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Protein Purification-free Method of Binding Affinity Determination by Microscale Thermophoresis
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TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity

Raffaele Mori1,2, Joris Wauman1,2, Laura Icardi1,2,3

  • 1Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium.

Scientific Reports
|November 23, 2017
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) activity is negatively controlled by Tyk2-induced Y640 phosphorylation. This phosphorylation site mutation enhances STAT3

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Immunology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor regulating cellular processes.
  • STAT3 activation typically involves Y705 phosphorylation, promoting homodimerization and transcriptional activity.
  • Understanding STAT3 regulation is crucial for various physiological and pathological conditions.

Purpose of the Study:

  • To investigate the role of a second tyrosine phosphorylation site, Y640, in STAT3 regulation.
  • To elucidate the impact of Tyk2-mediated Y640 phosphorylation on STAT3 activity.
  • To explore the functional consequences of Y640 phosphorylation on STAT3-dependent gene expression.

Main Methods:

  • Site-directed mutagenesis to create Y640F STAT3.
  • Analysis of STAT3 phosphorylation at Y705 and Y640.
  • Assessment of STAT3 homodimerization, nuclear translocation, and transcriptional activity.
  • Investigating STAT3 signaling in response to IL-6, LIF, and type I interferons.

Main Results:

  • Tyk2-induced Y640 phosphorylation negatively regulates STAT3 activity.
  • The Y640F mutation stabilizes activated STAT3 homodimers.
  • Y640F mutation accelerates nuclear translocation and enhances transcriptional activity upon IL-6 and LIF stimulation.
  • The Y640F mutation enables type I IFN-dependent STAT3 signaling in refractory cells.

Conclusions:

  • Y640 phosphorylation by Tyk2 acts as a negative feedback mechanism for STAT3.
  • Targeting Y640 phosphorylation could modulate STAT3 activity for therapeutic benefit.
  • This finding reveals a novel regulatory mechanism for STAT3 in immune and homeostatic responses.

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