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 Ephrin-Eph Signaling

Eph receptor tyrosine kinases and their cell-surface bound ligands, the Ephrins, are involved in a variety of cell to cell inter-communications that affect processes such as cell patterning, guidance, migration and adhesion. They define spatial boundaries. Ephrin-Eph interactions are frequently repulsive wherein cells containing a given Eph receptor are repelled by cells containing the corresponding Ephrin ligand. The Eph-Ephrin molecules are involved in the regulation of axon guidance, axon fasciculation, topological map formation of the retinotectal/tetinocolicular system, formation of brain commissures, migration of neuroal crest cells and vascularization.

The Eph receptor tyrosine kinase (RTK) family is composed of 14 members that are subdivided into two subclasses based upon their complementary Ephrin ligands. There are nine Ephrin ligands classified as either Ephrin A or Ephrin B. Ephrin A ligands are bound to the cell membrane by glycosylphosphatidylinositol (GPI) anchors, whereas Ephrin B ligands are transmembrane proteins.

The EphA family is composed of eight members: EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7 and EphA8 that inteact with EphrinA1, EphrinA2, EphrinA3, EphrinA4, EphrinA5, or EphrinA6. The EphB family is composed of six members: EphB1, EphB2, EphB3, EphB4, EphB5, and EphB6. The EphB receptor subfamily members interact with EphrinB1, EphrinB2, or EphrinB3.

EphA, EphB receptors and the Ephrin B ligands have cytoplasmic domains that initiate internal signaling cascades. EphrinA ligands do not have cytoplasmic domains. They are dependent upon membrane lipid raft proteins such as p120 to activate molecules such as integrins. The Eph receptors and ephrin-B counter-receptors have C-terminal sequences capable of interacting with PDZ-domain-containing proteins, including PICK1, syntenin, GRIP and PDZ-RGS.