E-cadherin regulates Eph family members

Cadherins comprise a family of calcium-dependent cell adhesion molecules that regulate many basic developmental processes and are fundamental for the maintenance of both embryonic and adult tissue structure (reviewed in Yap et al., 1997; Stappert and Kemler, 1999). The most studied member of the cadherin protein family is E-cadherin, a transmembrane adhesion protein localized in the adherens junctions (Boller et al., 1985; Gumbiner et al., 1988). During early embryonic development, E-cadherin is expressed in all cells (Butz and Larue, 1995; Damjanov et al., 1986; Ohsugi et al., 1996; Vestweber and Kemler, 1984), but it disappears in embryonic mesoderm cells, which delaminate from the embryonic ectoderm cell layer during gastrulation (Burdsal et al., 1993; Butz and Larue, 1995). It has been proposed that the downregulation of E-cadherin represents the initial step for cells to acquire mesodermal fate during epithelialmesenchymal transition (Burdsal et al., 1993; Huber et al., 1996a). Later in development, E-cadherin is expressed in most, if not all, epithelial tissues. In addition to its role in development and maintenance of epithelial integrity, there is compelling evidence for the involvement of E-cadherin in tumor progression. Lack of E-cadherin-mediated adhesion in human tumors correlates with the loss of epithelial morphology and the acquisition of mesenchymal characteristics. Blocking E-cadherin function in vitro with antibodies or antisense RNA increases tumor cell motility, invasion and metastatic potential (Behrens et al., 1989; Vleminckx et al., 1991). Downregulation of E-cadherin expression or its adhesive dysfunction due to mutations occurs in a number of malignant tumors of epithelial origin (reviewed in Birchmeier and Behrens, 1994). Eph receptor tyrosine kinases (RTKs) and their membranebound ligands, ephrins, form another large family of molecules that are involved in diverse developmental and differentiation processes (reviewed in Frisen et al., 1999; Holder and Klein, 1999). Eph receptors and ephrins are differentially expressed during development and mediate cell-contact-dependent interactions (Davis et al., 1994; Xu and Wilkinson, 1997) at segmental boundaries (Bergemann et al., 1995; Durbin et al., 1998; Rogers et al., 1999; Xu et al., 1996, 1999). They are also involved in neuronal pathfinding and topographic mapping (reviewed in Drescher et al., 1997; O’Leary and Wilkinson, 1999), neural crest cell migration (Krull et al., 1997; Smith et al., 1997; Wang and Anderson, 1997), remodeling of embryonic arteries and veins (Adams et al., 1999; Wang et al., 1998), restricting cell migration and intermingling (Mellitzer et al., 1999; Xu et al., 1999), signaling (reviewed in Bruckner and Klein, 1998; Holder and Klein, 1999) and tumor development (Andres et al., 1994; Easty et al., 1999; Hirai et al., 1987; Kiyokawa et al., 1994; Maru et al., 1990). The specificity of Eph receptor and ephrin signaling is in part achieved by preferential binding of ephrins to different Eph receptors. Eph receptors and ephrins have complementary 1793 Journal of Cell Science 113, 1793-1802 (2000) Printed in Great Britain © The Company of Biologists Limited JCS1269