2. Academic Validation
  3. TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity

TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity

  • Sci Rep. 2017 Nov 21;7(1):15919. doi: 10.1038/s41598-017-15912-6.
Raffaele Mori 1 2,  Joris Wauman 1 2,  Laura Icardi 1 2 3,  José Van der Heyden 1 2,  Lode De Cauwer 1 2 4,  Frank Peelman 1 2,  Karolien De Bosscher 1 5 2 6,  Jan Tavernier 7 8 9
Affiliations

Affiliations

  • 1 Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium.
  • 2 Department of Biochemistry, Ghent University, Ghent, Belgium.
  • 3 Università vita-salute San Raffaele, Via Olgettina Milano, 58, 20132, Milano, Italy.
  • 4 Argenx BVBA Industriepark Zwijnaarde 7, 9052 Zwijnaarde, Ghent, Belgium.
  • 5 Receptor Research Laboratories, Nuclear Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium.
  • 6 Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
  • 7 Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium. [email protected].
  • 8 Department of Biochemistry, Ghent University, Ghent, Belgium. [email protected].
  • 9 Cancer Research Institute Ghent (CRIG), Ghent, Belgium. [email protected].
PMID: 29162862 DOI: 10.1038/s41598-017-15912-6
Abstract

STAT3 is a pleiotropic transcription factor involved in homeostatic and host defense processes in the human body. It is activated by numerous Cytokines and Growth Factors and generates a series of cellular effects. Of the STAT-mediated signal transduction pathways, STAT3 transcriptional control is best understood. JAK kinase dependent activation of STAT3 relies on Y705 phosphorylation triggering a conformational switch that is stabilized by intermolecular interactions between SH2 domains and the pY705 motif. We here show that a second tyrosine phosphorylation within the SH2 domain at position Y640, induced by Tyk2, negatively controls STAT3 activity. The Y640F mutation leads to stabilization of activated STAT3 homodimers, accelerated nuclear translocation and superior transcriptional activity following IL-6 and LIF stimulation. Moreover, it unlocks type I IFN-dependent STAT3 signalling in cells that are normally refractory to STAT3 transcriptional activation.

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