Eph receptor

In molecular biology, ephrins and Eph receptors are components of cell signaling pathways involved in animal development, and implicated in some cancers. Eph receptors are classified as receptor tyrosine kinases (RTKs), and form the largest sub-family of RTKs.

Receptors and ligands

There are 16 known receptors (14 found in mammals):
* EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10
* EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6

There are 9 known ephrin ligands (8 found in mammals):
* EFNA1, EFNA2, EFNA3, EFNA4, EFNA5
* EFNB1, EFNB2, EFNB3

Discovery and history

The Eph receptors were initially identified in 1987 following a search for tyrosine kinases with possible roles in cancer, earning their name from the erythropoietin-producing hepatocellular carcinoma cell line from which their cDNA was obtained.cite journal|last=Murai|first=K. K.|coauthors=E. B. Pasquale|year=2003|title=Eph'ective signaling: forward, reverse and crosstalk|url=|journal=Journal of Cell Science|issn=|volume=116|issue=Pt 14|pages=2823–32|pmid=12808016|doi=10.1242/jcs.00625] These transmembranous receptors were initially classed as orphan receptors with no known ligands or functions and it was some time before possible functions of the receptors were known.cite journal|last=Flanagan|first=J. G.|coauthors=P. Vanderhaeghen|year=1998|title=The ephrins and Eph receptors in neural development|url=|journal=Annual Review of Neuroscience|issn=|volume=21|issue=|pages=309–45|doi=]

When it was shown that almost all Eph receptors were expressed during various well defined stages of development in assorted locations and concentrations, a role in cell positioning was proposed, initiating research that revealed the Eph/ephrin families as a principle cell guidance system during vertebrate and invertebrate development.cite journal|last=Boyd|first=A. W.|coauthors=M. Lackmann |year=2001|title=Signals from Eph and ephrin proteins: a developmental tool kit|url=|journal=Science's STKE : signal transduction knowledge environment|issn=1525-8882|volume=2001|issue=112|pages=RE20|doi=10.1126/stke.2001.112.re20|pmid=11741094]

Applications of the Eph guidance system

The ability of the Eph receptor and ephrin ligand guidance system to position cells and modulate cell morphology reflects their various roles in development.

= Segmentation =

Segmentation is a basic process of embryogenesis occurring in most invertebrates and all vertebrates by which the body is initially divided into functional units. In the segmented regions of the embryo, cells begin to present biochemical and morphological boundaries at which cell behavior is drastically different – vital for future differentiation and function.cite journal|last=Holder|first=N.|coauthors=R. Klein|year=1999|title=Eph receptors and ephrins: effectors of morphogenesis|url=|journal=Development|issn=|volume=126|issue=10|pages=2033–2044|doi=] In the hindbrain segmentation is a precisely defined process, contrasted to the paraxial mesoderm, which is a dynamic and adaptive process that adjusts according to posterior body growth. Various Eph receptors and ephrins are expressed in these regions and through functional analysis it has been determined that Eph signaling is crucial for the proper development and maintenance of these segment boundaries. Similar studies conducted in zebrafish have shown similar segmenting processes within the somites containing a striped expression pattern of Eph receptors and their ligands which is vital to proper segmentation - the disruption of expression resulting in misplaced or even absent boundaries. [cite journal|last=Durbin|first=L.|coauthors= Brennan, C; Shiomi, K; Cooke, J; Barrios, A; Shanmugalingam, S; Guthrie, B; Lindberg, R; Holder N|year=1998|title=Eph signaling is required for segmentation and differentiation of the somites|url=|journal=Genes & Development|issn=0890-9369|volume=12|issue=19|pages=3096–3109|pmid=9765210|doi=10.1101/gad.12.19.3096]

Axon guidance and fasciculation

As the nervous system develops, the predefined patterning of neuronal connections is established by molecular guides that direct axons along pathways by target and pathway derived signals. ] Initial evidence arose via the receptor EphB2, expressed in several regions of the chick and mouse brain – having been immunolocalised to the surface of growth cones for spinal motor and occulomotor neurons from their origin toward their targets. [cite journal|last=Pasquale|first=E. B.|coauthors=Deerinck, TJ; Singer, SJ; Ellisman, MH|year=1992|title=Cek5, a membrane receptor-type tyrosine kinase, is in neurons of the embryonic and postnatal avian brain|url=|journal=Journal of Neuroscience|issn=|volume=12|issue=10|pages=3956–3967|pmid=1403093] The Eph receptor is located on the neuron's growth cone, thus the cone grows toward a higher concentration of its ligand. Further evidence came with the role of Eph in topographic mapping in the visual system, with graded expression levels of both Eph receptors and ephrin ligands leading to the development of a resolved neuronal map.cite journal|last=Cheng|first=H. J.|coauthors=M. Nakamoto, "et al."|year=1995|title=Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map|url=|journal=Cell|issn=0092-8674|volume=82|issue=3|pages=371–381|pmid=7634327|doi=10.1016/0092-8674(95)90426-3] Further studies then showed the role of Eph’s in topographic mapping in other regions of the central nervous system, such as learning and memory via the formation of projections between the septum and hippocampus. [cite journal|last=Gao|first=P. P.|coauthors=J. H. Zhang, "et al."|year=1996|title=Regulation of topographic projection in the brain: Elf-1 in the hippocamposeptal system|url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=38301|journal=Proceedings of the National Academy of Sciences of the United States of America|issn=0027-8424|volume=93|issue=20|pages=11161–11166|accessdate=2007-06-08|doi=10.1073/pnas.93.20.11161|pmid=8855326]

Cell Migration

More than just axonal guidance, Eph’s have been implicated in the migration of neural crest cells during gastrulation. [cite journal|last=Robinson|first=V.|coauthors=A. Smith, "et al."|year=1997|title=Roles of Eph receptors and ephrins in neural crest pathfinding|url=|journal=Cell & Tissue Research|issn=0302-766X|volume=290|issue=2|pages=265–274|pmid=9321688|doi=10.1007/s004410050931] In the chick and rat embryo trunk, the migration of crest cells is partially mediated by EphB receptors. Similar mechanisms have been shown to control crest movement in the hindbrain within rhombomeres 4, 5 and 7 which distribute crest cells to brachial arches 2, 3 and 4 respectively. In C. elegans a knockout of locus VAB-1, known to encode an Eph receptor, results in two cell migratory processes being affected. ]

Angiogenesis

Eph receptors are present in high degrees during vasculogenesis and other early development of the circulatory system. This development is disturbed without it. It is thought to distinguish arterial and venous endothelium, stimulating the production of capillary sprouts as well as in the differentiation of mesenchyme into perivascular support cells.

The construction of blood vessels requires the coordination of endothelial and supportive mesenchymal cells through multiple phases to develop the intricate networks required for a fully functional circulatory system.cite journal|last=Cheng|first=N.|coauthors=D. M. Brantley, "et al."|year=2002|title=The ephrins and Eph receptors in angiogenesis|url=|journal=Cytokine & Growth Factor Reviews|issn=|volume=13|issue=1|pages=75–85|doi=] The dynamic nature and expression patterns of the Eph’s make them therefore ideal for roles in angiogenesis. Mouse embryonic models show expression of EphA1 in mesoderm and pre-endocardial cells, later spreading up into the dorsal aorta then primary head vein, intersomitic vessels and limb bud vasculature as would be consistent with a role in angiogenesis. Different class A Eph receptors have also been detected in the lining of the aorta, brachial arch arteries, umbilical vein and endocardium. ] Complementary expression of EphB2/ephrin-B4 was detected in developing arterial endothelial cells and EphB4 in venous endothelial cells.cite journal|last=Wang|first=H. U.|coauthors=Z. F. Chen, "et al."|year=1998|title=Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. [see comment] |url=|journal=Cell|issn=|volume=93|issue=5|pages=741–753|doi=] Expression of EphB2 and ephrin-B2 was also detected on supportive mesenchymal cells, suggesting a role in wall development through mediation of endothelial-mesenchymal interactions. [cite journal|last=Adams|first=R. H.|coauthors=G. A. Wilkinson, "et al."|year=1999|title=Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis|url=|journal=Genes & Development|issn=0890-9369|volume=13|issue=3|pages=295–306|pmid=9990854|doi=10.1101/gad.13.3.295] Blood vessel formation during embryogenesis consists of vasculogenesis, the formation of a primary capillary network followed by a second remodeling and restructuring into a finer tertiary network - studies utilizing ephrin-B2 deficient mice showed a disruption of the embryonic vasculature as a result of a deficiency in the restructuring of the primary network. ] Functional analysis of other mutant mice have led to the development of a hypothesis by which Eph’s and ephrins contribute to vascular development by restricting arterial and venous endothelial mixing, thus stimulating the production of capillary sprouts as well as in the differentiation of mesenchyme into perivascular support cells, an ongoing area of research. ]

Limb Development

While there is currently little evidence to support this (and mounting evidence to refute it), some early studies implicated the Eph’s to play a part in the signaling of limb development. ] In chicks, EphA4 is expressed in the developing wing and leg buds, as well as in the feather and scale primordia.cite journal|last=Patel|first=K.|coauthors=R. Nittenberg, "et al."|year=1996|title=Expression and regulation of Cek-8, a cell to cell signalling receptor in developing chick limb buds|url=|journal=Development|issn=|volume=122|issue=4|pages=1147–1155|doi=] This expression is seen in the distal end of the limb buds, where cells are still undifferentiated and dividing, and appears to be under the regulation of retinoic acid, FGF2, FGF4 and BMP-2 – known to regulate limb patterning. EphA4 defective mice don’t present abnormalities in limb morphogenesis (personal communication between Andrew Boyd and Nigel Holder), so it is possible that these expression patterns are related to neuronal guidance or vascularisation of the limb with further studies being required to confirm or deny a potential role of Eph in limb development.

Cancer

As a member of the RTK family and with responsibilities as diverse as Eph’s, it is not surprising to learn that the Eph’s have been implicated in several aspects of cancer. While used extensively throughout development, Eph’s are rarely detected in adult tissues. Elevated levels of expression and activity have been correlated with the growth of solid tumors, with Eph receptors of both classes A and B being over expressed in a wide range of cancers including melanoma, breast, prostate, pancreatic, gastric, esophageal and colon cancer as well as hematopoietic tumors.cite journal|last=Wicks|first=I. P.|coauthors=D. Wilkinson, "et al."|year=1992|title=Molecular cloning of HEK, the gene encoding a receptor tyrosine kinase expressed by human lymphoid tumor cell lines|url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1311845|journal=Proceedings of the National Academy of Sciences of the United States of America|issn=0027-8424|volume=89|issue=5|pages=1611–1615|pmid=1311845|doi=10.1073/pnas.89.5.1611] cite journal|last=Kiyokawa|first=E.|coauthors=S. Takai, "et al."|year=1994|title=Overexpression of ERK, an EPH family receptor protein tyrosine kinase, in various human tumors|url=http://cancerres.aacrjournals.org/cgi/reprint/54/14/3645|format=PDF|accessdate=2007-06-08|journal=Cancer Research|issn=0008-5472|volume=54|issue=14|pages=3645–3650|pmid=8033077] cite journal|last=Easty|first=D. J.|coauthors=M. Herlyn, "et al."|year=1995|title=Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis|url=|journal=International Journal of Cancer|issn=|volume=60|issue=1|pages=129–136|pmid=7814145|doi=10.1002/ijc.2910600119] Increased expression was also correlated with more malignant and metastatic tumors, consistent with the role of Eph’s governing cell movement. ]

It is possible that the increased expression of Eph in cancer plays several roles, firstly by acting as survival factors or as a promoter of abnormal growth.cite journal|last=Surawska|first=H.|coauthors= P. C. Ma, "et al."|year=2004|title=The role of ephrins and Eph receptors in cancer|url=|journal=Cytokine & Growth Factor Reviews|issn=1359-6101|volume=15|issue=6|pages=419–433|doi=] The angiogenic properties of the Eph system may increase vascularisation of and thus growth capacity of tumors. ] Secondly, elevated Eph levels may disrupt cell-cell adhesion via cadherin, known to alter expression and localisation of Eph receptors and ephrins which is known to further disrupt cellular adhesion, a key feature of metastatic cancers. ] Thirdly, Eph activity may alter cell matrix interactions via integrins by the sequestering of signaling molecules following Eph receptor activation, as well as providing potential adherence via ephrin ligand binding following metastasis. ] ]

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