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J. Biol. Chem., Vol. 282, Issue 38, 28137-28148, September 21, 2007

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Junctional Adhesion Molecule-A Is Critical for the Formation of Pseudocanaliculi and Modulates E-cadherin Expression in Hepatic Cells^*

From the Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53202

Hepatocytes are polarized epithelial cells whose function depends upon their ability to distinguish between the apical and basolateral surfaces that are located at intercellular tight junctions. It has been proposed that the signaling cascades originating at these junctions influence cellular activity by controlling gene expression in the cell nucleus. To assess the validity of this proposal with regard to hepatocytes, we depleted expression of the tight junction protein junctional adhesion molecule-A (JAM-A) in the HepG2 human hepatocellular carcinoma cell line. Reduction of JAM-A resulted in a striking change in cell morphology, with cells forming sheets 1-2 cells thick instead of the normal multilayered clusters. In the absence of JAM-A, other tight junction proteins were mislocalized, and pseudocanaliculi, which form the apical face of the hepatocyte, were consequently absent. There was a strong transcriptional induction of the adherens junction protein E-cadherin in cells with reduced levels of JAM-A. This increase in E-cadherin was partially responsible for the observed alterations in cell morphology and mislocalization of tight junction proteins. We therefore propose the existence of a novel mechanism of cross-talk between specific components of tight and adherens junctions that can be utilized to regulate adhesion between hepatic cells.

Received for publication, May 1, 2007 , and in revised form, June 18, 2007.

^* 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 Figs. 1-4.

¹ Supported by NIDDK grants from the National Institutes of Health.

² Present address: Dept. of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095.

³ To whom correspondence should be addressed: Dept. of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53202. Tel.: 414-456-8602; Fax: 414-456-6517; E-mail: duncans{at}mcw.edu.

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