Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state.
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.
Briscoe
J
J
Imperial Cancer Research Fund, London, UK.
Rogers
N C
NC
Witthuhn
B A
BA
Watling
D
D
Harpur
A G
AG
Wilks
A F
AF
Stark
G R
GR
Ihle
J N
JN
Kerr
I M
IM
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D016762:Genes, fos; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010766:Phosphorylation; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D014762:Viral Interference; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D007371:Interferon-gamma; D015850:Interleukin-6; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D009838:Oligodeoxyribonucleotides; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse