Abstract
Nontoxic concentrations of ouabain, causing partial inhibition of the cardiac myocyte Na(+)/K(+)-ATPase, induce hypertrophy and several growth-related genes through signal pathways that include the activation of Ras and p42/44 mitogen-activated protein kinase (MAPK). The aim of this work was to examine the ouabain-induced events upstream of the Ras/MAPK cascade. Treatment of myocytes with genistein antagonized ouabain-induced activation of the MAPK, suggesting that protein tyrosine phosphorylation has a role. Tyrosine phosphorylation of several myocyte proteins was increased rapidly upon cell exposure to ouabain. Lowering of extracellular K(+) had a similar ouabain-like effect. Ouabain also increased protein tyrosine phosphorylation in A7r5, HeLa, and L929 cells. In cardiac myocytes and A7r5 cells, herbimycin A antagonized the ouabain-induced increase in protein tyrosine phosphorylation and MAPK activation. In both cell types, ouabain stimulated Src kinase activity, Src translocation to the Triton-insoluble fraction, Src association with the epidermal growth factor receptor, and the tyrosine phosphorylation of this receptor on site(s) other than its major autophosphorylation site, Tyr(1173). The findings suggest that (a) the ouabain-induced activation of Src and the Src-induced phosphorylation of the growth factor receptor provide the scaffolding for the recruitment of adaptor proteins and Ras and the activation of Ras/MAPK cascade; and (b) the activation of such pathways may be a common feature of the signal-transducing function of Na(+)/K(+)-ATPase in most cells.
Highlights
Nontoxic concentrations of ouabain, causing partial inhibition of the cardiac myocyte Naⴙ/Kⴙ-ATPase, induce hypertrophy and several growth-related genes through signal pathways that include the activation of
In cardiac myocytes and A7r5 cells, herbimycin A antagonized the ouabain-induced increase in protein tyrosine phosphorylation and mitogen-activated protein kinase (MAPK) activation
The findings suggest that (a) the ouabain-induced activation of Src and the Src-induced phosphorylation of the growth factor receptor provide the scaffolding for the recruitment of adaptor proteins and Ras and the activation of Ras/
Summary
Nontoxic concentrations of ouabain, causing partial inhibition of the cardiac myocyte Naⴙ/Kⴙ-ATPase, induce hypertrophy and several growth-related genes through signal pathways that include the activation of. In cardiac myocytes and A7r5 cells, herbimycin A antagonized the ouabain-induced increase in protein tyrosine phosphorylation and MAPK activation. Partial inhibition of the Na⫹/K⫹-ATPase by ouabain and other cardiac glycosides produces a modest increase in intracellular Na⫹, which in turn causes significant increases in intracellular Ca2⫹ and cardiac contractility [3]. We have shown that the same nontoxic concentrations of ouabain that partially inhibit the Na⫹/K⫹-ATPase and increase intracellular Ca2⫹ stimulate hypertrophic growth of rat neonatal cardiac myocytes and regulate the transcription of the genes
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