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J. Biol. Chem., Vol. 279, Issue 46, 47589-47600, November 12, 2004

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3,3',5-Triiodo-L-thyronine Up-regulation of Na,K-ATPase Activity and Cell Surface Expression in Alveolar Epithelial Cells Is Src Kinase- and Phosphoinositide 3-Kinase-dependent^*

Jianxun Lei, Cary N. Mariash, and David H. Ingbar

From the Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455

We previously reported that thyroid hormone, 3,3',5-triiodo-L-thyronine (T3), increased Na,K-ATPase activity of adult rat alveolar epithelial cells in a transcription-independent manner via increased cell surface expression of the ₁ and ₁ subunits of Na,K-ATPase. Now we sought to identify signaling molecules necessary for T3 stimulation of Na,K-ATPase activity in alveolar epithelial cells. Whereas protein kinase A inhibitor H-8 and protein kinase C inhibitor bisindolymaleimide did not block the T3-induced increase in Na,K-ATPase activity, two inhibitors of phosphoinositide 3-kinase (PI3K), wortmannin and Ly294002, and two Src kinase inhibitors, PP1 and PP2, blocked the T3-induced Na,K-ATPase activity. T3 stimulated the activity of PI3K as measured by phosphatidylinositol 3-phosphate. T3 also stimulated the serine 473 phosphorylation of the PI3K downstream molecule PKB/Akt in a dose-dependent manner. Transient expression of a constitutively active mutant of the PI3K catalytic subunit p110 augmented Na,K-ATPase activity and increased the amount of cell surface Na,K-ATPase ₁ subunit protein. T3 also stimulated Src family kinase activity. Transient expression of a constitutively active Src kinase increased Na,K-ATPase activity, PI3K activity, and phosphorylation of PKB/Akt at serine 473. PP1 or PP2 blocked T3-stimulated PKB/Akt phosphorylation at serine 473 and PI3K activity that was activated by an active mutant of Src; however, wortmannin did not inhibit the T3-stimulated Src kinase activity. Although PP1 and wortmannin abolished the increase in Na,K-ATPase activity induced by the active mutant of Src, PP1 did not inhibit the active mutant of PI3K-up-regulated Na,K-ATPase activity. In summary, T3 stimulates the PI3K/PKB pathway via the Src family of tyrosine kinases, and activation of both the Src family kinases and PI3K is required for the T3-induced stimulation of Na,K-ATPase activity and its cell surface expression in adult rat alveolar epithelial cells.

Received for publication, May 17, 2004 , and in revised form, August 26, 2004.

^* This research was supported by a grant from the Will Rogers Institute and National Institutes of Health Grant P50-HL50152. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Pulmonary, Allergy, and Critical Care Division, MMC276, 420 Delaware St. S.E., Minneapolis, MN 55455. Tel.: 612-624-0999; Fax: 612-625-2174; E-mail: ingba001{at}umn.edu.

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