Eph Receptors and Ephrins

This is the authors' abstract. We don't add key points for this paper.

The Eph family of receptors is the largest known sub-family of receptor tyrosine kinases [1, 2]. The ligands are called ephrins. The ephrin-Eph interactions are important in development, especially in cell-cell interactions involved in nervous system patterning (axon guidance), angiogenesis, and possibly in cancer [1-5]. Prior to the adaptation of a common nomenclature, the receptors and ligands had multiple names [6]. Recent reviews on Eph receptors and ephrin ligands have been performed [3, 7, 8]. The Eph name is derived from the cell line from which the first member was isolated, erythropoietin-producing human hepatocellular carcinoma line [6]. Eph receptors have been divided into two groups, designated EphA and EphB, on the basis of sequence homology [9]. The extracellular region contains an Ig domain at the amino terminus, a cysteine-rich region, and two fibronectin type III repeats near a single membrane-spanning region. The cytoplasmic region contains a highly conserved tyrosine kinase domain flanked by a juxtamembrane region and a carboxy-terminal tail [3]. The Eph ligands are called ephrins, derived from an abbreviation for Eph family receptor interacting proteins [6]. They are cell-surface associated proteins, and they naturally divide into two groups, ephrin-A and ephrin-B, based on structure and function. Ephrin-As are anchored to the cell via a glycosylphosphatidylinositol (GPI) linkage [4, 6, 9], while ephrin-Bs are transmembrane proteins (Fig. 1) [4, 6, 9]. With few exceptions, EphA receptors bind ephrin-A and EphB receptors bind ephrin-B (Table 1) [3, 4, 6]. In vitro, each Eph receptor can bind multiple ligands and each ligand can bind multiple receptors [1, 3, 9]. In vivo, the receptors and ligands display reciprocal expression [3] and may display less promiscuous binding [7, 8]. Ligand binding results in Eph autophosphorylation on tyrosine and activation of receptor tyrosine kinase activity [9]. Only membrane-bound or Fc-clustered ligands are capable of activating the receptor in vitro [9, 10]. While soluble monomeric ligands bind the receptor, they do not induce receptor autophosphorylation and activation [10]. Several signaling molecules bind via their SH2 domain to the phosphorylated Eph receptor [3]. Phosphatidylinositol 3-kinase activity is increased in response to EphA2 receptor activation [3]. Ephrin-B ligands are also phosphorylated by an unidentified kinase upon binding the EphB receptor [3, 11]. The phosphorylated ephrin-B ligand can presumably interact with cellular signaling molecules [3, 11], providing a mechanism of bi-directional cell-cell signaling. However, detailed signaling pathways for the Eph receptors and ephrin-B ligands have not been elucidated. Fc-clustered soluble ligand can cause the growth cones of cultured temporal retinal neurons, bearing the appropriate Eph receptor, to collapse [3]. The collapse of the growth cone is accompanied by disruption of the actin cytoskeleton within the growth cone [3, 12]. In Xenopus, ectopic expression of activated EphA4 resulted in decreased cell-cell adhesion. This decrease in cell-cell adhesion was possibly due to an effect on the function of cadherin [3, 13]. Additional observations suggest that Eph receptor-mediated cell-cell recognition can result in the nullification of cell-cell adhesion mechanisms [3]. Many cancers display overexpression of Eph receptors and/or ephrin ligands, possibly resulting in downregulation of cell adhesion when the Eph receptor and/or ephrin ligand on the tumor cell encounters the other on adjacent cells. This may then play a role in cancer metastasis [3].