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J. Biol. Chem., Vol. 281, Issue 51, 39573-39587, December 22, 2006

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The Role of the ₁ Subunit of the Na,K-ATPase and Its Glycosylation in Cell-Cell Adhesion^*

From the Department of Physiology, School of Medicine, UCLA and Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, California 90073

Based on recent data showing that overexpression of the Na,K-ATPase ₁ subunit increased cell-cell adhesion of nonpolarized cells, we hypothesized that the ₁ subunit can also be involved in the formation of cell-cell contacts in highly polarized epithelial cells. In support of this hypothesis, in Madin-Darby canine kidney (MDCK) cells, the Na,K-ATPase ₁ and ₁ subunits were detected as precisely co-localized with adherens junctions in all stages of the monolayer formation starting from the initiation of cell-cell contact. The Na,K-ATPase and adherens junction protein, -catenin, stayed partially co-localized even after their internalization upon disruption of intercellular contacts by Ca²⁺ depletion of the medium. The Na,K-ATPase subunits remained co-localized with the adherens junctions after detergent treatment of the cells. In contrast, the heterodimer formed by expressed unglycosylated Na,K-ATPase ₁ subunit and the endogenous ₁ subunit was easily dissociated from the adherens junctions and cytoskeleton by the detergent extraction. The MDCK cell line in which half of the endogenous ₁ subunits in the lateral membrane were substituted by unglycosylated ₁ subunits displayed a decreased ability to form cell-to-cell contacts. Incubation of surface-attached MDCK cells with an antibody against the extracellular domain of the Na,K-ATPase ₁ subunit specifically inhibited cell-cell contact formation. We conclude that the Na,K-ATPase ₁ subunit is involved in the process of intercellular adhesion and is necessary for association of the heterodimeric Na,K-ATPase with the adherens junctions. Further, normal glycosylation of the Na,K-ATPase ₁ subunit is essential for the stable association of the pump with the adherens junctions and plays an important role in cell-cell contact formation.

Received for publication, July 10, 2006 , and in revised form, October 10, 2006.

^* This work was supported in part by National Institutes of Health Grants DK46917, DK58333, and D53642 and the United States Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Videos 1-5.

¹ To whom correspondence should be addressed: VAGLAHS/West LA, Bldg. 113, Rm. 324, 11301 Wilshire Blvd., Los Angeles, CA 90073. Tel.: 310-268-4672; Fax: 310-312-9478; E-mail: olgav{at}ucla.edu.

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