Differential Regulation of EphA2 in Normal and Malignant Cells

Abstract

Eph receptor tyrosine kinases (RTK) comprise the largest family of tyrosine kinases encoded in the human genome. 1,2 Fourteen Eph receptors and eight ephrin ligands have been identified to date and these molecules are increasingly understood to play important roles in disease and development. 3-5 Eph receptor family members share structural and functional similarities. Their extracellular regions include an N-terminal ligand binding domain, 6,7 a cysteine-rich motif, and two fibronectin-like repeats. Also, Eph receptors can be distinguished from other RTKs in that they all recognize ligands, known as ephrins, which are anchored to the membrane of apposing cells. 1,2,8,9 Ephrins do not necessarily share extensive homology and are so grouped based on their abilities to bind Eph receptors. The ephrins have been separated into two classes based on the means by which they are anchored to the cell membrane. 3,9 EphrinA ligands are linked to the cell membrane by a glycosylphophatidylinositol (GPI) linkage, whereas EphrinB ligands encode for a transmembrane domain. Based on the identity of their ligands, the Eph receptors themselves have been classified into either EphA or EphB subfamilies. 9 These families share a degree of specificity, which is determined by a four-amino-acid loop on the extracellular surface. 10 Moreover, Eph receptors and ephrin ligands each have overlapping specificity. 1,2,8 Several ligands can bind to one receptor and, in turn, several receptors can bind to one ligand. In general, however, EphA receptors bind EphrinA ligands and EphB receptors bind EphrinB ligands. 1,2,8,11-13 Ligand binding typically triggers tyrosine phosphorylation of Eph receptors. 2 In particular, two tyrosines near the transmembrane domain are highly conserved and phosphorylated in response to ligand binding. 14,15 These residues appear to be critical for function, as mutations of these tyrosines abolish the enzymatic activity of certain Eph kinases. 15 In addition, tyrosine phosphorylation creates binding sites for signaling or adapter proteins (Figure 1) ▶ . 16 Other sites of protein-protein interaction are also mediated by sterile α motifs (SAM) 17,18 and PDZ (postsynaptic density protein, disc large, zona occludens) binding motifs 19 located near the C-terminal end of some Eph receptors. Figure 1. Biological and biochemical pathways linked with EphA2. Shown is a synthesis of the reported protein interactions and cellular consequences of EphA2 signaling. The solid lines denote areas of known positive regulation, whereas dotted lines represent a ... Eph receptors have been studied extensively in the developing nervous system, where they regulate patterning during neural development. 2,11-13,20,21 At the cellular level, ephrin binding causes Eph receptors to initiate signals that promote cell-cell repulsion and these events appear to assist axon guidance and neural organization. 1