title: Downregulation of TGF-β Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase.
abstract: Transforming growth factor-beta (TGF-β) is a multi-functional cytokine implicated in the control of cell growth and differentiation. TGF-β signals through a complex of TGF-β receptors 1 and 2 (TGFβR1 and TGFβR2) that phosphorylate and activate Smad2/3 transcription factors driving transcription of the Smad-target genes. The Na+/K+-ATPase is an integral plasma membrane protein critical for maintaining the electro-chemical gradient of Na+ and K+ in the cell. We found that inhibition of the Na+/K+ ATPase by ouabain results in a dramatic decrease in the expression of TGFβR2 in human lung fibrobalsts (HLF) at the mRNA and protein levels. This was accompanied by inhibition of TGF-β-induced Smad phosphorylation and the expression of TGF-β target genes, such as fibronectin and smooth muscle alpha-actin. Inhibition of Na+/K+ ATPase by an alternative approach (removal of extracellular potassium) had a similar effect in HLF. Finally, treatment of lung alveolar epithelial cells (A549) with ouabain also resulted in the downregulation of TGFβR2, the inhibition of TGF-β-induced Smad phosphorylation and of the expression of mesenchymal markers, vimentin and fibronectin. Together, these data demonstrate a critical role of Na+/K+-ATPase in the control of TGFβR2 expression, TGF-β signaling and cell responses to TGF-β.
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: La
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, United States of America.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Reed
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Chan
authors.affiliation: Laboratory of Biomembranes, Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Smolyaninova
authors.affiliation: Laboratory of Biomembranes, Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Akomova
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, United States of America.
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.affiliation: Laboratory of Biomembranes, Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.|Siberian Medical State University, Tomsk, Russia.
authors.forename: Sergei N
authors.initials: SN
authors.lastname: Orlov
authors.affiliation: Department of Medicine, Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, United States of America.|Siberian Medical State University, Tomsk, Russia.
authors.forename: Nickolai O
authors.initials: NO
authors.lastname: Dulin
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D000254:Sodium-Potassium-Exchanging ATPase