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J. Biol. Chem. 284 (39): 26666-26675

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

The Sodium-Hydrogen Exchanger NHE1 Is an Akt Substrate Necessary for Actin Filament Reorganization by Growth Factors*Formula

Marcel E. Meima{ddagger}1, Bradley A. Webb{ddagger}2, H. Ewa Witkowska§, , and Diane L. Barber{ddagger}3

From the Departments of {ddagger}Cell and Tissue Biology and
§Obstetrics/Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143

ABSTRACT Back to Top

Abstract: The kinase Akt mediates signals from growth factor receptors for increased cell proliferation, survival, and migration, which contribute to the positive effects of Akt in cancer progression. Substrates are generally inhibited when phosphorylated by Akt; however, we show phosphorylation of the plasma membrane sodium-hydrogen exchanger NHE1 by Akt increases exchanger activity (H+ efflux). Our data fulfill criteria for NHE1 being a bona fide Akt substrate, including direct phosphorylation in vitro, using mass spectrometry and Akt phospho-substrate antibodies to identify Ser648 as the Akt phosphorylation site and loss of increased exchanger phosphorylation and activity by insulin and platelet-derived growth factor in fibroblasts expressing a mutant NHE1-S648A. How Akt induces actin cytoskeleton remodeling to promote cell migration and tumor cell metastasis is unclear, but disassembly of actin stress fibers by platelet-derived growth factor and insulin and increased proliferation in growth medium are inhibited in fibroblasts expressing NHE1-S648A. We predict that other functions shared by Akt and NHE1, including cell growth and survival, might be regulated by increased H+ efflux.

Received for publication May 10, 2009. Revision received July 9, 2009.


1 Present address: Div. of Pharmacology, Vascular and Metabolic Diseases, Dept. of Internal Medicine, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

2 Supported by National Institutes of Health Training Grant T32-DE7306-11.

3 To whom correspondence should be addressed: Dept. of Cell and Tissue Biology, Box 0512, 513 Parnassus Ave., University of California, San Francisco, San Francisco, CA 94143. Fax: 415-502-7338; E-mail: diane.barber{at}

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