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Vol. 16, Issue 3, 1082-1094, March 2005

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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 , Yi Zheng , 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; and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

Submitted May 21, 2004; Revised November 22, 2004; Accepted December 3, 2004
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 phosphatidylinositol 3-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 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.

Address correspondence to: Ayyappan K. Rajasekaran (arajasekaran{at}mednet.ucla.edu).

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