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A more recent version of this article appeared on March 1, 2005
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Submitted on May 21, 2004
Revised on November 22, 2004
Accepted on December 3, 2004
*Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Division of Experimental Hematology and Molecular Developmental Biology Program, Children’s Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45229; 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 
- and 
-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 1-subunit (Na,K-) 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- reduces cell motility remained elusive. Here, we demonstrate that Na,K- localizes to lamellipodia and suppresses cell motility by a novel signaling mechanism involving a cross talk between Na,K-ATPase 1-subunit (Na,K-) and Na,K- with proteins involved in PI3-kinase signaling pathway. We show that Na,K- associates with the regulatory subunit of PI3-kinase and Na,K- 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.
Corresponding author.
E-mail: arajasekaran{at}mednet.ucla.edu
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