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.

Details

Title
TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity
Author
Mori, Raffaele 1 ; Wauman, Joris 1 ; Icardi, Laura 2   VIAFID ORCID Logo  ; Van der Heyden, José 1 ; De Cauwer, Lode 3   VIAFID ORCID Logo  ; Peelman, Frank 1 ; De Bosscher, Karolien 4 ; Tavernier, Jan 5 

1  Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium 
2  Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium; Università vita-salute San Raffaele, Via Olgettina Milano, Milano, Italy 
3  Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium; Argenx BVBA Industriepark Zwijnaarde 7, 9052 Zwijnaarde, Ghent, Belgium 
4  Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium; Receptor Research Laboratories, Nuclear Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium 
5  Receptor Research Laboratories, Cytokine Receptor Lab, VIB-UGent Center for Medical Biotechnology, 9000, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium 
Pages
1-12
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-15912-6
ProQuest document ID
1967046832
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.