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Ephrin Edit Wikipedia article
structural and biophysical characterization of the ephb4-ephrinb2 protein protein interaction and receptor specificity.
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).
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, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has recently been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation.
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.
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). 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. However, there are a few exceptions to this intrasubclass binding specificity as it has recently been shown that ephrin-B3 is able bind to and activate EPH receptor A4 and ephrin-A5 can bind to and activate Eph receptor B2. 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.
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. 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, 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.
Although Eph-ephrin activation is usually associated with decreased growth cone survival and the repellence 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.
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. 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. 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.
Ephrins promote angiogenesis in physiological and pathological conditions (e.g. cancer angiogenesis, neovascularisation in cerebral arteriovenous malformation). 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. Ephrin-B2 affects VEGF-receptors (e.g.VEGFR3) through forward and reverse signalling pathways. The Epherin-B2 path extends to lymphangiogenesis, leading to internalization of VEGFR3 in cultured lymphatic endothelial cells. 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. Moreover, Ephrin-B2 and EphB4 may also contribute to tumor angiogenesis in addition to their positions in development, though the exact mechanism remains unclear. 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.
Several types of Ephrins and Eph receptors have been found to be upregulated in human cancers including breast, colon and liver cancers. 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. 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 signals the 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. Migration is caused 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". Cell remain in place once the interaction ceases to a stop. While the three stages of epithelial cell such as the mucus secreting Goblet cells, and the absorptive cells moves towards the lumen, the fourth cell in the intestine, mature Paneth cells moves the opposite direction to reside in crypt. With the exception of the ephrin ligand binding to EphA5, all other proteins from class A & B have been found in the intestines. However, ephrin proteins A4, A8, B2, and B4 has shown highest levels in fetal stage, and declines with age.
Experiment done with Eph receptor knockout mice display disorder in different cell types. Absorptive cells of various differentiation was still mixed with the stem cells within the villi. Without the receptor, the Ephrin ligand was proved to be ineffective in cell placement. Recent studies with knockout mice have also shown evidence of the ephrin-eph interaction indirectly monitor the suppression of colorectal cancer. The development of adenomatous polyps created by outgrowth of epithelial 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.
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 and ephrin-B1 was shown to promote dendritic spine maturation.
- Egea J, Klein R (May 2007). "Bidirectional Eph-ephrin signaling during axon guidance". Trends in Cell Biology 17 (5): 230–238. doi:10.1016/j.tcb.2007.03.004. PMID 17420126.
- Rohani N, Canty L, Luu O, Fagotto F, Winklbauer R (Mar 2011). Hamada H, ed. "EphrinB/EphB signaling controls embryonic germ layer separation by contact-induced cell detachment". PLoS Biology 9 (3): e1000597. doi:10.1371/journal.pbio.1000597. PMC 3046958. PMID 21390298.
- Davy A, Soriano P (Jan 2005). "Ephrin signaling in vivo: look both ways". Developmental Dynamics 232 (1): 1–10. doi:10.1002/dvdy.20200. PMID 15580616.
- Kullander K, Klein R (Jul 2002). "Mechanisms and functions of Eph and ephrin signalling". Nature Reviews Molecular Cell Biology 3 (7): 475–486. doi:10.1038/nrm856. PMID 12094214.
- Kuijper S, Turner CJ, Adams RH (Jul 2007). "Regulation of angiogenesis by Eph-ephrin interactions". Trends in Cardiovascular Medicine 17 (5): 145–151. doi:10.1016/j.tcm.2007.03.003. PMID 17574121.
- Genander M, Frisén J (Oct 2010). "Ephrins and Eph receptors in stem cells and cancer". Current Opinion in Cell Biology 22 (5): 611–616. doi:10.1016/j.ceb.2010.08.005. PMID 20810264.
- "Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee". Cell 90 (3): 403–404. Aug 1997. doi:10.1016/S0092-8674(00)80500-0. PMID 9267020.
- Pitulescu ME, Adams RH (Nov 2010). "Eph/ephrin molecules--a hub for signaling and endocytosis". Genes & Development 24 (22): 2480–2492. doi:10.1101/gad.1973910. PMC 2975924. PMID 21078817.
- Pasquale EB (Oct 1997). "The Eph family of receptors". Current Opinion in Cell Biology 9 (5): 608–615. doi:10.1016/S0955-0674(97)80113-5. PMID 9330863.
- Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M, Nikolov DB (May 2004). "Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling". Nature Neuroscience 7 (5): 501–509. doi:10.1038/nn1237. PMID 15107857.
- Himanen JP (Feb 2012). "Ectodomain structures of Eph receptors". Seminars in Cell & Developmental Biology 23 (1): 35–42. doi:10.1016/j.semcdb.2011.10.025. PMID 22044883.
- Marquardt T, Shirasaki R, Ghosh S, Andrews SE, Carter N, Hunter T, Pfaff SL (Apr 2005). "Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains". Cell 121 (1): 127–139. doi:10.1016/j.cell.2005.01.020. PMID 15820684.
- Reber M, Burrola P, Lemke G (Oct 2004). "A relative signalling model for the formation of a topographic neural map". Nature 431 (7010): 847–853. doi:10.1038/nature02957. PMID 15483613.
- Petros TJ, Bryson JB, Mason C (Sep 2010). "Ephrin-B2 elicits differential growth cone collapse and axon retraction in retinal ganglion cells from distinct retinal regions". Developmental Neurobiology 70 (11): 781–794. doi:10.1002/dneu.20821. PMC 2930402. PMID 20629048.
- Triplett JW, Feldheim DA (Feb 2012). "Eph and ephrin signaling in the formation of topographic maps". Seminars in Cell & Developmental Biology 23 (1): 7–15. doi:10.1016/j.semcdb.2011.10.026. PMC 3288406. PMID 22044886.
- Wilkinson DG (Mar 2001). "Multiple roles of EPH receptors and ephrins in neural development". Nature Reviews. Neuroscience 2 (3): 155–164. doi:10.1038/35058515. PMID 11256076.
- Cheng HJ, Nakamoto M, Bergemann AD, Flanagan JG (Aug 1995). "Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map". Cell 82 (3): 371–381. doi:10.1016/0092-8674(95)90426-3. PMID 7634327.
- Drescher U, Kremoser C, Handwerker C, Löschinger J, Noda M, Bonhoeffer F (Aug 1995). "In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases". Cell 82 (3): 359–370. doi:10.1016/0092-8674(95)90425-5. PMID 7634326.
- Mann F, Ray S, Harris W, Holt C (Aug 2002). "Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrin-B ligands". Neuron 35 (3): 461–473. doi:10.1016/S0896-6273(02)00786-9. PMID 12165469.
- Salvucci O, Tosato G (2012). "Essential roles of EphB receptors and EphrinB ligands in endothelial cell function and angiogenesis". Advances in Cancer Research 114 (2): 21–57. doi:10.1016/B978-0-12-386503-8.00002-8. PMID 22588055.
- Bai J, Wang YJ, Liu L, Zhao YL (Apr 2014). "Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation". The Journal of International Medical Research 42 (2): 405–15. doi:10.1177/0300060513478091. PMID 24517927.
- Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Lüthi U, Barberis A, Benjamin LE, Mäkinen T, Nobes CD, Adams RH (May 2010). "Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis". Nature 465 (7297): 483–486. doi:10.1038/nature09002. PMID 20445537.
- Pasquale EB (Mar 2010). "Eph receptors and ephrins in cancer: bidirectional signalling and beyond". Nature Reviews. Cancer 10 (3): 165–80. doi:10.1038/nrc2806. PMID 20179713.
- Mosch, Birgit; Reissenweber, Bettina; Neuber, Christin; Pietzsch, Jens (2010). "Eph Receptors and Ephrin Ligands: Important Players in Angiogenesis and Tumor Angiogenesis". Journal of Oncology 2010: 1–12. doi:10.1155/2010/135285. ISSN 1687-8450.
- Alberts B, Johnson A, lewis J, Raff M, Roberts K, Walter P (2007). Molecular Biology of the Cell. Garland Sciences. p. 1 440–1441. ISBN 978-0815341055.
- Batlle E. "Wnt signalling and EphB-ephrin interactions in intestinal stem cells and CRC progression" (PDF). 2007 Scientific Report.
- Islam S, Loizides AM, Fialkovich JJ, Grand RJ, Montgomery RK (Sep 2010). "Developmental expression of Eph and ephrin family genes in mammalian small intestine". Digestive Diseases and Sciences 55 (9): 2478–88. doi:10.1007/s10620-009-1102-z. PMID 20112066.
- Pitulescu M. "Eph/ephrin molecules-a hub for signaling and endocytosis" (PDF). 2010 Genes & Development. doi:10.1101/gad.1973910.
- Segura I, Essmann CL, Weinges S, Acker-Palmer A (Mar 2007). "Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation". Nature Neuroscience 10 (3): 301–310. doi:10.1038/nn1858. PMID 17310244.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001799
Ephrins are a family of proteins [PUBMED:7838529] that are ligands of class V (EPH-related) receptor protein-tyrosine kinases. These receptors and their ligands have been implicated in regulating neuronal axon guidance and in patterning of the developing nervous system and may also serve a patterning and compartmentalisation role outside of the nervous system as well.
Ephrins are membrane-attached proteins of 205 to 340 residues. Attachment appears to be crucial for their normal function. Type-A ephrins are linked to the membrane via a glycosylphosphatidylinositol (GPI)-linkage, while type-B ephrins are type-I membrane proteins.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Many of the proteins in this family contain multiple similar copies of this plastocyanin-like domain.
The clan contains the following 11 members:Copper-bind COX2 COX_ARM Cu-oxidase Cu-oxidase_2 Cu-oxidase_3 Cu_bind_like Cupredoxin_1 Ephrin PAD_N SoxE
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||Pfam-B_1390 (release 2.1)|
|Number in seed:||44|
|Number in full:||647|
|Average length of the domain:||125.90 aa|
|Average identity of full alignment:||38 %|
|Average coverage of the sequence by the domain:||48.12 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 5 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ephrin domain has been found. There are 42 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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