Receptor, EphA4
Receptor, EphA2
Ephrin-A2
Ephrin-A5
Receptor, EphA7
Receptor, EphA5
Receptor, EphA1
Ephrin-A1
Receptors, Eph Family
Ephrin-A4
Ephrins
Ephrin-A3
Ephrin-B3
Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity. (1/22)
Eph-related receptors and their ephrin ligands are highly conserved protein families which play important roles in targeting axons and migrating cells. In this study we have examined the functional roles of two major autophosphorylation sites, Tyr-615 and Tyr-838, in the EphA8 receptor. Two-dimensional phosphopeptide mapping analysis demonstrated that Tyr-615 and Tyr-838 constitute major autophosphorylation sites in EphA8. Tyr-615 was phosphorylated to the highest stoichiometry, suggesting that phosphorylation at this site may have a physiologically important role. Upon conservative mutation of Tyr-838 located in the tyrosine kinase domain, the catalytic activity of EphA8 was strikingly reduced both in vitro and in vivo, whereas a mutation at Tyr-615 in the juxtamembrane domain did not impair the tyrosine kinase activity. In vitro binding experiments revealed that phosphorylation at Tyr-615 in EphA8 mediates the preferential binding to Fyn-SH2 domain rather than Src and Ras GTPase-activating protein (Ras GAP)-SH2 domains. Additionally, a high level of EphA8 was detected in Fyn immunoprecipitates in intact cells, indicating that EphA8 and Fyn can physically associate in vivo. In contrast, the association of full-length Fyn to EphA8 containing mutation at either Tyr-615 or Tyr-838 was greatly reduced. These data indicate that phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites. Finally, it was observed that cell attachment responses are attenuated by overexpression of wild type EphA8 receptor but to much less extent by EphA8 mutants lacking phosphorylation at either Tyr-615 or Tyr-838. Furthermore, transient expression of kinase-inactive Fyn in EphA8-overexpressing cells blocked cell attachment responses attenuated by the EphA8 signaling. We therefore propose that Fyn kinase is one of the major downstream targets for the EphA8 signaling pathway leading to a modification of cell adhesion, and that autophosphorylation at Tyr-838 is critical for positively regulating the EphA8 signaling event. (+info)Characterization of ephrin-A1 and ephrin-A4 as ligands for the EphA8 receptor protein tyrosine kinase. (2/22)
The Eph receptors are the largest known family of receptor protein tyrosine kinases, which play important roles with their ligands called ephrin in the neural development, angiogenesis, and vascular network assembly. It was previously shown that ephrin-A2, -A3 and -A5 bind to, and activate the EphA8 receptor tyrosine kinase, respectively. In this study, we have examined if there are other additional ephrin ligands interacting with the EphA8 receptor tyrosine kinase expressed in NIH3T3 fibroblasts. For this purpose, we have constructed chimeric ephrin-A1, -A4, -B1, -B2 or -B3 ligands consisting of the Fc portion of human IgG fused to their carboxyl-terminus. Both ephrin-A1 and ephrin-A4 chimeric ligands efficiently bound to the EphA8 receptor expressed in NIH3T3 fibroblasts, whereas the transmembrane ligands including ephrin-B1, -B2 and -B3 did not. Additionally we have demonstrated that both the EphA8-TrkB chimeric receptor and the EphA8 receptor expressed in NIH3T3 fibroblasts are efficiently tyrosine-phosphorylated upon stimulating with epthin-A1 or -A4 but none of transmembrane ephrin-B proteins. These results strongly indicate that the EphA8 receptor functions exclusively as an glycosyl phosphatidylinositol (GPI)-linked ephrin ligand-dependent receptor protein tyrosine kinase. (+info)Ras/MEK/ERK Up-regulation of the fibroblast KCa channel FIK is a common mechanism for basic fibroblast growth factor and transforming growth factor-beta suppression of myogenesis. (3/22)
The 10T1/2-MRF4 fibroblast/myogenic cell system was used to address the following interrelated questions: whether distinct signaling pathways underlie myogenic inhibition by basic fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta; which of these pathways also up-regulates the fibroblast intermediate conductance calcium-activated potassium channel, FIK, a positive regulator of cell proliferation; and whether FIK up-regulation underlies some or all myogenic inhibitory signaling events. The results show that myogenic inhibition in 10T1/2-MRF4 cells, by both bFGF and TGF-beta, requires activation of the Ras/mitogen-activated protein (MAP) kinase/MAP kinase-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and resultant FIK up-regulation. We show that FIK is instrumental in MEK-dependent suppression of acetylcholine receptor channel expression but that MEK activation and FIK up-regulation are not essential to suppression of myosin heavy chain and myotube formation. These data indicate that Ras/MEK/ERK induction of FIK is pivotal to regulation of certain myogenic events by both receptor tyrosine kinases and TGF-beta receptor, and this is also the first demonstration of chronic FIK up-regulation by the TGF-beta receptor family. Furthermore, the results define the physiologic signaling requirements for growth factor-stimulated FIK up-regulation, whereas previous work has concentrated on constitutive FIK up-regulation in cells stably transfected with oncoprotein signaling molecules. This study, together with earlier work showing that FIK positively regulates cell proliferation, establishes this member of the IK channel family as a multifunctional, growth factor-regulated signaling molecule. (+info)The EphA8 receptor regulates integrin activity through p110gamma phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner. (4/22)
Recent genetic studies suggest that ephrins may function in a kinase-independent Eph receptor pathway. Here we report that expression of EphA8 in either NIH 3T3 or HEK293 cells enhanced cell adhesion to fibronectin via alpha(5)beta(1)- or beta(3) integrins. Interestingly, a kinase-inactive EphA8 mutant also markedly promoted cell attachment to fibronectin in these cell lines. Using a panel of EphA8 point mutants, we have demonstrated that EphA8 kinase activity does not correlate with its ability to promote cell attachment to fibronectin. Analysis using EphA8 extracellular and intracellular domain mutants has revealed that enhanced cell adhesion is dependent on ephrin A binding to the extracellular domain and the juxtamembrane segment of the cytoplasmic domain of the receptor. EphA8-promoted adhesion was efficiently inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor. Additionally, we found that EphA8 had associated PI 3-kinase activity and that the p110gamma isoform of PI 3-kinase is associated with EphA8. In vitro binding experiments revealed that the EphA8 juxtamembrane segment was sufficient for the formation of a stable complex with p110gamma. Similar results were obtained in assay using cells stripped of endogenous ephrin A ligands by treatment with preclustered ephrin A5-Fc proteins. In addition, a membrane-targeted lipid kinase-inactive p110gamma mutant was demonstrated to stably associate with EphA8 and suppress EphA8-promoted cell adhesion to fibronectin. Taken together, these results suggest the presence of a novel mechanism by which the EphA8 receptor localizes p110gamma PI 3-kinase to the plasma membrane in a tyrosine kinase-independent fashion, thereby allowing access to lipid substrates to enable the signals required for integrin-mediated cell adhesion. (+info)Identification of an enhancer region in the mouse ephA8 locus directing expression to the anterior region of the dorsal mesencephalon. (5/22)
Eph receptors and ephrins are dynamically expressed in a wide range of regions of the vertebrate during embryogenesis. The dorsal mesencephalon appears to be segmented into two broad regions demarcated by the mutually exclusive expression of EphA receptors and ephrinA ligands. It is of considerable interest to elucidate how these expression domains are established in the development of the mesencephalon. In this study, we used a transgenic approach to define the cis-acting DNA regulatory elements involved in the anterior mesencephalon-specific expression of the mouse ephA8 gene. Our analyses of the temporal and spatial expression patterns of various ephA8/lacZ gene fusions in transgenic mice revealed that the 10-kb genomic DNA 5' immediately upstream of the ephA8 coding sequence is capable of directing lacZ expression in an ephA8-specific manner. Further deletion analyses of the ephA8 genomic region led to the identification of a 1-kb enhancer region, which directs expression in the embryo to the anterior region of the developing midbrain. This ephA8-specific regulatory DNA sequences can now be used in biochemical analyses to identify proteins modulating the anterior differentiation of the optic tectum, and in functional analyses to direct the expression of other developmentally important genes to this region. (+info)The p110 gamma PI-3 kinase is required for EphA8-stimulated cell migration. (6/22)
This study provides evidence that treatment with preclustered ephrin A5-Fc results in a substantial increase in the stability of the p110 gamma PI-3 kinase associated with EphA8, thereby enhancing PI-3 kinase activity and cell migration on a fibronectin substrate. In contrast, co-expression of a lipid kinase-inactive p110 gamma mutant together with EphA8 inhibits ligand-stimulated PI-3 kinase activity and cell migration on a fibronectin substrate, suggesting that the mutant has a dominant negative effect against the endogenous p110 gamma PI-3 kinase. Significantly, the tyrosine kinase activity of EphA8 is not important for either of these processes. Taken together, our results demonstrate that the stimulation of cell migration on a fibronectin substrate by the EphA8 receptor depends on the p110 gamma PI-3 kinase but is independent of a tyrosine kinase activity. (+info)The EphA8 receptor phosphorylates and activates low molecular weight phosphotyrosine protein phosphatase in vitro. (7/22)
Low molecular weight phosphotyrosine protein phosphatase (LMW-PTP) has been implicated in modulating the EphB1-mediated signaling pathway. In this study, we demonstrated that the EphA8 receptor phosphorylates LMW-PTP in vitro. In addition, we discovered that mixing these two proteins leads to EphA8 dephosphorylation in the absence of phosphatase inhibitors. Finally, we demonstrated that LMW-PTP, modified by the EphA8 autokinase activity, possesses enhanced catalytic activity in vitro. These results suggest that LMW-PTP may also participate in a feedback-control mechanism of the EphA8 receptor autokinase activity in vivo. (+info)The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. (8/22)
LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation. (+info)EphA4 is a type of receptor tyrosine kinase that belongs to the Eph (Erythropoietin-producing hepatocellular) family of receptors. It is a transmembrane protein found on the surface of various types of cells, including neurons and glial cells in the nervous system.
EphA4 receptors play critical roles in several biological processes, such as cell migration, axon guidance, and synaptic plasticity during development and throughout adulthood. They interact with ephrin proteins, which are ligands (molecules that bind to receptors) found on adjacent cells. The interaction between EphA4 and ephrins triggers a cascade of intracellular signaling events that ultimately influence cell behavior.
In summary, EphA4 is a type of receptor involved in cell-cell communication, particularly during the development and functioning of the nervous system. Its dysfunction has been implicated in several neurological disorders, such as spinal cord injuries, Alzheimer's disease, and various forms of cancer.
EphA2 is a type of receptor tyrosine kinase (RTK) that belongs to the Eph (Erythropoietin-producing hepatocellular) family of receptors. It is a transmembrane protein found on the surface of many types of cells, including epithelial, endothelial, and cancer cells.
EphA2 receptors play critical roles in various biological processes such as cell growth, survival, migration, and angiogenesis. They interact with their ligands, called ephrins, which are also transmembrane proteins expressed on adjacent cells. The interaction between EphA2 and ephrins triggers bidirectional signaling that can regulate the adhesion, repulsion, or movement of cells in response to contact with other cells.
In cancer biology, EphA2 receptors have been implicated in tumor progression and metastasis. Overexpression of EphA2 has been observed in various types of human cancers, including breast, lung, prostate, ovarian, and colon cancer. High levels of EphA2 are often associated with poor clinical outcomes, making it an attractive therapeutic target for cancer treatment.
Ephrin-A2 is a type of protein that belongs to the ephrin family. It is a membrane-bound ligand for Eph receptors, which are tyrosine kinase receptors located on the cell surface. Ephrin-A2 and Eph receptors play critical roles in various biological processes, including axon guidance, tissue boundary formation, and tumorigenesis.
Ephrin-A2 is encoded by the EFNB2 gene and is expressed on the cell membrane as a glycosylphosphatidylinositol (GPI)-anchored protein. It can interact with several Eph receptors, including EphA3, EphA4, EphA5, and EphA7, leading to bidirectional signaling that regulates cell-cell interactions and communication.
In the nervous system, ephrin-A2 and its receptors are essential for the development and maintenance of neural circuits. They help to establish precise connections between neurons by mediating repulsive interactions that guide axon growth and fasciculation. Additionally, ephrin-A2 has been implicated in various pathological conditions, such as cancer, where it can contribute to tumor progression and metastasis.
Ephrin-A5 is a type of protein that belongs to the ephrin family. Ephrins are membrane-bound proteins that interact with Eph receptors, which are tyrosine kinase receptors found on the surface of cells. The interaction between ephrins and Eph receptors plays a crucial role in the development and function of the nervous system, including axon guidance, cell migration, and synaptic plasticity.
Ephrin-A5 is specifically classified as a glycosylphosphatidylinositol (GPI)-anchored protein, which means it is attached to the outer layer of the cell membrane through a GPI anchor. It is primarily expressed in various tissues, including the brain, heart, and lungs.
In the nervous system, Ephrin-A5 and its receptor, EphA4, are involved in repulsive guidance cues that help to establish proper neuronal connections during development. Dysregulation of this interaction has been implicated in several neurological disorders, such as spinal cord injuries, Alzheimer's disease, and schizophrenia.
EphA7 is a type of receptor that belongs to the EPH receptor tyrosine kinase family. These receptors are involved in intracellular signaling and play crucial roles in various biological processes, including cell growth, differentiation, and migration.
EphA7 receptors are specifically activated by ephrin-A ligands, which are membrane-bound proteins expressed on adjacent cells. When an ephrin-A ligand binds to an EphA7 receptor, it triggers a cascade of intracellular signaling events that can affect various cellular functions.
EphA7 receptors have been implicated in several physiological and pathological processes, including nervous system development, angiogenesis, and cancer. In the nervous system, EphA7 receptors help to establish connections between neurons and guide their migration during development. In cancer, abnormal expression or activation of EphA7 receptors has been linked to tumor growth, progression, and metastasis.
It's worth noting that while I strive to provide accurate and up-to-date information, medical definitions can be complex and nuanced. Therefore, it may be helpful to consult authoritative medical resources or speak with a healthcare professional for more detailed information on this topic.
EphA5 is a type of receptor tyrosine kinase that belongs to the Eph receptor family. Eph receptors are the largest subfamily of receptor tyrosine kinases and play critical roles in various biological processes, including cell migration, axon guidance, and tissue boundary formation during embryonic development.
EphA5 receptor specifically binds to ephrin-A5 ligand, which is a member of the ephrin family of membrane-bound proteins. The binding of ephrin-A5 to EphA5 triggers bidirectional signaling, meaning that both the receptor and the ligand can transmit signals into their respective cells. This interaction leads to various cellular responses, such as changes in cytoskeletal organization, cell adhesion, and intracellular signaling pathways.
EphA5 has been implicated in several physiological and pathological processes, including neural development, vascular remodeling, tumor angiogenesis, and cancer metastasis. Mutations in the EPHA5 gene have been associated with various human diseases, such as intellectual disability, epilepsy, and congenital heart defects.
EphA1 is a type of receptor tyrosine kinase (RTK) that belongs to the Eph family of receptors. It is a single-pass transmembrane protein that contains an extracellular domain with a binding site for its ligand, ephrin-A5, and an intracellular domain with tyrosine kinase activity.
EphA1 receptors are involved in various biological processes, including cell migration, axon guidance, and tissue boundary formation during embryonic development. They also play a role in angiogenesis, neuroprotection, and tumorigenesis in adults.
The binding of ephrin-A5 to EphA1 receptors triggers bidirectional signaling, affecting both the receptor-expressing cell and the ephrin-presenting cell. This interaction can lead to repulsion, adhesion, or collapse of the growth cone, depending on the context and the specific Eph/ephrin pair involved.
Mutations in EphA1 have been associated with various diseases, including cancer, neurodevelopmental disorders, and cardiovascular disease.
Ephrin-A1 is a type of protein that belongs to the ephrin family. It is a membrane-bound ligand for Eph receptors, which are tyrosine kinase receptors located on the cell surface. Ephrin-A1 and its receptors play critical roles in various biological processes, including cell migration, axon guidance, and tissue boundary formation during embryonic development. Ephrin-A1 is also involved in angiogenesis, tumorigenesis, and metastasis in cancer. It is encoded by the EFNAs gene in humans.
Eph family receptors are a group of tyrosine kinase receptors that play crucial roles in the development and function of the nervous system, as well as in other tissues. They are named after the first discovered member of this family, EPH (Erythropoietin-Producing Human Hepatocellular carcinoma) receptor.
These receptors are divided into two subfamilies: EphA and EphB, based on their binding preferences for ephrin ligands. Ephrins are membrane-bound proteins that can be either GPI-anchored (ephrin-A) or transmembrane (ephrin-B), and they interact with Eph receptors in a bidirectional manner, activating both forward signaling in the receptor-expressing cell and reverse signaling in the ephrin-expressing cell.
Eph receptors and ephrins are essential for axon guidance, topographic mapping, and synaptic plasticity during neural development. They also participate in various processes in adult tissues, such as angiogenesis, tumorigenesis, and immune responses. Dysregulation of Eph family receptors has been implicated in several diseases, including cancer, neurological disorders, and vascular diseases.
Ephrin-A4 is a type of protein that belongs to the ephrin family. Ephrins are membrane-bound proteins that play crucial roles in various biological processes, including cell signaling and communication during development. Specifically, Ephrin-A4 is a ligand for Eph receptors, which are tyrosine kinase receptors located on the cell membrane.
Ephrin-A4 is composed of a glycosylphosphatidylinositol (GPI) anchor that attaches it to the cell membrane and an extracellular domain that interacts with Eph receptors. When Ephrin-A4 binds to an Eph receptor on a neighboring cell, it triggers a cascade of intracellular signaling events that can regulate various cellular processes, such as cell adhesion, migration, and proliferation.
In the medical field, Ephrin-A4 has been studied in the context of various diseases, including cancer. For example, abnormal expression of Ephrin-A4 has been observed in several types of tumors, and it has been suggested to play a role in tumor progression and metastasis. However, more research is needed to fully understand the functional significance of Ephrin-A4 in health and disease.
Ephrins are a family of membrane-bound proteins that play crucial roles in various biological processes, including cell migration, axon guidance, and tissue boundary formation during embryonic development. They interact with Eph receptors, which are tyrosine kinase receptors found on the surface of neighboring cells. This interaction results in bidirectional signaling between the two cells, affecting their behaviors and influencing the organization of tissues and organs.
There are two main types of ephrins: Ephrin-A (also known as GPI-anchored ephrins) and Ephrin-B (transmembrane ephrins). Ephrin-A proteins are attached to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor, while Ephrin-B proteins have a transmembrane domain and a cytoplasmic tail. Both types of ephrins interact with Eph receptors, leading to the initiation of intracellular signaling cascades that regulate various cellular responses.
Dysregulation of ephrin/Eph receptor interactions has been implicated in several human diseases, including cancer, where they can contribute to tumor growth, progression, and metastasis. Therefore, understanding the functions and regulation of ephrins and their receptors is essential for developing novel therapeutic strategies to treat various diseases.
Ephrin-A3 is a type of protein that belongs to the ephrin family. Ephrins are membrane-bound proteins that play crucial roles in various biological processes, including cell signaling and communication during development. Specifically, Ephrin-A3 binds to Eph receptors, which are tyrosine kinase receptors found on the surface of neighboring cells. This binding leads to bidirectional signals that regulate cell adhesion, repulsion, and migration, thereby helping to establish proper tissue and organ architecture during development. Additionally, Ephrin-A3 has been implicated in various physiological and pathological processes, such as angiogenesis, neurogenesis, and cancer.
Ephrin-B3 is a type of protein that belongs to the ephrin family and is involved in cell signaling, particularly during the development and functioning of the nervous system. It is a transmembrane protein, which means it spans the membrane of the cell and has a domain outside the cell and a domain inside the cell.
Ephrin-B3 interacts with Eph receptors on neighboring cells to initiate bidirectional signaling, which means that both the cells that express ephrin-B3 and the cells that express the Eph receptor are affected by this interaction. This signaling is important for various processes such as axon guidance, cell migration, and tissue boundaries formation during development. In addition, ephrin-B3 has been implicated in the regulation of synaptic plasticity and vascular remodeling in adults.
Mutations in the gene that encodes ephrin-B3 have been associated with certain neurological disorders, such as intellectual disability and epilepsy.
EPHA8 - Wikipedia
MMRRC:040341-MU
Phospho.ELM Result
MPD: Genes and genomic regions
FYN and EPHA8 Interaction - Wiki-Pi
Target Information | Therapeutic Target Database
Efrinas/genética
EPHA8-H00A-Wuxi Biortus Biosciences Co. Ltd.
DeCS
Recombinant Mouse EphA7 Protein (His Tag) | Beta LifeScience
Semi-Quantitative Arrays
Eph
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Expression Pattern and Prognostic Value of EPHA/EFNA in Breast Cancer by Bioinformatics Analysis: Revealing Its Importance in...
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