Ephrin

Ephrins (also known as ephrin ligands or Eph family receptor interacting proteins) are

Since ephrin ligands (ephrins) and Eph receptors (Ephs) are both

Ephrin ligands are divided into two subclasses of ephrin-A and ephrin-B based on their structure and linkage to the cell membrane. Ephrin-As are anchored to the membrane by a glycosylphosphatidylinositol (GPI) linkage and lack a cytoplasmic domain, while ephrin-Bs are attached to the membrane by a single transmembrane domain that contains a short cytoplasmic PDZ-binding motif. The genes that encode the ephrin-A and ephrin-B proteins are designated as EFNA and EFNB respectively. Eph receptors in turn are classified as either EphAs or EphBs based on their binding affinity for either the ephrin-A or ephrin-B ligands.^[7]

Of the eight ephrins that have been identified in humans there are five known ephrin-A ligands (ephrin-A1-5) that interact with nine EphAs (EphA1-8 and EphA10) and three ephrin-B ligands (ephrin-B1-3) that interact with five EphBs (EphB1-4 and EphB6).

During the development of the central nervous system Eph/ephrin signaling plays a critical role in the cell–cell mediated migration of several types of neuronal axons to their target destinations. Eph/ephrin signaling controls the guidance of neuronal axons through their ability to inhibit the survival of axonal growth cones, which repels the migrating axon away from the site of Eph/ephrin activation.^[12] The growth cones of migrating axons do not simply respond to absolute levels of Ephs or ephrins in cells that they contact, but rather respond to relative levels of Eph and ephrin expression,^[13] which allows migrating axons that express either Ephs or ephrins to be directed along gradients of Eph or ephrin expressing cells towards a destination where axonal growth cone survival is no longer completely inhibited.^[12]

Although Eph-ephrin activation is usually associated with decreased growth cone survival and the repulsion of migrating axons, it has recently been demonstrated that growth cone survival does not depend just on Eph-ephrin activation, but rather on the differential effects of "forward" signaling by the Eph receptor or "reverse" signaling by the ephrin ligand on growth cone survival.^[12][14]

Retinotopic mapping

The formation of an organized

Ephrins promote angiogenesis in physiological and pathological conditions (e.g. cancer angiogenesis, neovascularisation in

Several types of Ephrins and Eph receptors have been found to be upregulated in human cancers including breast, colon and liver cancers.[24] Surprisingly, the downregulation of other types of Ephrins and their receptors may also contribute to tumorigenesis; namely, EphA1 in colorectal cancers and EphB6 in melanoma.^[24] Displaying similar utility, different ephrins incorporate similar mechanistic pathways to supplement growth of different structures.

Migration factor in intestinal epithelial cell migration

The ephrin protein family of class A and class B guides ligands with the EphB family cell-surface receptors to provide a steady, ordered, and specific migration of the

Experiments performed with Eph receptor knockout mice revealed disorder in the distribution of different cell types.[26] Absorptive cells of various differentiation were mixed with the stem cells within the villi. Without the receptor, the Ephrin ligand was proved to be insufficient for the correct cell placement.^[27] Recent studies with knockout mice have also shown evidence of the ephrin-eph interaction indirect role in the suppression of colorectal cancer. The development of adenomatous polyps created by uncontrolled outgrowth of epithelial cells is controlled by ephrin-eph interaction. Mice with APC mutation, without ephrin-B protein lack the means to prevent the spread of ephB positive tumor cells throughout the crypt-villi junction.^[28]

Reverse signaling

One unique property of the ephrin ligands is that many have the capacity to initiate a "reverse" signal that is separate and distinct from the intracellular signal activated in Eph receptor-expressing cells. Although the mechanisms by which "reverse" signaling occurs are not completely understood, both ephrin-As and ephrin-Bs have been shown to mediate cellular responses that are distinct from those associated with activation of their corresponding receptors. Specifically,