Eph receptors comprise the largest family of receptor tyrosine kinases, consisting of eight EphA receptors (with five corresponding glycosylphosphatidylinisotol [GPI]-anchored ephrinA ligands) and six EphB receptors (with three corresponding transmembrane ephrinB ligands) (Figure 38.1). They were originally identified as neuronal path finding molecules (1,2). Yet, genetic loss-of-function experiments have surprisingly revealed that EphB receptors and ephrinB ligands act also as critical regulators of vascular assembly and arteriovenous differentiation. This chapter summarizes the current knowledge about the vascular functions of Eph receptors and ephrin ligands and discusses some emerging roles of these molecules in the regulation of vascular homeostasis, leukocyte trafficking, and tumor progression.

CHARACTERISTICS OF EPH RECEPTORS AND EPHRIN LIGANDS

Eph receptors and their corresponding ephrin ligands are grouped into A and B subfamilies based on distinct structural properties of the ephrin ligands (see Figure 38.1). EphrinA ligands are GPI-anchored peripheral membrane molecules. EphrinB ligands are transmembrane molecules whose cytoplasmic domain is capable of engaging in various signaling activities. The corresponding Eph receptors act as classical transmembrane tyrosine kinases. Correspondingly, the activation of Eph receptors by ephrin ligands is referred to as “forward signaling,” whereas the EphB receptor-mediated activation of ephrinB ligands is designated as “reverse signaling.”

Eph receptors and ephrin ligands were originally described as neuronal path finding molecules. Given that both receptor and ligand are transmembrane molecules, trans Eph/ephrin signaling is dependent on the juxtapositional contact of neighboring cells. As such, they elicit propulsive and repulsive activities on outgrowing axons and are, thus, critical mediators of neuronal network formation (1,3,4).