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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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Published on: January 24, 2016

Multiple kinases in the interferon-gamma response.

D Watling1, C R Carmo, I M Kerr

  • 1Department of Oncology, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|April 18, 2008
PubMed
Summary
This summary is machine-generated.

This study identified new kinases crucial for interferon-gamma (IFN-gamma) responses using a flow cytometry screen. Ataxia telangiectasia-mutated (ATM) kinase plays a key role in early IFN-gamma signaling and gene regulation.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) mediate responses to interferons (IFNs) and other cytokines.
  • However, JAK/STAT signaling alone is insufficient for a complete IFN-gamma response.

Purpose of the Study:

  • To identify novel kinases involved in IFN-gamma signaling pathways.
  • To characterize the role of these kinases in different IFN-gamma-mediated cellular responses.

Main Methods:

  • A quantitative, flow cytometry-based kinome-wide siRNA screen was employed.
  • The screen assessed requirements for IFN-gamma class II HLA, antiviral, and encephalomyocarditis virus (EMCV) cytopathic responses.

Main Results:

  • Nine additional kinases were identified for the IFN-gamma class II HLA response.
  • Seven kinases were implicated in the antiviral response, and two in the EMCV cytopathic response.
  • Ataxia telangiectasia-mutated (ATM) kinase was shown to differentially affect IFN-gamma-stimulated mRNAs early in the response.

Conclusions:

  • Quantitative flow cytometry-based siRNA screens are powerful tools for dissecting complex cellular signaling.
  • ATM kinase is involved in early transcriptional control during IFN-gamma responses, potentially via chromatin modulation.
  • Multiple novel kinases are essential for robust IFN-gamma signaling and cellular defense mechanisms.