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Vol. 10, Issue 9, 2847-2859, September 1999

Insulin-induced Stimulation of Na⁺,K⁺-ATPase Activity in Kidney Proximal Tubule Cells Depends on Phosphorylation of the -Subunit at Tyr-10

Eric Féraille,^* Maria Luisa Carranza,^* Sandrine Gonin,^* Pascal Béguin, Carlos Pedemonte,^§ Martine Rousselot,^* Joseph Caverzasio, Käthi Geering, Pierre-Yves Martin,^* and Hervé Favre^*

 ^*Division de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland;  Institut de Pharmacologie et de Toxicologie, 1005 Lausanne, Switzerland;  ^§College of Pharmacy, University of Houston, Houston, Texas 77204; and  Division des Maladies Osseuses, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland

Phosphorylation of the -subunit of Na⁺,K⁺-ATPase plays an important role in the regulation of this pump. Recent studies suggest that insulin, known to increase solute and fluid reabsorption in mammalian proximal convoluted tubule (PCT), is stimulating Na⁺,K⁺-ATPase activity through the tyrosine phosphorylation process. This study was therefore undertaken to evaluate the role of tyrosine phosphorylation of the Na⁺,K⁺-ATPase -subunit in the action of insulin. In rat PCT, insulin and orthovanadate (a tyrosine phosphatase inhibitor) increased tyrosine phosphorylation level of the -subunit more than twofold. Their effects were not additive, suggesting a common mechanism of action. Insulin-induced tyrosine phosphorylation was prevented by genistein, a tyrosine kinase inhibitor. The site of tyrosine phosphorylation was identified on Tyr-10 by controlled trypsinolysis in rat PCTs and by site-directed mutagenesis in opossum kidney cells transfected with rat -subunit. The functional relevance of Tyr-10 phosphorylation was assessed by 1) the abolition of insulin-induced stimulation of the ouabain-sensitive ⁸⁶Rb uptake in opossum kidney cells expressing mutant rat 1-subunits wherein tyrosine was replaced by alanine or glutamine; and 2) the similarity of the time course and dose dependency of the insulin-induced increase in ouabain-sensitive ⁸⁶Rb uptake and tyrosine phosphorylation. These findings indicate that phosphorylation of the Na⁺,K⁺-ATPase -subunit at Tyr-10 likely participates in the physiological control of sodium reabsorption in PCT.

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   Corresponding author. E-mail address: feraille{at}cmu.unige.ch.

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Molecular Biology of the Cell
Vol. 10, 2847-2859, September 1999
Copyright © 1999 by The American Society for Cell Biology

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