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Novel Role for Na,K-ATPase in Phosphatidylinositol 3-Kinase Signaling and Suppression of Cell Motility
Sonali P. Barwe *,
Gopalakrishnapillai Anilkumar *,
Sun Y. Moon,
Julian P. Whitelegge,
Sigrid A. Rajasekaran *, and
Ayyappan K. Rajasekaran *
* 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 and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
Received for publication May 21, 2004.
Revision received November 22, 2004.
Accepted for publication December 3, 2004.
Monitoring Editor: Guido Guidotti
The Na,K-ATPase, consisting of - and -subunits, regulates intracellularion homeostasis. Recent studies have demonstrated that Na,K-ATPasealso regulates epithelial cell tight junction structure andfunctions. Consistent with an important role in the regulationof epithelial cell structure, both Na,K-ATPase enzyme activityand subunit levels are altered in carcinoma. Previously, wehave shown that repletion of Na,K-ATPase 1-subunit (Na,K-) inhighly motile Moloney sarcoma virus-transformed Madin-Darbycanine kidney (MSV-MDCK) cells suppressed their motility. However,until now, the mechanism by which Na,K- reduces cell motilityremained elusive. Here, we demonstrate that Na,K- localizesto lamellipodia and suppresses cell motility by a novel signalingmechanism involving a cross-talk between Na,K-ATPase 1-subunit(Na,K-) and Na,K- with proteins involved in phosphatidylinositol3-kinase (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 activatePI3-kinase at the lamellipodia and suppress cell motility inMSV-MDCK cells, independent of Na,K-ATPase ion transport activity.Thus, these results demonstrate a new role for Na,K-ATPase inregulating carcinoma cell motility.
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