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PMID: 8631301 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 15 ·No. 4 ·1996-02-15 ·Pages 799-809

Briscoe J, Rogers NC, Witthuhn BA, Watling D, Harpur AG, Wilks AF, Stark GR, Ihle JN, Kerr IM

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.

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
Chemicals
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
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Briscoe J
Imperial Cancer Research Fund, London, UK.
Rogers N C
Witthuhn B A
Watling D
Harpur A G
Wilks A F
Stark G R
Ihle J N
Kerr I M
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-02-15
Pages
799-809
Language
English
Region
England
NLM ID
8208664
PMCID
PMC450278
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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