TYK2-induced phosphorylation of Y640 suppresses STAT3 transcriptional activity
Autor: | José Van der Heyden, Karolien De Bosscher, Joris Wauman, Raffaele Mori, Laura Icardi, Jan Tavernier, Frank Peelman, Lode De Cauwer |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Transcription Genetic lcsh:Medicine SH2 domain Phosphorylation cascade ACTIVATION chemistry.chemical_compound Mice NECK-CANCER Transcriptional regulation Phosphorylation Promoter Regions Genetic lcsh:Science TYROSINE PHOSPHORYLATION Multidisciplinary Chemistry Protein Stability SRC KINASES Cell biology Protein Transport CYTOKINE RECEPTORS Signal transduction Protein Binding STAT3 Transcription Factor ACUTE-PHASE RESPONSE SIGNAL-TRANSDUCTION Article 03 medical and health sciences Protein Domains Animals Humans Phosphotyrosine Transcription factor Cell Nucleus TYK2 Kinase lcsh:R Interferon-alpha Biology and Life Sciences Tyrosine phosphorylation SERINE PHOSPHORYLATION GRANULAR LYMPHOCYTIC-LEUKEMIA 030104 developmental biology HEK293 Cells Suppressor of Cytokine Signaling 3 Protein Mutation NIH 3T3 Cells Mutant Proteins lcsh:Q Protein Multimerization Janus kinase EMBRYONIC STEM-CELLS |
Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) SCIENTIFIC REPORTS Scientific Reports |
ISSN: | 2045-2322 |
Popis: | 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. |
Databáze: | OpenAIRE |
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