TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity

• Published in: Scientific reports Vol. 7; no. 1; pp. 15919 - 12
• Main Authors: Mori, Raffaele, Wauman, Joris, Icardi, Laura, Van der Heyden, José, De Cauwer, Lode, Peelman, Frank, De Bosscher, Karolien, Tavernier, Jan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.11.2017; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 38/77; 38/90; 42/44; 631/67/395; 631/80/458/1733; 631/80/86; 82/29; 82/80; Animals; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Growth factors; HEK293 Cells; Humanities and Social Sciences; Humans; Interferon; Interferon-alpha - pharmacology; Interleukin 6; Janus kinase; Kinases; Mice; multidisciplinary; Mutant Proteins - metabolism; Mutation - genetics; NIH 3T3 Cells; Nuclear transport; Phosphorylation; Phosphorylation - drug effects; Phosphotyrosine - metabolism; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein Domains; Protein Multimerization - drug effects; Protein Stability - drug effects; Protein Transport - drug effects; Science; Science (multidisciplinary); Signal transduction; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein - genetics; Suppressor of Cytokine Signaling 3 Protein - metabolism; Transcription activation; Transcription, Genetic - drug effects; Translocation; TYK2 Kinase - chemistry; TYK2 Kinase - metabolism; Tyk2 protein; Tyrosine
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-15912-6

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.