EphA2 Destabilizes Adherens Junctions

Abstract

Ephs are receptor tyrosine kinases that are activated by membrane-bound ephrin ligands on adjacent cells. The Eph-ephrin system plays an important role in coordinating cell movement and organization in development. Some Ephs are associated with certain cancers, and their abundance in cancer cells seems to correlate with tumor malignancy; however, there has been some controversy as to the strength of this relationship. Fang et al . investigated the involvement of Ephs in promoting tumor malignancy in their study of EphA2 signaling in a human breast epithelial cell line (MCF-10A). The authors used a retrovirus to increase the abundance of EphA2 in these cells and demonstrated in cell-cell adhesion assays that MCF-10A cells that expressed wild-type EphA2, but not a signaling-deficient mutant EphA2 (ΔC), exhibited decreased cell-cell adhesion in response to ephrinA. Cell-cell contacts are mediated by E-cadherin (in a Ca 2+ -dependent fashion) and its associated catenin proteins, which are localized at contact points known as adherens junction complexes. Western blotting and immunofluorescence studies showed that the increased abundance of EphA2 had no effect on the abundance or phosphorylation state of any of the known components of the adherens junction complexes. However, depletion of Ca 2+ from the culture medium resulted in accelerated loss of E-cadherin from adherens junctions of cells that contained wild-type EphA2 compared to that in cells that contained ΔC. Further studies showed EphA2-mediated adherens junction destabilization involved Src protein kinase–mediated inhibition of p190RhoGAP, an inhibitor of the small guanosine triphosphatase Rho. These results suggest that the EphA2-stimulated increase in Rho activity may lead to a redistribution of E-cadherin and a loss in cell-cell adhesion, which could be a contributing factor in cancer cell migration and malignancy. W. B. Fang, R. C. Ireton, G. Zhuang, T. Takahashi, A. Reynolds, J. Chen, Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J . Cell Sci . 121 , 358-368 (2008). [Abstract] [Full Text]