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Focal adhesion kinase regulates the activity of the osmosensitive transcription factor TonEBP/NFAT5 under hypertonic conditions.
Neuhofer, Wolfgang; Küper, Christoph; Lichtnekert, Julia; Holzapfel, Konstantin; Rupanagudi, Khader V; Fraek, Maria-Luisa; Bartels, Helmut; Beck, Franz-Xaver.
Afiliación
  • Neuhofer W; Division of Nephrology, Medical Clinic and Policlinic IV, University of Munich Munich, Germany ; Department of Cellular Physiology, University of Munich Munich, Germany.
  • Küper C; Department of Cellular Physiology, University of Munich Munich, Germany.
  • Lichtnekert J; Division of Nephrology, Medical Clinic and Policlinic IV, University of Munich Munich, Germany.
  • Holzapfel K; Department of Radiology, Klinikum Rechts der Isar, Technical University of Munich Munich, Germany.
  • Rupanagudi KV; Division of Nephrology, Medical Clinic and Policlinic IV, University of Munich Munich, Germany.
  • Fraek ML; Department of Cellular Physiology, University of Munich Munich, Germany.
  • Bartels H; Center of Anatomy, Institute of Functional and Applied Anatomy, Hannover Medical School Hannover, Germany.
  • Beck FX; Department of Cellular Physiology, University of Munich Munich, Germany.
Front Physiol ; 5: 123, 2014.
Article en En | MEDLINE | ID: mdl-24772088
TonEBP/NFAT5 is a major regulator of the urinary concentrating process and is essential for the osmoadaptation of renal medullary cells. Focal adhesion kinase (FAK) is a mechanosensitive non-receptor protein tyrosine kinase expressed abundantly in the renal medulla. Since osmotic stress causes cell shrinkage, the present study investigated the contribution of FAK on TonEBP/NFAT5 activation. Osmotic stress induced time-dependent activation of FAK as evidenced by phosphorylation at Tyr-397, and furosemide reduces FAK Tyr-397 phosphorylation in the rat renal medulla. Both pharmacological inhibition of FAK and siRNA-mediated knockdown of FAK drastically reduced TonEBP/NFAT5 transcriptional activity and target gene expression in HEK293 cells. This effect was not mediated by impaired nuclear translocation or by reduced transactivating activity of TonEBP/NFAT5. However, TonEBP/NFAT5 abundance under hypertonic conditions was diminished by 50% by FAK inhibition or siRNA knockdown of FAK. FAK inhibition only marginally reduced transcription of the TonEBP/NFAT5 gene. Rather, TonEBP/NFAT5 mRNA stability was diminished significantly by FAK inhibition, which correlated with reduced reporter activity of the TonEBP/NFAT5 mRNA 3' untranslated region (3'-UTR). In conclusion, FAK is a major regulator of TonEBP/NFAT5 activity by increasing its abundance via stabilization of the mRNA. This in turn, depends on the presence of the TonEBP/NFAT5 3'-UTR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Physiol Año: 2014 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Physiol Año: 2014 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Suiza