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TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity

Raffaele Mori (UGent) , Joris Wauman (UGent) , Laura Icardi (UGent) , José Van Der Heyden (UGent) , Lode De Cauwer (UGent) , Frank Peelman (UGent) , Karolien De Bosscher (UGent) and Jan Tavernier (UGent)
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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.
Keywords
ACUTE-PHASE RESPONSE, GRANULAR LYMPHOCYTIC-LEUKEMIA, EMBRYONIC STEM-CELLS, SIGNAL-TRANSDUCTION, TYROSINE PHOSPHORYLATION, SERINE PHOSPHORYLATION, CYTOKINE RECEPTORS, SRC KINASES, NECK-CANCER, ACTIVATION

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MLA
Mori, Raffaele et al. “TYK2-induced Phosphorylation of Y640 Suppresses STAT3 Transcriptional Activity.” SCIENTIFIC REPORTS 7 (2017): n. pag. Print.
APA
Mori, R., Wauman, J., Icardi, L., Van Der Heyden, J., De Cauwer, L., Peelman, F., De Bosscher, K., et al. (2017). TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity. SCIENTIFIC REPORTS, 7.
Chicago author-date
Mori, Raffaele, Joris Wauman, Laura Icardi, José Van Der Heyden, Lode De Cauwer, Frank Peelman, Karolien De Bosscher, and Jan Tavernier. 2017. “TYK2-induced Phosphorylation of Y640 Suppresses STAT3 Transcriptional Activity.” Scientific Reports 7.
Chicago author-date (all authors)
Mori, Raffaele, Joris Wauman, Laura Icardi, José Van Der Heyden, Lode De Cauwer, Frank Peelman, Karolien De Bosscher, and Jan Tavernier. 2017. “TYK2-induced Phosphorylation of Y640 Suppresses STAT3 Transcriptional Activity.” Scientific Reports 7.
Vancouver
1.
Mori R, Wauman J, Icardi L, Van Der Heyden J, De Cauwer L, Peelman F, et al. TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity. SCIENTIFIC REPORTS. 2017;7.
IEEE
[1]
R. Mori et al., “TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity,” SCIENTIFIC REPORTS, vol. 7, 2017.
@article{8544229,
  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.},
  articleno    = {15919},
  author       = {Mori, Raffaele and Wauman, Joris and Icardi, Laura and Van Der Heyden, José and De Cauwer, Lode and Peelman, Frank and De Bosscher, Karolien and Tavernier, Jan},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keywords     = {ACUTE-PHASE RESPONSE,GRANULAR LYMPHOCYTIC-LEUKEMIA,EMBRYONIC STEM-CELLS,SIGNAL-TRANSDUCTION,TYROSINE PHOSPHORYLATION,SERINE PHOSPHORYLATION,CYTOKINE RECEPTORS,SRC KINASES,NECK-CANCER,ACTIVATION},
  language     = {eng},
  pages        = {12},
  title        = {TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity},
  url          = {http://dx.doi.org/10.1038/s41598-017-15912-6},
  volume       = {7},
  year         = {2017},
}

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