Eph receptor
Encyclopedia
Eph receptors
are components of cell signalling pathways involved in animal growth
and development
, forming the largest sub-family of receptor tyrosine kinase
s (RTKs). The extracellular domain of an Eph receptor interacts with ephrin
ligands, which may be tethered to neighbouring cells. Ligand-mediated activation of Ephs induce various important downstream effects and Eph receptors have been studied for their potential roles in the development of cancer
. Some Eph receptors, such as EPHB4, participate in both forward and reverse signalling pathways, by either transducing a signal through their own kinase
domain, or by initiating a signalling cascade through certain ephrin
ligands.
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.
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. In the hindbrain, segmentation is a precisely defined process. In the paraxial mesoderm, however, development 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.
) 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. 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. 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.
of neural crest cells during gastrulation. 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
) 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. The dynamic nature and expression patterns of the Ephs 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. 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. 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 Ephs 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.
. In chicks, EphA4 is expressed in the developing wing and leg buds, as well as in the feather and scale primordia. 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 do not 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.
. While used extensively throughout development, Ephs 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. Increased expression was also correlated with more malignant and metastatic tumors, consistent with the role of Ephs in governing cell movement.
It is possible that the increased expression of Eph in cancer plays several roles, first, by acting as survival factors or as a promoter of abnormal growth. The angiogenic properties of the Eph system may increase vascularisation of and thus growth capacity of tumors. Second, 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. Third, 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.
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
are components of cell signalling pathways involved in animal growth
Growth
Growth refers to an increase in some quantity over time.The quantity can be:*Physical *Abstract ....
and development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
, forming the largest sub-family of receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s 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....
s (RTKs). The extracellular domain of an Eph receptor interacts with ephrin
Ephrin
In molecular biology, ephrins are a family of proteins that are ligands of class V 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...
ligands, which may be tethered to neighbouring cells. Ligand-mediated activation of Ephs induce various important downstream effects and Eph receptors have been studied for their potential roles in the development of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Some Eph receptors, such as EPHB4, participate in both forward and reverse signalling pathways, by either transducing a signal through their own kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
domain, or by initiating a signalling cascade through certain ephrin
Ephrin
In molecular biology, ephrins are a family of proteins that are ligands of class V 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...
ligands.
Receptors
There are 16 known receptors (14 found in mammals):- EPHA1EPHA1EPH receptor A1 is a protein that in humans is encoded by the EPHA1 gene.-Further reading:...
, EPHA2, EPHA3EPHA3EPH receptor A3 is a protein that in humans is encoded by the EPHA3 gene.-Interactions:EPH receptor A3 has been shown to interact with EFNB2 and EFNA5.-Further reading:...
, EPHA4, EPHA5EPHA5EPH receptor A5 is a protein that in humans is encoded by the EPHA5 gene.-Further reading:...
, EPHA6EPHA6Ephrin type-A receptor 6 is a protein that in humans is encoded by the EPHA6 gene.-Further reading:...
, EPHA7EPHA7Ephrin type-A receptor 7 is a protein that in humans is encoded by the EPHA7 gene.-Further reading:...
, EPHA8EPHA8Ephrin type-A receptor 8 is a protein that in humans is encoded by the EPHA8 gene.-Further reading:...
, EPHA9, EPHA10 - EPHB1, EPHB2, EPHB3EPHB3Ephrin type-B receptor 3 is a protein that in humans is encoded by the EPHB3 gene.-Interactions:EPHB3 has been shown to interact with MLLT4 and RAS p21 protein activator 1.-Further reading:...
, EPHB4, EPHB5, EPHB6EPHB6Ephrin type-B receptor 6 is a protein that in humans is encoded by the EPHB6 gene.-Further reading:...
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. 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.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.
Function
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
SegmentationSegmentation (biology)
Segmentation in biology refers to either a type of gastrointestinal motility or the division of some animal and plant body plans into a series of repetitive segments. This article will focus on the segmentation of animal body plans, specifically using the examples of the phyla Arthropoda,...
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. In the hindbrain, segmentation is a precisely defined process. In the paraxial mesoderm, however, development 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.
Axon guidance
As the nervous system develops, the predefined patterning of neuronal connections is established by molecular guides that direct axons (axon guidanceAxon guidance
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach the correct targets...
) 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. 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. 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.
Cell migration
More than just axonal guidance, Ephs have been implicated in the migrationCell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
of neural crest cells during gastrulation. 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 vasculogenesisVasculogenesis
Vasculogenesis is the process of blood vessel formation occurring by a de novo production of endothelial cells.-Process:Though similar to angiogenesis, the two are different in one aspect: The term angiogenesis denotes the formation of new blood vessels from pre-existing ones, whereas...
(angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
) and other early development of the circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
. This development is disturbed without it. It is thought to distinguish arterial and venous endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, stimulating the production of capillary sprouts as well as in the differentiation of mesenchyme
Mesenchyme
Mesenchyme, or mesenchymal connective tissue, is a type of undifferentiated loose connective tissue that is derived mostly from mesoderm, although some are derived from other germ layers; e.g. some mesenchyme is derived from neural crest cells and thus originates from the ectoderm...
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. The dynamic nature and expression patterns of the Ephs 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. 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. 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 Ephs 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 Ephs to play a part in the signaling of limb developmentLimb development
Limb development in tetrapods — animals with four limbs — is an area of active research in developmental biology. Limb formation begins in the limb field, as a limb "bud." Fibroblast growth factor induces formation of an organizer, called the apical ectodermal ridge , which guides further...
. In chicks, EphA4 is expressed in the developing wing and leg buds, as well as in the feather and scale primordia. 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 do not 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 Ephs, it is not surprising to learn that the Ephs have been implicated in several aspects of cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. While used extensively throughout development, Ephs 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. Increased expression was also correlated with more malignant and metastatic tumors, consistent with the role of Ephs in governing cell movement.
It is possible that the increased expression of Eph in cancer plays several roles, first, by acting as survival factors or as a promoter of abnormal growth. The angiogenic properties of the Eph system may increase vascularisation of and thus growth capacity of tumors. Second, 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. Third, 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.