JAM-C Regulates Tight Junctions and Integrin-mediated Cell Adhesion and Migration

Sandra Iden,Beat A. Imhof,Michel Aurrand-Lions,Guillaume Mandicourt,Klaus Ebnet

doi:10.1074/jbc.m605666200

Abstract

Junctional Adhesion Molecules (JAMs) have been described as major components of tight junctions in endothelial and epithelial cells. Tight junctions are crucial for the establishment and maintenance of cell polarity. During tumor development, they are remodeled, enabling neoplastic cells to escape from constraints imposed by intercellular junctions and to adopt a migratory behavior. Using a carcinoma cell line we tested whether JAM-C could affect tight junctions and migratory properties of tumor cells. We show that transfection of JAM-C improves the tight junctional barrier in tumor cells devoid of JAM-C expression. This is dependent on serine 281 in the cytoplasmic tail of JAM-C because serine mutation into alanine abolishes the specific localization of JAM-C in tight junctions and establishment of cell polarity. More importantly, the same mutation stimulates integrin-mediated cell migration and adhesion via the modulation of beta1 and beta3 integrin activation. These results highlight an unexpected function for JAM-C in controlling epithelial cell conversion from a static, polarized state to a pro-migratory phenotype.

Highlights

Maintenance of cell polarity is crucial for tissue integrity
We investigated the role of Junctional Adhesion Molecules (JAMs)-C in tight junction plasticity and integrin activation associated to the tumor process
Having previously shown that the localization of JAM-C at cell-cell borders of non-polarized cells is negatively regulated by serine phosphorylation [8], we looked to see whether it is the case in the polarized KLN205 cells

Summary

Introduction

Maintenance of cell polarity is crucial for tissue integrity. The development of cancers is frequently associated with loss of cellular apico-basal polarity, enabling tumor epithelial cells to escape the constraints imposed by intercellular junctions and tissue organization. We show that JAM-C expression in KLN205 cells restores an epithelial phenotype in respect to tight junction formation and trans-epithelial electrical resistance. Junctional Localization of JAM-C in Epithelial Cells Is Controlled by Phosphorylation of Serine 281—To explore the function of JAM-C in polarized cells, we took advantage of the mouse tumor cell line of epithelial origin, KLN205, which lacks endogenous expression of JAM-C (Fig. 1).

Results

Conclusion