Signaling through a mutant IFN-gamma receptor.
Activation of STAT1 and the IFN-gamma response are thought to be mediated exclusively through the Y440 motif of the human IFNGR1 receptor subunit. Contrary to this accepted dogma, here it is shown that IFNGR1 with a mutant (Y440F) motif, when stably expressed in IFNGR1-negative human fibroblasts at levels similar to wild type, can sustain a substantial IFN-gamma response. The mutant receptor supports selective induction of IFN-gamma-inducible genes but is notably defective in the CIITA, class II HLA, suppressor of cytokine signaling and antiviral responses. Remarkably, similar selective defects are observed in human fibrosarcoma cells expressing a mutant JAK1. The phenotypes are novel and appear distinct from those observed in response to the inhibition of known additional pathways. Data from different cell types further emphasizes the importance of cellular background in determining the response.
Costa-Pereira
Ana P
AP
Cancer Research UK, London. ana.costa-pereira@cancer.org.uk
Hermanns
Heike M
HM
Is'harc
Hayaatun
H
Williams
Timothy M
TM
Watling
Diane
D
Arulampalam
Velmurugesan
V
Newman
Sally J
SJ
Heinrich
Peter C
PC
Kerr
Ian M
IM
D005347:Fibroblasts / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D017471:Receptors, Interferon / Q000032:analysis / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D053613:Janus Kinase 1; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C083728:MHC class II transactivator protein; C507904:JAK1 protein, human