Ephrin

Last updated
Ephrin
PDB 2hle EBI.jpg
Ectodomains of the Ephb4-Ephrinb2 protein complex
Identifiers
SymbolEphrin
Pfam PF00812
Pfam clan CL0026
InterPro IPR001799
PROSITE PDOC01003
SCOP2 1kgy / SCOPe / SUPFAM
CDD cd02675
Membranome 70
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Ephrins (also known as ephrin ligands or Eph family receptor interacting proteins) are a family of proteins that serve as the ligands of the Eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).

Contents

Since ephrin ligands (ephrins) and Eph receptors (Ephs) are both membrane-bound proteins, binding and activation of Eph/ephrin intracellular signaling pathways can only occur via direct cell–cell interaction. Eph/ephrin signaling regulates a variety of biological processes during embryonic development including the guidance of axon growth cones, [1] formation of tissue boundaries, [2] cell migration, and segmentation. [3] Additionally, Eph/ephrin signaling has been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, [4] angiogenesis, [5] and stem cell differentiation. [6]

Classification

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). [4] [8] Ephs of a particular subclass demonstrate an ability to bind with high affinity to all ephrins of the corresponding subclass, but in general have little to no cross-binding to ephrins of the opposing subclass. [9] However, there are a few exceptions to this intrasubclass binding specificity as it has recently been shown that ephrin-B3 is able to bind to and activate EPH receptor A4 and ephrin-A5 can bind to and activate Eph receptor B2. [10] EphAs/ephrin-As typically bind with high affinity, which can partially be attributed to the fact that ephrinAs interact with EphAs by a "lock-and-key" mechanism that requires little conformational change of the EphAs upon ligand binding. In contrast EphBs typically bind with lower affinity than EphAs/ephring-As since they utilize an "induced fit" mechanism that requires a greater conformational change of EphBs to bind ephrin-Bs. [11]

Function

Axon guidance

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 retinotopic map in the superior colliculus (SC) (referred to as the optic tectum in lower vertebrates) requires the proper migration of the axons of retinal ganglion cells (RGCs) from the retina to specific regions in the SC that is mediated by gradients of Eph and ephrin expression in both the SC and in migrating RGCs leaving the retina. [15] The decreased survival of axonal growth cones discussed above allows for a gradient of high posterior to low anterior ephrin-A ligand expression in the SC to direct migrating RGCs axons from the temporal region of the retina that express a high level of EphA receptors toward targets in the anterior SC and RGCs from the nasal retina that have low EphA expression toward their final destination in the posterior SC. [16] [17] [18] Similarly, a gradient of ephrin-B1 expression along the medial-ventral axis of the SC directs the migration of dorsal and ventral EphB-expressing RGCs to the lateral and medial SC respectively. [19]

Angiogenesis

The EphB4 receptor protein, known to assist in developmental and tumor angiogenesis. PDB 2bba EBI.png
The EphB4 receptor protein, known to assist in developmental and tumor angiogenesis.

Ephrins promote angiogenesis in physiological and pathological conditions (e.g. cancer angiogenesis, neovascularisation in cerebral arteriovenous malformation). [20] [21] In particular, Ephrin-B2 and EphB4 determine the arterial and venous fate of endothelial cells, respectively, though regulation of angiogenesis by mitigating expression in the VEGF signalling pathway. [20] [22] Ephrin-B2 affects VEGF-receptors (e.g.VEGFR3) through forward and reverse signalling pathways. [22] The Ephrin-B2 path extends to lymphangiogenesis, leading to internalization of VEGFR3 in cultured lymphatic endothelial cells. [22] Though the role of ephrins in developmental angiogenesis is elucidated, tumor angiogenesis remains nebulous. Based on observations in Ephrin-A2 deficient mice, Ephrin-A2 may function in forward signalling in tumor angiogenesis; however, this ephrin does not contribute to vascular deformities during development. [23] Moreover, Ephrin-B2 and EphB4 may also contribute to tumor angiogenesis in addition to their positions in development, though the exact mechanism remains unclear. [23] The Ephrin B2/EphB4 and Ephrin B3/EphB1 receptor pairs contribute more to vasculogenesis in addition to angiogenesis whilst Ephrin A1/EphA2 appear to exclusively contribute to angiogenesis. [24]

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 intestinal epithelial cells from the crypt [ clarification needed ] to villus. The Wnt protein triggers expression of the EphB receptors deep within the crypt, leading to decreased Eph expression and increased ephrin ligand expression, the more superficial a progenitor cell's placement. [25] Migration is caused by a bi-directional signaling mechanism in which the engagement of the ephrin ligand with the EphB receptor regulates the actin cytoskeleton dynamics to cause a "repulsion". Cells remain in place once the interaction ceases to a stop. While the mucus secreting Goblet cells and the absorptive cells move towards the lumen, mature Paneth cells move in the opposite direction, to the bottom of the crypt, where they reside. [26] With the exception of the ephrin ligand binding to EphA5, all other proteins from class A and B have been found in the intestine. However, ephrin proteins A4, A8, B2, and B4 have highest levels in fetal stage, and decline with age.

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, ephrin-A5 was shown to stimulate growth cone spreading in spinal motor neurons [12] and ephrin-B1 was shown to promote dendritic spine maturation. [29]

Related Research Articles

<span class="mw-page-title-main">Retinal ganglion cell</span> Type of cell within the eye

A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

<span class="mw-page-title-main">Juxtacrine signalling</span> Contact-based cell-cell signalling

In biology, juxtracrine signalling is a type of cell–cell or cell–extracellular matrix signalling in multicellular organisms that requires close contact. In this type of signalling, a ligand on one surface binds to a receptor on another adjacent surface. Hence, this stands in contrast to releasing a signaling molecule by diffusion into extracellular space, the use of long-range conduits like membrane nanotubes and cytonemes or the use of extracellular vesicles like exosomes or microvesicles. There are three types of juxtracrine signaling:

  1. A membrane-bound ligand and a membrane protein of two adjacent cells interact.
  2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
  3. An extracellular matrix glycoprotein and a membrane protein interact.
<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">Ephrin receptor</span> Protein family

Eph receptors are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs). Both Eph receptors and their corresponding ephrin ligands are membrane-bound proteins that require direct cell-cell interactions for Eph receptor activation. Eph/ephrin signaling has been implicated in the regulation of a host of processes critical to embryonic development including axon guidance, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.

<span class="mw-page-title-main">Plexin</span> Protein

A plexin is a protein which acts as a receptor for semaphorin family signaling proteins. It is classically known for its expression on the surface of axon growth cones and involvement in signal transduction to steer axon growth away from the source of semaphorin. Plexin also has implications in development of other body systems by activating GTPase enzymes to induce a number of intracellular biochemical changes leading to a variety of downstream effects.

<span class="mw-page-title-main">Ephrin B2</span> Protein-coding gene in the species Homo sapiens

Ephrin-B2 is a protein that in humans is encoded by the EFNB2 gene.

<span class="mw-page-title-main">EPH receptor B2</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 2 is a protein that in humans is encoded by the EPHB2 gene.

<span class="mw-page-title-main">EPH receptor A2</span> Protein-coding gene in humans

EPH receptor A2 is a protein that in humans is encoded by the EPHA2 gene.

<span class="mw-page-title-main">EPH receptor B4</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 4 is a protein that in humans is encoded by the EPHB4 gene.

<span class="mw-page-title-main">EPH receptor B1</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 1 is a protein that in humans is encoded by the EPHB1 gene.

<span class="mw-page-title-main">EPHB6</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 6 is a protein that in humans is encoded by the EPHB6 gene.

<span class="mw-page-title-main">EPHA8</span> Protein-coding gene in the species Homo sapiens

Ephrin type-A receptor 8 is a protein that in humans is encoded by the EPHA8 gene.

<span class="mw-page-title-main">Ephrin A2</span> Protein-coding gene in the species Homo sapiens

Ephrin-A2 is a protein that in humans is encoded by the EFNA2 gene.

<span class="mw-page-title-main">Ephrin B3</span> Protein-coding gene in the species Homo sapiens

Ephrin-B3 is a protein that in humans is encoded by the EFNB3 gene.

<span class="mw-page-title-main">EPHB3</span> Protein-coding gene in the species Homo sapiens

Ephrin type-B receptor 3 is a protein that in humans is encoded by the EPHB3 gene.

<span class="mw-page-title-main">Roundabout family</span>

The Roundabout (Robo) family of proteins are single-pass transmembrane receptors that are highly conserved across many branches of the animal kingdom, from C. elegans to humans. They were first discovered in Drosophila, through a mutant screen for genes involved in axon guidance. The Drosophila roundabout mutant was named after its phenotype, which resembled the circular traffic junctions. The Robo receptors are most well known for their role in the development of the nervous system, where they have been shown to respond to secreted Slit ligands. One well-studied example is the requirement for Slit-Robo signaling in regulation of axonal midline crossing. Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation. In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast. Mutations in Robo genes have been linked to multiple neurodevelopmental disorders in humans.

<span class="mw-page-title-main">Ephrin A5</span> Protein-coding gene in the species Homo sapiens

Ephrin A5 is a protein that in humans is encoded by the EFNA5 gene.

<span class="mw-page-title-main">Tropic cues involved in growth cone guidance</span>

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.

<span class="mw-page-title-main">Synaptic stabilization</span> Modifying synaptic strength via cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.

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This article incorporates text from the public domain Pfam and InterPro: IPR001799