The Eph family of receptors is the largest known subfamily 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) and possibly in cancer.1-4 An Eph nomenclature committee adopted a common nomenclature for the receptors and ligands (http://cbweb.med.harvard.edu/eph-nomenclature/).5 See reference 3 for a recent review on Eph receptors and ephrins.
The Eph name is derived from the cell line from which the first member was isolated, erythropoietin-producing human hepatocellular carcinoma line.5 Eph receptors have been divided into two groups, designated EphA and EphB, on the basis of sequence homology.6 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.5 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 while ephrin-Bs are transmembrane proteins.4-6 With few exceptions, EphA receptors bind ephrin-A and EphB receptors bind ephrin-B.3-5 In vitro, each Eph receptor can bind multiple ligands and each ligand can bind multiple receptors.1, 3, 6 In vivo, the receptors and ligands display reciprocal expression.3
Ligand binding results in Eph autophosphorylation on tyrosine and activation of receptor tyrosine kinase activity.6 Only membrane-bound or Fc-clustered ligands are capable of activating the receptor in vitro;6, 7 while soluble monomeric ligands bind the receptor, they do not induce receptor autophosphorylation and activation.7 Several signalling 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 The cytosolic domain of Ephrin-B ligands are also phosphorylated by an unidentified kinase upon binding the EphB receptor.3, 8 The phosphorylated ephrin-B ligand can presumably interact with cellular signalling molecules,3, 8 providing a mechanism of bi-directional cell-cell signalling.
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, 9 In Xenopus, ectopic expression of activated EphA4 resulted in decreased cell-cell adhesion, possibly due to an effect on cadherin.3, 10 Eph receptor-mediated cell-cell recognition may result in the nullification of cell-cell adhesion mechanisms.3 Many cancers display over-expression of Eph receptors or ephrin ligands, possibly resulting in down-regulation 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 metastatis.3