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MBC in Press, published online ahead of print December 22, 2004
Mol. Biol. Cell 10.1091/mbc.E04-05-0427

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Submitted on May 21, 2004
Revised on November 22, 2004
Accepted on December 3, 2004

Novel Role for Na,K-ATPase in PI3-Kinase Signaling and Suppression of Cell Motility

Sonali P. Barwe,* Gopalakrishnapillai Anilkumar,* Sun Y. Moon,{dagger} Yi Zheng,{dagger} Julian P. Whitelegge,{ddagger} Sigrid A. Rajasekaran,* and Ayyappan K. Rajasekaran*{sect}

*Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; {dagger}Division of Experimental Hematology and Molecular Developmental Biology Program, Children’s Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45229; {ddagger}Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

Monitoring Editor: Guido Guidotti

The Na,K-ATPase, consisting of {alpha}- and {beta}-subunits, regulates intracellular ion homeostasis. Recent studies have demonstrated that Na,K-ATPase also regulates epithelial cell tight junction structure and functions. Consistent with an important role in the regulation of epithelial cell structure, both Na,K-ATPase enzyme activity and subunit levels are altered in carcinoma. Previously, we have shown that repletion of Na,K-ATPase {beta}1-subunit (Na,K-{beta}) in highly motile Moloney sarcoma virus-transformed Madin-Darby canine kidney (MSV-MDCK) cells suppressed their motility. However, until now, the mechanism by which Na,K-{beta} reduces cell motility remained elusive. Here, we demonstrate that Na,K-{beta} localizes to lamellipodia and suppresses cell motility by a novel signaling mechanism involving a cross talk between Na,K-ATPase {alpha}1-subunit (Na,K-{alpha}) and Na,K-{beta} with proteins involved in PI3-kinase signaling pathway. We show that Na,K-{alpha} associates with the regulatory subunit of PI3-kinase and Na,K-{beta} binds to annexin II. These molecular interactions locally activate PI3-kinase at the lamellipodia and suppress cell motility in MSV-MDCK cells, independent of Na,K-ATPase ion transport activity. Thus, these results demonstrate a new role for Na,K-ATPase in regulating carcinoma cell motility.

{sect}Corresponding author. E-mail: arajasekaran{at}mednet.ucla.edu






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