Downregulation of TGF-beta Receptor-2 Expression and Signaling through Inhibition of Na/K-ATPase

作者：La Jennifer; Reed Eleanor; Chan Lan; Smolyaninova Larisa V; Akomova Olga A; Mutlu Gokhan M; Orlov Sergei N^*; Dulin Nickolai O^*

来源：PLos One, 2016, 11(12): e0168363.

DOI：10.1371/journal.pone.0168363

Transforming growth factor-beta (TGF-beta) is a multi-functional cytokine implicated in the control of cell growth and differentiation. TGF-beta signals through a complex of TGF-beta receptors 1 and 2 (TGF beta R1 and TGF beta R2) 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 TGF beta R2 in human lung fibrobalsts (HLF) at the mRNA and protein levels. This was accompanied by inhibition of TGF-beta-induced Smad phosphorylation and the expression of TGF-beta 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 TGF beta R2, the inhibition of TGF-beta-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 TGF beta R2 expression, TGF-beta signaling and cell responses to TGF-beta.

• 出版日期2016-12-22