Nonmelanoma Skin Cancer: Use of Epha1 Receptor as a Prognostic Marker

Abstract

The Eph receptors represent the largest family of receptor tyrosine kinases and interact with ephrin ligands. Since the identification of the first receptor of this family, EphA1, in an erythropoietin producing hepatocellular carcinoma cell line (Hirai et al. 1987), the evolving family of related receptors was termed Eph receptor tyrosine kinases. Based on the sequence homology, structure, and binding affinity, both Eph receptors and ephrin ligands are divided into the subclasses A and B (Eph Nomenclature Committee 1997). Presently, 14 Eph receptors and 8 ephrin ligands are known in humans (Figure 28.1). EphA10 has been recently described as a novel member of the family (Aasheim et al. 2005). Two receptors, EphA10 and EphB6, lack a tyrosine kinase activity (Gurniak and Berg 1996). EphA receptors promiscuously bind ephrin-A ligands, and EphB receptors likewise bind ephrin-B ligands. The binding affinity between the single members varies considerably. As an exception, EphA4 can also bind ephrin-B ligands, and ephrin-A5 can act with EphB2 at a high concentration level (Himanen et al. 2004). Ephrin-A ligands are tethered to the outer leaflet of the plasma membrane with a glycosyl-phosphatidyl-inositol anchor, while ephrinB ligands share a transmembrane domain and a short intracytoplasmatic tail. Because Eph receptors and ephrin ligands are both membrane-bound, a direct cell–cell contact is necessary for ligand binding and consecutive activation of intracellular signaling cascades. Structural data revealed that typically Eph-ephrin dimers form tetramers bridging the gap between neighbouring cells and promoting higher-order clustering of signaling centers at cell-cell interfaces (Himanen et al. 2001; Pasquale 2005). As a unique feature, bidirectional signaling is initialized in both the receptor and the ligand bearing cell upon receptor–ligand interaction (Bruckner and Klein 1998). This bidirectional Eph/ephrin signaling between cells is fundamentally involved in developmental processes which depend on organized patterning and movement of cells such as patterning of hindbrain rhombomeres, axonal guidance, and maintenance of cellular boundaries in the organogenesis of the central nervous system (Pasquale 1997) or during the remodeling of blood vessels (Cheng et al. 2002). Currently, the role of Eph-receptors and ephrins in adult human tissues beyond their well defined role in developmental processes is not well defined for most tissue types (Poliakov et al. 2004).