kinases JAK1 and JAK2 are both required for the interferon (IFN)-gamma response. The effects of expressing kinase-negative JAK mutant proteins on signal transduction in response to IFN-gamma 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-gamma-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-gamma-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-gamma response. Further analysis of the JAK/STAT pathway suggests a model for the IFN-gamma response in which the initial phosphorylation of JAK1 and JAK2 is mediated by JAK2, whereas phosphorylation of the IFN-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Base Sequence
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Enzymologic
  • Genes, fos
  • Humans
  • Interferon-alpha / physiology
  • Interferon-gamma / physiology*
  • Interleukin-6 / physiology
  • Janus Kinase 1
  • Janus Kinase 2
  • Mice
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides / chemistry
  • Phosphorylation
  • Point Mutation
  • Protein-Tyrosine Kinases / physiology*
  • Proto-Oncogene Proteins*
  • Receptors, Interferon / metabolism
  • Regulatory Sequences, Nucleic Acid
  • STAT1 Transcription Factor
  • Signal Transduction
  • Structure-Activity Relationship
  • Trans-Activators / metabolism
  • Viral Interference*

Substances

  • Antigens, CD
  • DNA-Binding Proteins
  • Interferon-alpha
  • Interleukin-6
  • Oligodeoxyribonucleotides
  • Proto-Oncogene Proteins
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Trans-Activators
  • interferon gamma receptor
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • JAK2 protein, human
  • Jak1 protein, mouse
  • Jak2 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 2