Journal articles on the topic 'Ephrin'
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1
PRESTOZ, LAETITIA, ELLI CHATZOPOULOU, GREGORY LEMKINE, NATHALIE SPASSKY, BARBARA LEBRAS, TETSUSHI KAGAWA, KATZUHIRO IKENAKA, BERNARD ZALC, and JEAN-LÉON THOMAS. "Control of axonophilic migration of oligodendrocyte precursor cells by Eph–ephrin interaction." Neuron Glia Biology 1, no. 1 (February 2004): 73–83. http://dx.doi.org/10.1017/s1740925x04000109.
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The migration of oligodendrocyte precursor cells (OPCs) is modulated by secreted molecules in their environment and by cell–cell and matrix–cell interactions. Here, we ask whether membrane-anchored guidance cues, such as the ephrin ligands and their Eph receptors, participate in the control of OPC migration in the optic nerve. We postulate that EphA and EphB receptors, which are expressed on axons of retinal ganglion cells, interact with ephrins on the surface of OPCs. We show the expression of ephrinA5, ephrinB 2 and ephrinB3 in the migrating OPCs of the optic nerve as well as in the diencephalic sites from where they originate. In addition, we demonstrate that coated EphB2-Fc receptors, which are specific for ephrinB2/B3 ligands, induce dramatic changes in the contact and migratory properties of OPCs, indicating that axonal EphB receptors activate ephrinB signaling in OPCs. Based on these findings, we propose that OPCs are characterized by an ephrin code, and that Eph–ephrin interactions between axons and OPCs control the distribution of OPCs in the optic axonal tracts, and the progress and arrest of their migration.
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Kuang, Shao-qing, Zhi-Hong Fang, Gonzalo Lopez, Weigang Tong, Hui Yang, and Guillermo Garcia-Manero. "Eph Receptor Tyrosine Kinases and Ephrin Ligands Are Epigenetically Inactivated in Acute Lymphoblastic Leukemia and Are Potential New Tumor Suppressor Genes in Human Leukemia." Blood 110, no. 11 (November 16, 2007): 2128. http://dx.doi.org/10.1182/blood.v110.11.2128.2128.
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Abstract The Eph (erythroprotein-producing hepatoma amplified sequence) family receptor tyrosine kinases and their ephrin ligands (ephrins) are involved in a variety of functions in normal cell development and cancer. We have identified several members of this family as potential targets of aberrant DNA methylation using Methylated CpG Island Amplification (MCA) / DNA promoter microarray technology. This is of importance as there are no prior reports of potential Eph receptor or Ephrin epigenetic inactivation in human leukemia. To further investigate the role of Eph receptor and ephrin family genes in leukemia, we have analyzed their DNA methylation status in a panel of 23 leukemia cell lines and 65 primary ALL patient samples. Aberrant DNA methylation of 9 of these genes (EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3) was detected in multiple leukemia cell lines but not in normal samples by bisulfite pyrosequencing. In ALL patient samples, the frequencies of DNA methylation detected in the promoter regions of these genes ranged from 23% to 87% for EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3. Expression analysis of 3 of these genes (EPHA5, EPHB4 and Ephrin B2) in leukemia cell lines by real-time PCR further confirmed methylation associated gene silencing. Treatment of methylated/silenced cell lines with DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine resulted in gene re-expression. Forced overexpression of EPHB4 using a lentivirus transduction system in Raji cell lines resulted in decreased cell proliferation and adhesion-independent cell growth, as well as in an increase in staurosporine induction of apoptosis. In addition, EPHB4 overexpression resulted in a significant downregulation of phosphorylated Akt pathway but had no effect on mitogen-activated protein kinase pathway. In summary, we describe for the first time the epigenetic suppression of Ephrin receptors and their ligands in human leukemia, indicating that these genes may be potential tumor suppressors in leukemia. Targeting of these pathways may result in the development of new potential therapies and biomarkers for patients with ALL.
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Li, Wenqing, Lai Wen, Bhavisha Rathod, Anne-Claude Gingras, Klaus Ley, and Ho-Sup Lee. "Kindlin2 enables EphB/ephrinB bi-directional signaling to support vascular development." Life Science Alliance 6, no. 3 (December 27, 2022): e202201800. http://dx.doi.org/10.26508/lsa.202201800.
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Direct contact between cells expressing either ephrin ligands or Eph receptor tyrosine kinase produces diverse developmental responses. Transmembrane ephrinB ligands play active roles in transducing bi-directional signals downstream of EphB/ephrinB interaction. However, it has not been well understood how ephrinB relays transcellular signals to neighboring cells and what intracellular effectors are involved. Here, we report that kindlin2 can mediate bi-directional ephrinB signaling through binding to a highly conserved NIYY motif in the ephrinB2 cytoplasmic tail. We show this interaction is important for EphB/ephrinB-mediated integrin activation in mammalian cells and for blood vessel morphogenesis during zebrafish development. A mixed two-cell population study revealed that kindlin2 (in ephrinB2-expressing cells) modulates transcellular EphB4 activation by promoting ephrinB2 clustering. This mechanism is also operative for EphB2/ephrinB1, suggesting that kindlin2-mediated regulation is conserved for EphB/ephrinB signaling pathways. Together, these findings show that kindlin2 enables EphB4/ephrinB2 bi-directional signal transmission.
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Riedl, Jurgen A., Dominique T. Brandt, Eduard Batlle, Leo S. Price, Hans Clevers, and Johannes L. Bos. "Down-regulation of Rap1 activity is involved in ephrinB1-induced cell contraction." Biochemical Journal 389, no. 2 (July 5, 2005): 465–69. http://dx.doi.org/10.1042/bj20050048.
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Ephrins are cell surface ligands that activate Eph receptor tyrosine kinases. This ligand–receptor interaction plays a central role in the sorting of cells. We have previously shown that the ephrinB–EphB signalling pathway is also involved in the migration of intestinal precursor cells along the crypts. Using the colon cell line DLD1 expressing the EphB2 receptor, we showed that stimulation of these cells with soluble ephrinB1 results in a rapid retraction of cell extensions and a detachment of cells. On ephrinB1 stimulation, the small GTPases Rho and Ras are activated and Rap1 is inactivated. Importantly, when a constitutively active Rap1 mutant was introduced into these cells, ephrinB1-induced retraction was inhibited. From these results, we conclude that down-regulation of Rap1 is a prerequisite for ephrin-induced cell retraction in colon cells.
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Minami, Masayoshi, Tatsuya Koyama, Yuki Wakayama, Shigetomo Fukuhara, and Naoki Mochizuki. "EphrinA/EphA signal facilitates insulin-like growth factor-I–induced myogenic differentiation through suppression of the Ras/extracellular signal–regulated kinase 1/2 cascade in myoblast cell lines." Molecular Biology of the Cell 22, no. 18 (September 15, 2011): 3508–19. http://dx.doi.org/10.1091/mbc.e11-03-0183.
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Insulin-like growth factor-I (IGF-I) activates not only the phosphatidylinositol 3-kinase (PI3K)–AKT cascade that is essential for myogenic differentiation but also the extracellular signal–regulated kinase (ERK) 1/2 cascade that inhibits myogenesis. We hypothesized that there must be a signal that inhibits ERK1/2 upon cell–cell contact required for skeletal myogenesis. Cell–cell contact–induced engagement of ephrin ligands and Eph receptors leads to downregulation of the Ras-ERK1/2 pathway through p120 Ras GTPase-activating protein (p120RasGAP). We therefore investigated the significance of the ephrin/Eph signal in IGF-I–induced myogenesis. EphrinA1-Fc suppressed IGF-I–induced activation of Ras and ERK1/2, but not that of AKT, in C2C12 myoblasts, whereas ephrinB1-Fc affected neither ERK1/2 nor AKT activated by IGF-I. IGF-I–dependent myogenic differentiation of C2C12 myoblasts was potentiated by ephrinA1-Fc. In p120RasGAP-depleted cells, ephrinA1-Fc failed to suppress the Ras-ERK1/2 cascade by IGF-I and to promote IGF-I–mediated myogenesis. EphrinA1-Fc did not promote IGF-I–dependent myogenesis when the ERK1/2 was constitutively activated. Furthermore, a dominant-negative EphA receptor blunted IGF-I–induced myogenesis in C2C12 and L6 myoblasts. However, the inhibition of IGF-I–mediated myogenesis by down-regulation of ephrinA/EphA signal was canceled by inactivation of the ERK1/2 pathway. Collectively, these findings demonstrate that the ephrinA/EphA signal facilitates IGF-I–induced myogenesis by suppressing the Ras-ERK1/2 cascade through p120RasGAP in myoblast cell lines.
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Gaitanos, Thomas N., Jorg Koerner, and Ruediger Klein. "Tiam–Rac signaling mediates trans-endocytosis of ephrin receptor EphB2 and is important for cell repulsion." Journal of Cell Biology 214, no. 6 (September 5, 2016): 735–52. http://dx.doi.org/10.1083/jcb.201512010.
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Ephrin receptors interact with membrane-bound ephrin ligands to regulate contact-mediated attraction or repulsion between opposing cells, thereby influencing tissue morphogenesis. Cell repulsion requires bidirectional trans-endocytosis of clustered Eph–ephrin complexes at cell interfaces, but the mechanisms underlying this process are poorly understood. Here, we identified an actin-regulating pathway allowing ephrinB+ cells to trans-endocytose EphB receptors from opposing cells. Live imaging revealed Rac-dependent F-actin enrichment at sites of EphB2 internalization, but not during vesicle trafficking. Systematic depletion of Rho family GTPases and their regulatory proteins identified the Rac subfamily and the Rac-specific guanine nucleotide exchange factor Tiam2 as key components of EphB2 trans-endocytosis, a pathway previously implicated in Eph forward signaling, in which ephrins act as in trans ligands of Eph receptors. However, unlike in Eph signaling, this pathway is not required for uptake of soluble ligands in ephrinB+ cells. We also show that this pathway is required for EphB2-stimulated contact repulsion. These results support the existence of a conserved pathway for EphB trans-endocytosis that removes the physical tether between cells, thereby enabling cell repulsion.
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FINNE, Eivind F., Else MUNTHE, and Hans-Christian AASHEIM. "A new ephrin-A1 isoform (ephrin-A1b) with altered receptor binding properties abrogates the cleavage of ephrin-A1a." Biochemical Journal 379, no. 1 (April 1, 2004): 39–46. http://dx.doi.org/10.1042/bj20031619.
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Ephrins are ligands for the Eph receptor tyrosine kinases, which play important roles in patterning nervous and vascular systems. Ephrin-A1 is a glycosylphosphatidylinositol-anchored ligand that binds to the EphA receptor tyrosine kinases. In the present study, we have identified a new ephrin-A1 isoform, denoted ephrin-A1b (ephrin-A1 isoform b). Compared with the originally described ephrin-A1 sequence, ephrin-A1a [Holzman, Marks and Dixit (1990) Mol. Cell. Biol. 10, 5830–5838], ephrin-A1b lacks a segment of 22 amino acids (residues 131–152). At the transcript level, exon 3 is spliced out in the transcript encoding ephrin-A1b. Transfection of HEK-293T cells (human embryonic kidney 293 cells) with an ephrin-A1b-expressing plasmid resulted in a significant expression of the protein on the cell surface. However, soluble EphA2 receptor (EphA2-Fc) bound weakly to ephrin-A1b-expressing transfectants, but bound strongly to ephrin-A1a-expressing transfectants. Ephrins have been shown to undergo regulated cleavage after interaction with their receptors. This process is inhibited by co-expression of ephrin-A1a and ephrin-A1b, indicating that ephrin-A1b influences the cleavage process. Taken together, these findings indicate that this newly described isoform may regulate the function of its ephrin-A1a counterpart.
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Gong, Jingyi, Roman Körner, Louise Gaitanos, and Rüdiger Klein. "Exosomes mediate cell contact–independent ephrin-Eph signaling during axon guidance." Journal of Cell Biology 214, no. 1 (June 27, 2016): 35–44. http://dx.doi.org/10.1083/jcb.201601085.
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The cellular release of membranous vesicles known as extracellular vesicles (EVs) or exosomes represents a novel mode of intercellular communication. Eph receptor tyrosine kinases and their membrane-tethered ephrin ligands have very important roles in such biologically diverse processes as neuronal development, plasticity, and pathological diseases. Until now, it was thought that ephrin-Eph signaling requires direct cell contact. Although the biological functions of ephrin-Eph signaling are well understood, our mechanistic understanding remains modest. Here we report the release of EVs containing Ephs and ephrins by different cell types, a process requiring endosomal sorting complex required for transport (ESCRT) activity and regulated by neuronal activity. Treatment of cells with purified EphB2+ EVs induces ephrinB1 reverse signaling and causes neuronal axon repulsion. These results indicate a novel mechanism of ephrin-Eph signaling independent of direct cell contact and proteolytic cleavage and suggest the participation of EphB2+ EVs in neural development and synapse physiology.
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Psilopatis, Iason, Eleni Souferi-Chronopoulou, Kleio Vrettou, Constantinos Troungos, and Stamatios Theocharis. "EPH/Ephrin-Targeting Treatment in Breast Cancer: A New Chapter in Breast Cancer Therapy." International Journal of Molecular Sciences 23, no. 23 (December 3, 2022): 15275. http://dx.doi.org/10.3390/ijms232315275.
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Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC.
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Matsui, Toshimitsu, Hiroshi Matsuoka, Akira Tamekane, Ryuichi Inoue, Manabu Shimoyama, Atsushi Okamura, Hiroya Obama, Meghan L. Kelly, and Masaru Nakamoto. "Cell Adhesion and Migration Regulated by EphB6 Expressed on Human Hematopoietic Progenitors." Blood 106, no. 11 (November 16, 2005): 1386. http://dx.doi.org/10.1182/blood.v106.11.1386.1386.
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Abstract Normal human hematopoietic progenitors as well as leukemia/lymphoma cells express kinase-defective EphB6 receptors. The only unique high affinity ligand for EphB6 among eight known mammalian ephrins, ephrins-B2 is expressed not only on hematopoietic malignancies, but also on mesenchymal stem cells. However, the biological functions of the receptor and its ligand in hematopoietic cells are largely unknown. In the present study, we showed that the interaction between EphB6 and ephrinB2 could initiate forward as well as reverse signaling in vitro. Both pre-clustered and unclustered ligands could trigger the signal transduction, but pre-clustered ones more rapidly down-regulated the signaling. We also examined the EphB6/ephrinB2 function in cell adhesion and migration. Figure Figure HEK-EphB6 cells placed in the upper chamber of a Transwell apparatus, in which the lower side of filter was coated with different concentrations of ephrin-B2-Fc or Fc, were allowed to migrate to the lower side at 37°C overnight. Vector-transfected cells were used as controls. The cells that had migrated to the lower side of filter were stained, photographed. A BSA-coated filter is shown as a control. EphB6 exerted biphasic effects in response to different concentrations of the ephrin-B2. EphB6 promoted cell adhesion and migration when stimulated with low concentrations of ephrin-B2, whereas it induced repulsion and inhibited migration upon stimulation with high concentrations of ephrin-B2. A truncated EphB6 receptor lacking the cytoplasmic domain showed monophasic positive effects on cell adhesion and migration, indicating that the cytoplasmic domain is essential for the negative effects. We further explored the signal transduction of the biphasic effects. Figure Figure The Src family kinase, Fyn was co-immunoprecipitated with anti-EphB6 antibody in the absence or presence of ephrin-B2 stimulation. High concentrations of ephrin-B2 induced tyrosine phosphorylation of EphB6 through a Src family kinase activity. These results indicate that EphB6 can both positively and negatively regulate cell adhesion and migration, and suggest that tyrosine phosphorylation of the kinase-defective EphB6 receptor by a Src family kinase acts as the molecular switch for the functional transition. Thus, EphB6 expressed on hematopoietic cells may play an important role in the regulation of cell homing to hematopoietic tissues as well as leukemia cell infiltration.
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Ratner, Stuart, Charles A. Schiffer, and Jeffrey A. Zonder. "Inhibition of Multiple Myeloma Cell Adhesion to Fibronectin by Ephrin Ligation." Blood 104, no. 11 (November 16, 2004): 2360. http://dx.doi.org/10.1182/blood.v104.11.2360.2360.
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Abstract Multiple myeloma (MM) cell adhesion to fibronectin (FN), mediated via VLA-4 and VLA-5, has been shown to induce resistance to several chemotherapeutic drugs. Disruption of MM cell adhesion to FN and other marrow microenvironment elements might therefore enhance the effects of therapy. We now present the first evidence that Eph-ephrin signaling may be exploited to inhibit MM cell binding to fibronectin. Ephs are transmembrane tyrosine kinases and ephrins are their cell-surface ligands. There are two classes of Ephs and ephrins, A and B. Both Ephs and ephrins can transduce repulsive signals that cause interacting cells to lose contact with each other and with extracellular matrix. We are not aware of any previous systematic study of Eph and ephrin expression or function in MM cells. We have found MM cell lines H929, U266, and RPMI 8226 express members of the A classes of both Ephs and ephrins, but not the B classes. First, we demonstrated ligation with commercially available anti-ephrin A3 antibody was followed by ephrin capping and shedding from the cell surface. We next explored whether ephrin ligation affects MM cell adhesiveness in culture. Whereas H929, U266, and RPMI 8226 cells adhered rapidly to fibronectin-coated plastic surfaces, all three cell lines failed completely to adhere to a mixed coating of FN and rabbit anti-ephrin A3 antibody for a period of 2 hrs. This effect was not seen with FN + normal rabbit Ig. This suggests binding of ephrin A3 (or another cross-reacting A-class ephrin) by solid-state antibody triggers intracellular signals that interfere with initial steps of integrin-mediated adhesion. After 2 hr, spontaneous partial recovery of adhesion occurred, reaching a plateau of approximately 30% of control values by 24 hr. We postulate this recovery occurs via clipping of the extracellular ephrin domain by transmembrane metalloproteases, since recovery of FN adhesion was partially prevented by the metalloprotease inhibitor GM6001 (25 uM). Also consistent with this theory, we found in a separate experiment that GM6001 reduced the shedding of cross-linked A-class ephrins from MM cell lines. In summary, we have demonstrated that manipulation of EPH-ephrin signaling can impair MM-cell adhesion to FN, and that this effect is enhanced by simultaneous inhibition of metalloprotease activity. We are currently studying the effect of A-class ephrin ligation on adhesion-mediated drug resistance in MM cell lines. We also intend to evaluate EPH-ephrin expression in marrow specimens from patients with MM.
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Psilopatis, Iason, Ioannis Karniadakis, Konstantinos Stylianos Danos, Kleio Vrettou, Kleita Michaelidou, Konstantinos Mavridis, Sofia Agelaki, and Stamatios Theocharis. "May EPH/Ephrin Targeting Revolutionize Lung Cancer Treatment?" International Journal of Molecular Sciences 24, no. 1 (December 21, 2022): 93. http://dx.doi.org/10.3390/ijms24010093.
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Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHs/ephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPH/ephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPH/ephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHs/ephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPH/ephrin targeting in the clinical setting.
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Laing, Eric D., Chanakha K. Navaratnarajah, Sofia Cheliout Da Silva, Stephanie R. Petzing, Yan Xu, Spencer L. Sterling, Glenn A. Marsh, et al. "Structural and functional analyses reveal promiscuous and species specific use of ephrin receptors by Cedar virus." Proceedings of the National Academy of Sciences 116, no. 41 (September 23, 2019): 20707–15. http://dx.doi.org/10.1073/pnas.1911773116.
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Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.
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Papadakos, Stavros P., Nikolaos Dedes, Nikolina Gkolemi, Nikolaos Machairas, and Stamatios Theocharis. "The EPH/Ephrin System in Pancreatic Ductal Adenocarcinoma (PDAC): From Pathogenesis to Treatment." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 3015. http://dx.doi.org/10.3390/ijms24033015.
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Pancreatic ductal adenocarcinoma (PDAC) is a major concern for health care systems worldwide, since its mortality remains unaltered despite the surge in cutting-edge science. The EPH/ephrin signaling system was first investigated in the 1980s. EPH/ephrins have been shown to exert bidirectional signaling and cell-to-cell communication, influencing cellular morphology, adhesion, migration and invasion. Recent studies have highlighted the critical role of the EPH/ephrin system in various physiologic processes, including cellular proliferation, survival, synaptic plasticity and angiogenesis. Thus, it has become evident that the EPH/ephrin signaling system may have compelling effects on cell homeostasis that contribute to carcinogenesis. In particular, the EPH/ephrins have an impact on pancreatic morphogenesis and development, whereas several EPHs and ephrins are altered in PDAC. Several clinical and preclinical studies have attempted to elucidate the effects of the EPH/ephrin pathway, with multilayered effects on PDAC development. These studies have highlighted its highly promising role in the diagnosis, prognosis and therapeutic management of PDAC. The aim of this review is to explore the obscure aspects of the EPH/ephrin system concerning the development, physiology and homeostasis of the pancreas.
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Peixoto, Francisca O., Patrícia Pereira-Terra, Rute S. Moura, Emanuel Carvalho-Dias, Jorge Correia-Pinto, and Cristina Nogueira-Silva. "The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development." Cellular Physiology and Biochemistry 35, no. 1 (2015): 104–15. http://dx.doi.org/10.1159/000369679.
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Background/ Aims: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis. Methods: Ephrins-B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed. Results: Ephrin-B1 presents mesenchymal expression, whereas ephrin-B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development. Conclusion: Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters.
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Huynh-Do, Uyen, Cécile Vindis, Hua Liu, Douglas Pat Cerretti, Jeffrey T. McGrew, Miriam Enriquez, Jin Chen, and Thomas O. Daniel. "Ephrin-B1 transduces signals to activate integrin-mediated migration,attachment and angiogenesis." Journal of Cell Science 115, no. 15 (August 1, 2002): 3073–81. http://dx.doi.org/10.1242/jcs.115.15.3073.
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Ephrin-B/EphB family proteins are implicated in bidirectional signaling and were initially defined through the function of their ectodomain sequences in activating EphB receptor tyrosine kinases. Ephrin-B1-3 are transmembrane proteins sharing highly conserved C-terminal cytoplasmic sequences. Here we use a soluble EphB1 ectodomain fusion protein (EphB1/Fc) to demonstrate that ephrin-B1 transduces signals that regulate cell attachment and migration. EphB1/Fc induced endothelial ephrin-B1 tyrosine phosphorylation, migration and integrin-mediated (αvβ3 andα 5β1) attachment and promoted neovascularization, in vivo, in a mouse corneal micropocket assay. Activation of ephrin-B1 by EphB1/Fc induced phosphorylation of p46 JNK but not ERK-1/2 or p38 MAPkinases. By contrast, mutant ephrin-B1s bearing either a cytoplasmic deletion (ephrin-B1ΔCy) or a deletion of four C-terminal amino acids(ephrin-B1ΔPDZbd) fail to activate p46 JNK. Transient expression of intact ephin-B1 conferred EphB1/Fc migration responses on CHO cells, whereas the ephrin-B1ΔCy and ephrin-B1ΔPDZbd mutants were inactive. Thus ephrin-B1 transduces `outside-in' signals through C-terminal protein interactions that affect integrin-mediated attachment and migration.
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Chong, Lisa D., Eui Kyun Park, Erin Latimer, Robert Friesel, and Ira O. Daar. "Fibroblast Growth Factor Receptor-Mediated Rescue of x-Ephrin B1-Induced Cell Dissociation in XenopusEmbryos." Molecular and Cellular Biology 20, no. 2 (January 15, 2000): 724–34. http://dx.doi.org/10.1128/mcb.20.2.724-734.2000.
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ABSTRACT The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. Genetic evidence suggests that ephrins may transduce signals and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Here, we report that when we used ectopically expressed proteins, we found that an activated fibroblast growth factor (FGF) receptor associated with and induced the phosphorylation of ephrin B1 on tyrosine. Moreover, this phosphorylation reduced the ability of overexpressed ephrin B1 to reduce cell adhesion. In addition, we identified a region in the cytoplasmic tail of ephrin B1 that is critical for interaction with the FGF receptor; we also report FGF-induced phosphorylation of ephrins in a neural tissue. This is the first demonstration of communication between the FGF receptor family and the Eph ligand family and implicates cross talk between these two cell surface molecules in regulating cell adhesion.
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Santiago, Alicia, and Carol A. Erickson. "Ephrin-B ligands play a dual role in the control of neural crest cell migration." Development 129, no. 15 (August 1, 2002): 3621–32. http://dx.doi.org/10.1242/dev.129.15.3621.
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Little is known about the mechanisms that direct neural crest cells to the appropriate migratory pathways. Our aim was to determine how neural crest cells that are specified as neurons and glial cells only migrate ventrally and are prevented from migrating dorsolaterally into the skin, whereas neural crest cells specified as melanoblasts are directed into the dorsolateral pathway. Eph receptors and their ephrin ligands have been shown to be essential for migration of many cell types during embryonic development. Consequently, we asked if ephrin-B proteins participate in the guidance of melanoblasts along the dorsolateral pathway, and prevent early migratory neural crest cells from invading the dorsolateral pathway. Using Fc fusion proteins, we detected the expression of ephrin-B ligands in the dorsolateral pathway at the stage when neural crest cells are migrating ventrally. Furthermore, we show that ephrins block dorsolateral migration of early-migrating neural crest cells because when we disrupt the Eph-ephrin interactions by addition of soluble ephrin-B ligand to trunk explants, early neural crest cells migrate inappropriately into the dorsolateral pathway. Surprisingly, we discovered the ephrin-B ligands continue to be expressed along the dorsolateral pathway during melanoblast migration. RT-PCR analysis, in situ hybridisation, and cell surface-labelling of neural crest cell cultures demonstrate that melanoblasts express several EphB receptors. In adhesion assays, engagement of ephrin-B ligands to EphB receptors increases melanoblast attachment to fibronectin. Cell migration assays demonstrate that ephrin-B ligands stimulate the migration of melanoblasts. Furthermore, when Eph signalling is disrupted in vivo, melanoblasts are prevented from migrating dorsolaterally, suggesting ephrin-B ligands promote the dorsolateral migration of melanoblasts. Thus, transmembrane ephrins act as bifunctional guidance cues: they first repel early migratory neural crest cells from the dorsolateral path, and then later stimulate the migration of melanoblasts into this pathway. The mechanisms by which ephrins regulate repulsion or attraction in neural crest cells are unknown. One possibility is that the cellular response involves signalling to the actin cytoskeleton, potentially involving the activation of Cdc42/Rac family of GTPases. In support of this hypothesis, we show that adhesion of early migratory cells to an ephrin-B-derivatized substratum results in cell rounding and disruption of the actin cytoskeleton, whereas plating of melanoblasts on an ephrin-B substratum induces the formation of microspikes filled with F-actin.
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Lawrenson, Isobel D., Sabine H. Wimmer-Kleikamp, Peter Lock, Simone M. Schoenwaelder, Michelle Down, Andrew W. Boyd, Paul F. Alewood, and Martin Lackmann. "Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling." Journal of Cell Science 115, no. 5 (March 1, 2002): 1059–72. http://dx.doi.org/10.1242/jcs.115.5.1059.
Full textAbstract:
Eph receptor tyrosine kinases and ephrins regulate morphogenesis in the developing embryo where they effect adhesion and motility of interacting cells. Although scarcely expressed in adult tissues, Eph receptors and ephrins are overexpressed in a range of tumours. In malignant melanoma, increased Eph and ephrin expression levels correlate with metastatic progression. We have examined cellular and biochemical responses of EphA3-expressing melanoma cell lines and human epithelial kidney 293T cells to stimulation with polymeric ephrin-A5 in solution and with surfaces of defined ephrin-A5 densities. Within minutes, rapid reorganisation of the actin and myosin cytoskeleton occurs through activation of RhoA, leading to the retraction of cellular protrusions,membrane blebbing and detachment, but not apoptosis. These responses are inhibited by monomeric ephrin-A5, showing that receptor clustering is required for this EphA3 response. Furthermore, the adapter CrkII, which associates with tyrosine-phosphorylated EphA3 in vitro, is recruited in vivo to ephrin-A5-stimulated EphA3. Expression of an SH3-domain mutated CrkII ablates cell rounding, blebbing and detachment. Our results suggest that recruitment of CrkII and activation of Rho signalling are responsible for EphA3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-A5-mediated receptor clustering and EphA3 tyrosine kinase activity are essential for this response.
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Prospéri, Marie-Thérèse, Priscilla Lépine, Florent Dingli, Perrine Paul-Gilloteaux, René Martin, Damarys Loew, Hans-Joachim Knölker, and Evelyne Coudrier. "Myosin 1b functions as an effector of EphB signaling to control cell repulsion." Journal of Cell Biology 210, no. 2 (July 20, 2015): 347–61. http://dx.doi.org/10.1083/jcb.201501018.
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Eph receptors and their membrane-tethered ligands, the ephrins, have important functions in embryo morphogenesis and in adult tissue homeostasis. Eph/ephrin signaling is essential for cell segregation and cell repulsion. This process is accompanied by morphological changes and actin remodeling that drives cell segregation and tissue patterning. The actin cortex must be mechanically coupled to the plasma membrane to orchestrate the cell morphology changes. Here, we demonstrate that myosin 1b that can mechanically link the membrane to the actin cytoskeleton interacts with EphB2 receptors via its tail and is tyrosine phosphorylated on its tail in an EphB2-dependent manner. Myosin 1b regulates the redistribution of myosin II in actomyosin fibers and the formation of filopodia at the interface of ephrinB1 and EphB2 cells, which are two processes mediated by EphB2 signaling that contribute to cell repulsion. Together, our results provide the first evidence that a myosin 1 functions as an effector of EphB2/ephrinB signaling, controls cell morphology, and thereby cell repulsion.
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Angmalisang, Elvin C. "Peran Sinyal Ephrin-B2/EPH-B4 pada Angiogenesis Postnatal." Jurnal Biomedik:JBM 12, no. 2 (July 12, 2020): 77. http://dx.doi.org/10.35790/jbm.12.2.2020.29161.
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Abstract: Angiogenesis is the process of developing new blood vessels that play an important role in embryogenesis as well as postnatal period. The postnatal angiogenesis is regulated by pro- and anti-angiogenic factors and several signals, one of which is the ephrin/Eph signal. Ephrin-B2 and its receptor EphB4 are transmembrane tyrosine kinase (RTKs) receptors which have an important role in angiogenesis inter alia promoting angiogenesis sprouting and participating in blood vessel maturation (remodeling and stabilization).Keywords: angiogenesis, Ephrin-B2, EphB4, EphrinB2/EphB4 signaling Abstrak: Angiogenesis adalah proses perkembangan pembuluh darah baru yang berperan penting pada embriogenesis, dan juga saat postnatal. Proses postnatal angiogenesis diregulasi oleh faktor-faktor pro- dan anti-angiogenik serta sinyal-sinyal, salah satunya ialah sinyal ephrin/Eph. Ephrin-B2 dan reseptornya EphB4 merupakan reseptor tirosin kinase (RTKs) transmembran yang berperan penting pada angiogenesis, yaitu untuk memromosikan angio-genesis sprouting, serta berpartisipasi dalam pematangan pembuluh darah (remodeling dan stabilisasi).Kata kunci: angiogenesis, Ephrin-B2, EphB4, sinyal EphrinB2/EphB4
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Fukusumi, Yoshiyasu, Ying Zhang, Ryohei Yamagishi, Kanako Oda, Toru Watanabe, Katsuyuki Matsui, and Hiroshi Kawachi. "Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway." Journal of the American Society of Nephrology 29, no. 5 (March 30, 2018): 1462–74. http://dx.doi.org/10.1681/asn.2017090993.
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Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear.Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti-nephrin antibody-induced nephropathy.Results Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing a mutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1–promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody-induced nephropathy.Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury.
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Psilopatis, Iason, Alexandros Pergaris, Kleio Vrettou, Gerasimos Tsourouflis, and Stamatios Theocharis. "The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management." International Journal of Molecular Sciences 23, no. 6 (March 17, 2022): 3249. http://dx.doi.org/10.3390/ijms23063249.
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Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients’ gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact.
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Holen, Halvor L., Lillian Zernichow, Kristine E. Fjelland, Ida M. Evenroed, Kristian Prydz, Heidi Tveit, and Hans-Christian Aasheim. "Ephrin-B3 binds to a sulfated cell-surface receptor." Biochemical Journal 433, no. 1 (December 15, 2010): 215–23. http://dx.doi.org/10.1042/bj20100865.
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The ephrins are a family of proteins known to bind the Eph (erythropoietin-producing hepatocellular) receptor tyrosine kinase family. In the present paper, we provide data showing that ephrin-B3 binds a sulfated cell-surface protein on HEK-293T (human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40) and HeLa cells, a binding that is nearly completely blocked by treatment of these cell lines with chlorate or heparinase, or by addition of the heavily sulfated glycosaminoglycan heparin. This indicates that heparan sulfate on these cells is essential for cell-surface binding of ephrin-B3. Heparin did not affect ephrin-B3 binding to EphB receptors expressed on transfected HEK-293T cells, indicating further that ephrin-B3 binds an alternative receptor which is a heparan sulfate proteoglycan. Site-directed mutagenesis analysis revealed that Arg178 and Lys179 are important for heparin binding of ephrin-B3 and also for ephrin-B3 binding to cells. These amino acids, when introduced in the non-heparin-binding ephrin-B1, conferred the heparin-binding property. Functional studies reveal that ephrin-B3 binding to cells induces cellular signalling and influences cell rounding and cell spreading. In conclusion, our data provide evidence for an unknown ephrin-B3-binding cell-surface proteoglycan involved in cellular signalling.
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Gong, Jingyi, Thomas N. Gaitanos, Olivia Luu, Yunyun Huang, Louise Gaitanos, Jana Lindner, Rudolf Winklbauer, and Rüdiger Klein. "Gulp1 controls Eph/ephrin trogocytosis and is important for cell rearrangements during development." Journal of Cell Biology 218, no. 10 (August 13, 2019): 3455–71. http://dx.doi.org/10.1083/jcb.201901032.
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Trogocytosis, in which cells nibble away parts of neighboring cells, is an intercellular cannibalism process conserved from protozoa to mammals. Its underlying molecular mechanisms are not well understood and are likely distinct from phagocytosis, a process that clears entire cells. Bi-directional contact repulsion induced by Eph/ephrin signaling involves transfer of membrane patches and full-length Eph/ephrin protein complexes between opposing cells, resembling trogocytosis. Here, we show that the phagocytic adaptor protein Gulp1 regulates EphB/ephrinB trogocytosis to achieve efficient cell rearrangements of cultured cells and during embryonic development. Gulp1 mediates trogocytosis bi-directionally by dynamic engagement with EphB/ephrinB protein clusters in cooperation with the Rac-specific guanine nucleotide exchange factor Tiam2. Ultimately, Gulp1’s presence at the Eph/ephrin cluster is a prerequisite for recruiting the endocytic GTPase dynamin. These results suggest that EphB/ephrinB trogocytosis, unlike other trogocytosis events, uses a phagocytosis-like mechanism to achieve efficient membrane scission and engulfment.
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Bossing, Torsten, and Andrea H. Brand. "Dephrin, a transmembrane ephrin with a unique structure, prevents interneuronal axons from exiting the Drosophila embryonic CNS." Development 129, no. 18 (September 15, 2002): 4205–18. http://dx.doi.org/10.1242/dev.129.18.4205.
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Ephrin/Eph signalling is crucial for axonal pathfinding in vertebrates and invertebrates. We identified the Drosophila ephrin orthologue, Dephrin, and describe for the first time the role of ephrin/Eph signalling in the embryonic central nervous system (CNS). Dephrin is a transmembrane ephrin with a unique N terminus and an ephrinB-like cytoplasmic tail. Dephrin binds and interacts with DEph, the Drosophila Eph-like receptor, and Dephrin and DEph are confined to different neuronal compartments. Loss of Dephrin or DEph causes the abberant exit of interneuronal axons from the CNS, whereas ectopic expression of Dephrin halts axonal growth. We propose that the longitudinal tracts in the Drosophila CNS are moulded by a repulsive outer border of Dephrin expression.
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Vu, Michael P., and Catherine Cheng. "Mapping the Universe of Eph Receptor and Ephrin Ligand Transcripts in Epithelial and Fiber Cells of the Eye Lens." Cells 11, no. 20 (October 19, 2022): 3291. http://dx.doi.org/10.3390/cells11203291.
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The eye lens is a transparent, ellipsoid organ in the anterior chamber of the eye that is required for fine focusing of light onto the retina to transmit a clear image. Cataracts, defined as any opacity in the lens, remains the leading cause of blindness in the world. Recent studies in humans and mice indicate that Eph–ephrin bidirectional signaling is important for maintaining lens transparency. Specifically, mutations and polymorphisms in the EphA2 receptor and the ephrin-A5 ligand have been linked to congenital and age-related cataracts. It is unclear what other variants of Ephs and ephrins are expressed in the lens or whether there is preferential expression in epithelial vs. fiber cells. We performed a detailed analysis of Eph receptor and ephrin ligand mRNA transcripts in whole mouse lenses, epithelial cell fractions, and fiber cell fractions using a new RNA isolation method. We compared control samples with EphA2 knockout (KO) and ephrin-A5 KO samples. Our results revealed the presence of transcripts for 12 out of 14 Eph receptors and 8 out of 8 ephrin ligands in various fractions of lens cells. Using specific primer sets, RT-PCR, and sequencing, we verified the variant of each gene that is expressed, and we found two epithelial-cell-specific genes. Surprisingly, we also identified one Eph receptor variant that is expressed in KO lens fibers but is absent from control lens fibers. We also identified one low expression ephrin variant that is only expressed in ephrin-A5 control samples. These results indicate that the lens expresses almost all Ephs and ephrins, and there may be many receptor–ligand pairs that play a role in lens homeostasis.
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Arcas, Aida, David G. Wilkinson, and M. Ángela Nieto. "The Evolutionary History of Ephs and Ephrins: Toward Multicellular Organisms." Molecular Biology and Evolution 37, no. 2 (October 7, 2019): 379–94. http://dx.doi.org/10.1093/molbev/msz222.
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Abstract Eph receptor (Eph) and ephrin signaling regulate fundamental developmental processes through both forward and reverse signaling triggered upon cell–cell contact. In vertebrates, they are both classified into classes A and B, and some representatives have been identified in many metazoan groups, where their expression and functions have been well studied. We have extended previous phylogenetic analyses and examined the presence of Eph and ephrins in the tree of life to determine their origin and evolution. We have found that 1) premetazoan choanoflagellates may already have rudimental Eph/ephrin signaling as they have an Eph-/ephrin-like pair and homologs of downstream-signaling genes; 2) both forward- and reverse-downstream signaling might already occur in Porifera since sponges have most genes involved in these types of signaling; 3) the nonvertebrate metazoan Eph is a type-B receptor that can bind ephrins regardless of their membrane-anchoring structure, glycosylphosphatidylinositol, or transmembrane; 4) Eph/ephrin cross-class binding is specific to Gnathostomata; and 5) kinase-dead Eph receptors can be traced back to Gnathostomata. We conclude that Eph/ephrin signaling is of older origin than previously believed. We also examined the presence of protein domains associated with functional characteristics and the appearance and conservation of downstream-signaling pathways to understand the original and derived functions of Ephs and ephrins. We find that the evolutionary history of these gene families points to an ancestral function in cell–cell interactions that could contribute to the emergence of multicellularity and, in particular, to the required segregation of cell populations.
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Imondi, Ralph, and Zaven Kaprielian. "Commissural axon pathfinding on the contralateral side of the floor plate: a role for B-class ephrins in specifying the dorsoventral position of longitudinally projecting commissural axons." Development 128, no. 23 (December 1, 2001): 4859–71. http://dx.doi.org/10.1242/dev.128.23.4859.
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In both invertebrate and lower vertebrate species, decussated commissural axons travel away from the midline and assume positions within distinct longitudinal tracts. We demonstrate that in the developing chick and mouse spinal cord, most dorsally situated commissural neuron populations extend axons across the ventral midline and through the ventral white matter along an arcuate trajectory on the contralateral side of the floor plate. Within the dorsal (chick) and intermediate (mouse) marginal zone, commissural axons turn at a conserved boundary of transmembrane ephrin expression, adjacent to which they form a discrete ascending fiber tract. In vitro perturbation of endogenous EphB-ephrinB interactions results in the failure of commissural axons to turn at the appropriate dorsoventral position on the contralateral side of the spinal cord; consequently, axons inappropriately invade more dorsal regions of B-class ephrin expression in the dorsal spinal cord. Taken together, these observations suggest that B-class ephrins act locally during a late phase of commissural axon pathfinding to specify the dorsoventral position at which decussated commissural axons turn into the longitudinal axis.
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Giorgio, Carmine, Marika Allodi, Simone Palese, Andrea Grandi, Massimiliano Tognolini, Riccardo Castelli, Alessio Lodola, et al. "UniPR1331: Small Eph/Ephrin Antagonist Beneficial in Intestinal Inflammation by Interfering with Type-B Signaling." Pharmaceuticals 14, no. 6 (May 24, 2021): 502. http://dx.doi.org/10.3390/ph14060502.
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Eph receptors, comprising A and B classes, interact with cell-bound ephrins generating bidirectional signaling. Although mainly related to carcinogenesis and organogenesis, the role of Eph/ephrin system in inflammation is growingly acknowledged. Recently, we showed that EphA/ephrin-A proteins can modulate the acute inflammatory responses induced by mesenteric ischemia/reperfusion, while beneficial effects were granted by EphB4, acting as EphB/ephrin-B antagonist, in a murine model of Crohn’s disease (CD). Accordingly, we now aim to evaluate the effects of UniPR1331, a pan-Eph/ephrin antagonist, in TNBS-induced colitis and to ascertain whether UniPR1331 effects can be attributed to A- or B-type signaling interference. The potential anti-inflammatory action of UniPR1331 was compared to those of the recombinant proteins EphA2, a purported EphA/ephrin-A antagonist, and of ephrin-A1-Fc and EphA2-Fc, supposedly activating forward and reverse EphA/ephrin-A signaling, in murine TNBS-induced colitis and in stimulated cultured mononuclear splenocytes. UniPR1331 antagonized the inflammatory responses both in vivo, mimicking EphB4 protection, and in vitro; EphA/ephrin-A proteins were inactive or only weakly effective. Our findings represent a further proof-of-concept that blockade of EphB/ephrin-B signaling is a promising pharmacological strategy for CD management and highlight UniPR1331 as a novel drug candidate, seemingly working through the modulation of immune responses.
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Miao, Hui, Christian H. Nickel, Lloyd G. Cantley, Leslie A. Bruggeman, Laura N. Bennardo, and Bingcheng Wang. "EphA kinase activation regulates HGF-induced epithelial branching morphogenesis." Journal of Cell Biology 162, no. 7 (September 29, 2003): 1281–92. http://dx.doi.org/10.1083/jcb.200304018.
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Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)–induced branching morphogenesis in collagen gel. Cotreatment with HGF and ephrin-A1 reduced sprouting of cell protrusions, an early step in branching morphogenesis. Moreover, addition of ephrin-A1 after HGF stimulation resulted in collapse and retraction of preexisting cell protrusions. In a newly developed assay that simulates the localized interactions between Ephs and ephrins in vivo, immobilized ephrin-A1 suppressed HGF-induced MDCK cell scattering. Ephrin-A1 inhibited basal ERK1/2 mitogen-activated protein kinase activity; however, the ephrin-A1 effect on cell protrusion was independent of the mitogen-activated protein kinase pathway. Ephrin-A1 suppressed HGF-induced activation of Rac1 and p21-activated kinase, whereas RhoA activation was retained, leading to the preservation of stress fibers. Moreover, dominant-negative RhoA or inhibitor of Rho-associated kinase (Y27632) substantially negated the inhibitory effects of ephrin-A1. These data suggest that interfering with c-Met signaling to Rho GTPases represents a major mechanism by which EphA kinase activation inhibits HGF-induced MDCK branching morphogenesis.
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Xu, Qiling, Georg Mellitzer, and David G. Wilkinson. "Roles of Eph receptors and ephrins in segmental patterning." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1399 (July 29, 2000): 993–1002. http://dx.doi.org/10.1098/rstb.2000.0635.
Full textAbstract:
Eph receptor tyrosine kinases and their membrane–bound ligands, ephrins, have key roles in patterning and morphogenesis. Interactions between these molecules are promiscuous, but largely fall into two groups: EphA receptors bind to glycosylphosphatidyl inositol–anchored ephrin–A ligands, and EphB receptors bind to transmembrane ephrin–B proteins. Ephrin–B proteins transduce signals, such that bidirectional signalling can occur upon interaction with the Eph receptor. In many tissues, there are complementary and overlapping expression domains of interacting Eph receptors and ephrins. An important role of Eph receptors and ephrins is to mediate cell contact–dependent repulsion, and this has been implicated in the pathfinding of axons and neural crest cells, and the restriction of cell intermingling between hindbrain segments. Studies in an in vitro system show that bidirectional activation is required to prevent intermingling between cell populations, whereas unidirectional activation can restrict cell communication via gap junctions. Recent work indicates that Eph receptors can also upregulate cell adhesion, but the biochemical basis of repulsion versus adhesion responses is unclear. Eph receptors and ephrins have thus emerged as key regulators that, in parallel with cell adhesion molecules, underlie the establishment and maintenance of patterns of cellular organization.
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Fujiwara, Hiroshi, Yoshihiro Nishioka, Hisanori Matsumoto, Koh Suginami, Akihito Horie, Hirohiko Tani, Noriomi Matsumura, et al. "Eph-Ephrin A System Regulates Human Choriocarcinoma–Derived JEG-3 Cell Invasion." International Journal of Gynecologic Cancer 23, no. 3 (March 2013): 576–82. http://dx.doi.org/10.1097/igc.0b013e3182849e36.
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ObjectivesThe Eph-ephrin system is a unique system that can induce multiple cellular responses such as cell migration, regulation of angiogenesis, and axonal guidance. Previously, the Eph-ephrin system was reported to regulate human extravillous trophoblast invasion. In this study, we examined the possible involvement of the Eph-ephrin system in the invasion of malignant gestational trophoblastic diseases using a human choriocarcinoma–derived cell line, JEG-3.MethodsThe mRNA expression of class A Ephs and ephrins on JEG-3 cells was examined by reverse transcription–polymerase chain reaction. The effects of recombinant human Eph A1 (r-Eph A1) and r-ephrin A4 on the proliferation and invasion of JEG-3 cells were investigated by cell proliferation and Matrigel invasion assays. The alterations of integrin expression on JEG-3 cells in the presence of r-Eph A1 and r-ephrin A4 were investigated by flow cytometry. The induction of phosphorylation of focal adhesion kinase in JEG-3 cells by r-ephrin A4 was examined by Western blot analysis.ResultsBy reverse transcription–polymerase chain reaction, mRNAs of Eph A1, A2, and A4 and ephrin A1, A4, and A5 were detected on JEG-3 cells. In Matrigel invasion assay, both r-Eph A1 and r-ephrin A4 promoted the invasion of JEG-3 cells without affecting cell proliferation. During 24-hour culture with r-Eph A1 and r-ephrin A4, the increase in integrin α 5 expression on JEG-3 cells was observed by flow cytometry. Western blotting analysis showed that r-ephrin A4 induced dephosphorylation of focal adhesion kinase in JEG-3 cells.ConclusionsThese findings suggest that Eph-ephrin interaction plays some role in the regulation of choriocarcinoma invasion in cooperation with integrins.
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Arvanitis, Dina N., Thomas Jungas, Annie Behar, and Alice Davy. "Ephrin-B1 Reverse Signaling Controls a Posttranscriptional Feedback Mechanism via miR-124." Molecular and Cellular Biology 30, no. 10 (March 22, 2010): 2508–17. http://dx.doi.org/10.1128/mcb.01620-09.
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ABSTRACT Eph receptors and ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known about the mechanisms regulating their expression. Here we report that the expression of ephrin-B1 is controlled by a feedback loop involving posttranscriptional regulatory mechanisms. We observed that the EfnB1 3′ untranslated region (3′-UTR) confers instability to mRNA transcripts, and we identified miR-124 as a posttranscriptional repressor of EfnB1 expression. Furthermore, we showed that miR-124 is itself regulated by ephrin-B1 reverse signaling, thus revealing the existence of a mutually repressive interaction between ephrin-B1 and this microRNA (miRNA). Lastly, we demonstrated the relevance of this mutual inhibition for neuronal differentiation. Our results suggest that miRNAs could be important effectors of Eph/ephrin signaling to refine domains of expression and to regulate function.
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Noren, Nicole K., Nai-Ying Yang, Morgan Silldorff, Ravi Mutyala, and Elena B. Pasquale. "Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor." Biochemical Journal 422, no. 3 (August 27, 2009): 433–42. http://dx.doi.org/10.1042/bj20090014.
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Receptor tyrosine kinases of the Eph family become tyrosine phosphorylated and initiate signalling events upon binding of their ligands, the ephrins. Eph receptors such as EphA2 and EphB4 are highly expressed but poorly tyrosine phosphorylated in many types of cancer cells, suggesting a limited interaction with ephrin ligands. Nevertheless, decreasing the expression of these receptors affects the malignant properties of cancer cells, suggesting that Eph receptors may influence cancer cells independently of ephrin stimulation. Ligand-independent activities of Eph receptors in cancer, however, have not been demonstrated. By using siRNA (small interfering RNA) to downregulate EphB4 in MCF7 and MDA-MB-435 cancer cells, we found that EphB4 inhibits integrin-mediated cell substrate adhesion, spreading and migration, and reduces β1-integrin protein levels. Low expression of the EphB4 preferred ligand, ephrin-B2, and minimal contact between cells in these assays suggest that cell contact-dependent stimulation of EphB4 by the transmembrane ephrin-B2 ligand does not play a role in these effects. Indeed, inhibitors of ephrin-B2 binding to endogenous EphB4 did not influence cell substrate adhesion. Increasing EphB4 expression by transient transfection inhibited cell substrate adhesion, and this effect was also independent of ephrin stimulation because it was not affected by single amino acid mutations in EphB4 that impair ephrin binding. The overexpressed EphB4 was tyrosine phosphorylated, and we found that EphB4 kinase activity is important for inhibition of integrin-mediated adhesion, although several EphB4 tyrosine phosphorylation sites are dispensable. These findings demonstrate that EphB4 can affect cancer cell behaviour in an ephrin-independent manner.
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Ivanov, Andrei I., Alexandre A. Steiner, Adrienne C. Scheck, and Andrej A. Romanovsky. "Expression of Eph receptors and their ligands, ephrins, during lipopolysaccharide fever in rats." Physiological Genomics 21, no. 2 (April 14, 2005): 152–60. http://dx.doi.org/10.1152/physiolgenomics.00043.2004.
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Erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinases and their ligands, ephrins, are involved in embryogenesis and oncogenesis by mediating cell adhesion and migration. Although ephrins can be induced by bacterial LPS in vitro, whether they are involved in inflammation in vivo is unknown. Using differential mRNA display, we found that a febrigenic dose of LPS (50 μg/kg iv) induces a strong transcriptional upregulation of ephrin-A1 in rat liver. We confirmed this finding by real-time RT-PCR. We then quantified the mRNA expression of different ephrins and Eph receptors at phases 1–3 of LPS fever in different organs. Febrile phases 2 (90 min post-LPS) and 3 (300 min) were characterized by robust upregulation (up to 16-fold) and downregulation (up to 21-fold) of several ephrins and Eph receptors. With the exception of EphA2, which showed upregulation in the brain at phase 2, expressional changes of Eph receptors and ephrins were limited to the LPS-processing organs: liver and lung. Characteristic, counter-directed changes in expressional regulation of Eph receptors and their corresponding ligands were found: upregulation of EphA2, downregulation of ephrin-A1 in the liver and lung at phase 2; downregulation of EphB3, upregulation of ephrin-B2 in the liver at phase 2; downregulation of EphA1 and EphA3, upregulation of ephrins-A1 and -A3 in liver at phase 3. In the liver, transcriptional changes of EphA2 and EphB3 at phase 2 were confirmed at protein level. These coordinated, phase-specific responses suggest that different sets of ephrins and Eph receptors may be involved in cellular events (such as disruption of tissue barriers and leukocyte transmigration) underlying different stages of systemic inflammatory response to LPS.
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Batista, Chary Marquez, Leonardo Luis Torres Bianqui, Bruno Bonganha Zanon, Mauricio Menezes Aben Athar Ivo, Gabriela Pintar de Oliveira, Jessica Ruivo Maximino, and Gerson Chadi. "Behavioral Improvement and Regulation of Molecules Related to Neuroplasticity in Ischemic Rat Spinal Cord Treated with PEDF." Neural Plasticity 2014 (2014): 1–16. http://dx.doi.org/10.1155/2014/451639.
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Pigment epithelium derived factor (PEDF) exerts trophic actions to motoneurons and modulates nonneuronal restorative events, but its effects on neuroplasticity responses after spinal cord (SC) injury are unknown. Rats received a low thoracic SC photothrombotic ischemia and local injection of PEDF and were evaluated behaviorally six weeks later. PEDF actions were detailed in SC ventral horn (motor) in the levels of the lumbar central pattern generator (CPG), far from the injury site. Molecules related to neuroplasticity (MAP-2), those that are able to modulate such event, for instance, neurotrophic factors (NT-3, GDNF, BDNF, and FGF-2), chondroitin sulfate proteoglycans (CSPG), and those associated with angiogenesis and antiapoptosis (laminin and Bcl-2) and Eph (receptor)/ephrin system were evaluated at cellular or molecular levels. PEDF injection improved motor behavioral performance and increased MAP-2 levels and dendritic processes in the region of lumbar CPG. Treatment also elevated GDNF and decreased NT-3, laminin, and CSPG. Injury elevated EphA4 and ephrin-B1 levels, and PEDF treatment increased ephrin A2 and ephrins B1, B2, and B3. Eph receptors and ephrins were found in specific populations of neurons and astrocytes. PEDF treatment to SC injury triggered neuroplasticity in lumbar CPG and regulation of neurotrophic factors, extracellular matrix molecules, and ephrins.
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Wahl, Siegfried, Holger Barth, Thomas Ciossek, Klaus Aktories, and Bernhard K. Mueller. "Ephrin-A5 Induces Collapse of Growth Cones by Activating Rho and Rho Kinase." Journal of Cell Biology 149, no. 2 (April 17, 2000): 263–70. http://dx.doi.org/10.1083/jcb.149.2.263.
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The ephrins, ligands of Eph receptor tyrosine kinases, have been shown to act as repulsive guidance molecules and to induce collapse of neuronal growth cones. For the first time, we show that the ephrin-A5 collapse is mediated by activation of the small GTPase Rho and its downstream effector Rho kinase. In ephrin-A5–treated retinal ganglion cell cultures, Rho was activated and Rac was downregulated. Pretreatment of ganglion cell axons with C3-transferase, a specific inhibitor of the Rho GTPase, or with Y-27632, a specific inhibitor of the Rho kinase, strongly reduced the collapse rate of retinal growth cones. These results suggest that activation of Rho and its downstream effector Rho kinase are important elements of the ephrin-A5 signal transduction pathway.
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Holder, N., and R. Klein. "Eph receptors and ephrins: effectors of morphogenesis." Development 126, no. 10 (May 15, 1999): 2033–44. http://dx.doi.org/10.1242/dev.126.10.2033.
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Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.
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Prévost, Nicolas, Donna S. Woulfe, Massimiliano Tognolini, Takako Tanaka, Wenying Jian, Ryan R. Fortna, Hong Jiang, and Lawrence F. Brass. "Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1." Blood 103, no. 4 (February 15, 2004): 1348–55. http://dx.doi.org/10.1182/blood-2003-06-1781.
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Abstract We have previously shown that platelets express 2 receptor tyrosine kinases, EphA4 and EphB1, and the Eph kinase ligand, ephrinB1, and proposed that transcellular Eph/ephrin interactions made possible by the onset of platelet aggregation promote the further growth and stability of the hemostatic plug. The present study examines how this might occur. The results show that clustering of either ephrinB1 or EphA4 causes platelets to adhere to immobilized fibrinogen via αIIbβ3. Adhesion occurs more slowly than with adenosine diphosphate (ADP) and requires phosphatidylinositol 3 (PI3)–kinase and protein kinase C activity but not ephrinB1 phosphorylation. By itself, Eph and ephrin signaling is insufficient to cause aggregation or the binding of soluble fibrinogen, but it can potentiate aggregation initiated by a Ca++ ionophore or by agonists for thrombin and thromboxane receptors. It also enhances Rap1 activation without requiring ADP secretion, ephrinB1 phosphorylation, or the activation of PI3-kinase and Src. From this we conclude that (1) Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca++; (2) this is accomplished in part by activating Rap1; and (3) these effects require oligomerization of ephrinB1 but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domain.
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Pergaris, Alexandros, Eugene Danas, Dimitrios Goutas, Alexandros G. Sykaras, Angelos Soranidis, and Stamatios Theocharis. "The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread." International Journal of Molecular Sciences 22, no. 16 (August 5, 2021): 8412. http://dx.doi.org/10.3390/ijms22168412.
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Erythropoietin-producing human hepatocellular receptors (EPHs) compose the largest known subfamily of receptor tyrosine kinases (RTKs). They bind and interact with the EPH family receptor interacting proteins (ephrins). EPHs/ephrins are implicated in a variety of physiological processes, as well as in cancer pathogenesis. With neoplastic disease remaining a leading cause of death world-wide, the development of novel biomarkers aiding in the field of diagnosis, prognosis, and disease monitoring is of utmost importance. A multitude of studies have proven the association between the expression of members of the EPH/ephrin system and various clinicopathological parameters, including disease stage, tumor histologic grade, and patients’ overall survival. Besides their utilization in timely disease detection and assessment of outcome, EPHs/ephrins could also represent possible novel therapeutic targets. The aim of the current review of the literature was to present the existing data regarding the association between EPH/ephrin system expression and the clinical characteristics of malignant tumors.
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de Saint-Vis, Blandine, Caroline Bouchet, Grégory Gautier, Jenny Valladeau, Christophe Caux, and Pierre Garrone. "Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin." Blood 102, no. 13 (December 15, 2003): 4431–40. http://dx.doi.org/10.1182/blood-2003-02-0500.
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AbstractEph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34+ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. EphB3 was specifically expressed by Langerhans cells, and EphA2 and EphA7 were expressed by both Langerhans- and interstitial-type DCs. EphA and EphB protein expression on DCs generated in vitro was confirmed by staining with ephrin-A3-Fc and ephrin-B3-Fc fusion proteins that bind to different Eph members, in particular EphA2 and EphB3. Immunostaining with anti-EphA2 antibodies demonstrated the expression of EphA2 by immature DCs and by skin Langerhans cells isolated ex vivo. Interestingly, ephrin expression was detected in epidermal keratinocytes and also in DCs. Adhesion of CD34+-derived DCs to fibronectin, but not to poly-l-lysine, was increased in the presence of ephrin-A3-Fc, a ligand of EphA2, through a β1 integrin activation pathway. As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking. (Blood. 2003;102:4431-4440)
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Vreeken, Dianne, Huayu Zhang, Anton Jan van Zonneveld, and Janine M. van Gils. "Ephs and Ephrins in Adult Endothelial Biology." International Journal of Molecular Sciences 21, no. 16 (August 6, 2020): 5623. http://dx.doi.org/10.3390/ijms21165623.
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Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.
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Olatunde, Adesola C., Patrice N. Mimche, Spencer O. Seely, Taryn P. Stewart, and Tracey J. Lamb. "Ephrin B receptor tyrosine kinase ligands modulate the germinal center reaction and control humoral immune responses to malaria." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.29. http://dx.doi.org/10.4049/jimmunol.202.supp.190.29.
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Abstract Malaria remains a global health priority causing half a million deaths annually. Protective antibody responses that can control the Plasmodium parasites that cause malaria are an essential component of naturally acquired immunity and develop after years of continuous exposure to Plasmodium parasites. The protective humoral response is short-lived and tends to wane in the absence of parasite re-infections. The cellular and molecular mechanisms that prevent the development of long-lived humoral immunity against malaria remain poorly understood. Recently, ephrin B1, a ligand for the Eph B receptor tyrosine kinase subfamily, was shown to be involved in T follicular helper (Tfh) cell recruitment, retention and contact-dependent interaction with germinal center (GC) B cells, key processes in the production of efficacious antibody responses. We hypothesize that EphB/EphrinB signaling pathway is required for the development of Plasmodium humoral responses. Using a non-lethal P. yoelii XNL infection model, we observed an upregulation in the expression of Ephrin B on both GC B cell and Tfh cells at the peak of the infection in wild type mice. Selective deficiency of Ephrin B1/B2 on B cells (CD19cre+ Ephrin B1/B2fl/fl mice) led to lethality in some mice infected with an otherwise non-lethal P. yoelii XNL infection. On the other hand mice that lack the expression of Ephrin B1/B2 on T cells (CD4cre+ Eprhin B1/B2fl/fl mice) were able to control P. yoelii XNL infection. Our data show a requirement for Ephrin B1/B2 signaling on B cells for an effective contact-dependent interaction with Tfh cells and for optimal antibody responses during Plasmodium infection.
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Kawano, Hiroki, Yoshio Katayama, Kentaro Minagawa, Manabu Shimoyama, Mark Henkemeyer, and Toshimitsu Matsui. "A Novel Feedback Mechanism by Ephrin-B1/B2 In T Cell Activation: Concentration-Dependent Switch From Costimulation to Inhibition." Blood 116, no. 21 (November 19, 2010): 277. http://dx.doi.org/10.1182/blood.v116.21.277.277.
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Abstract Abstract 277 Eph is the largest known family of receptor tyrosine kinases, and bind to a cell surface-associated ligand, ephrin on neighboring cells upon direct cell-cell contact. The ensuing bidirectional signals have been recognized as a major form of contact-dependent cell communications, such as cell attraction and repulsion to control accurate spatial and temporal patterning in the development of the central nervous system. EphBs, EphB6 in particular, are expressed in T cells and its specific ligand, ephrin-B2 has been shown to act as a costimulatory molecule for the T cell receptor (TCR)-mediated cell proliferation. Recently, another remarkable feature of ephrins, a concentration-dependent transition from promotion to inhibition in axon growth has emerged in ephrin-As. Thus, we postulated that this type of ligand concentration dependent functional transition would be suitable for the delicate tuning of immune responses to avoid reckless drive. To figure this out, we carefully evaluated the costimulatory effects of ephrin-Bs by using murine primary T cells. Interestingly, low doses of solid phase ephrin-B1 as well as ephrin-B2 (at up to 5μ g/ml) costimulated, to the comparable level with anti-CD28, T cell proliferation induced by suboptimal concentration of immobilized anti-CD3 antibody, but high concentrations of ephrin-B1/B2 inhibited the TCR-mediated proliferation significantly (by approximately 70% reduction from the baseline at 20μ g/ml). The similar concentration-dependent transition from coactivation to inhibition was also observed under the optimal CD3 stimulation. The concentration-dependent biphasic effects, positively at low concentration and negatively at high concentration, by ephrin-B1/B2 in T cell activation were confirmed in the cytokine production such as TNF-α, IL-2, and IFN-γ. In contrast, ephrin-B3 showed steadily increasing stimulatory effect even in higher concentrations in proliferation and cytokine production. We speculated that these unique modulations were partly mediated by EphB6 because EphB6 transfected in HEK293T cells has been shown to exert biphasic effects in cell adhesion and migration in response to different concentrations of ephrin-B2. T cell derived from Ephb6 -/- mice showed decreased CD3-stimulated cell proliferation as reported previously. However, the unique comodulatory pattern by each ephrin-B was virtually preserved in Ephb6 -/- T cells. Since the functions of Eph family could be redundant, we further investigated by generating multiple EphB knockout mice lacking four genes, Ephb1, Ephb2, Ephb3 and Ephb6. Surprisingly, no further alteration was observed in T cells from the quadruple knockout mice compared to the Ephb6 single deficiency. We also confirmed that EphA4, an exception in EphA receptor family which binds ephrin-Bs, was not expressed in T cells by RT-PCR. Taken together with the fact that EphB5 does not exist in mammals, the unique comodification by ephrin-Bs might be regulated by EphB4. Next, we examined the cross-talk of EphB forward signaling with TCR pathway. The inhibitor of p38MAPK and p44/42MAPK significantly reduced the TCR-mediated proliferation, but did conserve the concentration-dependent effects of ephrin-B1/B2, suggesting the interference with EphB signaling in TCR signal transduction at the upstream of MAPKs which are important for cell growth and survival. Immuno-blot analyses revealed that high concentrations of ephrin-B1/B2, but not ephrin-B3, clearly inhibited the anti-CD3 induced phosphorylation of Lck and its downstream signaling molecules such as ZAP70, c-Raf, MEK1/2, Erk, and Akt, although the phosphorylation of CD3ζ was not inhibited by high concentrations of any ephrin-Bs. These data suggest that Eph signaling upon stimulation by high concentrations of ephrin-B1/B2 may engage in negative feedback to TCR signals via Lck. The present studies demonstrate that TCR-mediated primary T cell activation may be highly governed by EphB/ephrin-B axis with a complexity determined by the combination as well as the concentration of different ephrin-Bs expressed in immunological microenvironments. EphB-involved in negative feedback of T cell activation could be a novel therapeutic target to inhibit the most proximal TCR signaling molecule, Lck. The generation of strong signaling molecule which mimics ephrin-B1/B2 would be an effective strategy to control T cell mediated immune disorders. Disclosures: No relevant conflicts of interest to declare.
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Mohd-Zin, Siti Waheeda, Amelia Cheng Wei Tan, Wahib M. Atroosh, Meow-Keong Thong, Abu Bakar Azizi, Nicholas D. E. Greene, and Noraishah Mydin Abdul-Aziz. "Eph and Ephrin Variants in Malaysian Neural Tube Defect Families." Genes 13, no. 6 (May 26, 2022): 952. http://dx.doi.org/10.3390/genes13060952.
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Neural tube defects (NTDs) are common birth defects with a complex genetic etiology. Mouse genetic models have indicated a number of candidate genes, of which functional mutations in some have been found in human NTDs, usually in a heterozygous state. This study focuses on Ephs-ephrins as candidate genes of interest owing to growing evidence of the role of this gene family during neural tube closure in mouse models. Eph-ephrin genes were analyzed in 31 Malaysian individuals comprising seven individuals with sporadic spina bifida, 13 parents, one twin-sibling and 10 unrelated controls. Whole exome sequencing analysis and bioinformatic analysis were performed to identify variants in 22 known Eph-ephrin genes. We reported that three out of seven spina bifida probands and three out of thirteen family members carried a variant in either EPHA2 (rs147977279), EPHB6 (rs780569137) or EFNB1 (rs772228172). Analysis of public databases shows that these variants are rare. In exome datasets of the probands and parents of the probands with Eph-ephrin variants, the genotypes of spina bifida-related genes were compared to investigate the probability of the gene–gene interaction in relation to environmental risk factors. We report the presence of Eph-ephrin gene variants that are prevalent in a small cohort of spina bifida patients in Malaysian families.
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Hadjimichael, Argyris C., Alexandros Pergaris, Angelos Kaspiris, Athanasios F. Foukas, Stefania Kokkali, Gerasimos Tsourouflis, and Stamatios Theocharis. "The EPH/Ephrin System in Bone and Soft Tissue Sarcomas’ Pathogenesis and Therapy: New Advancements and a Literature Review." International Journal of Molecular Sciences 23, no. 9 (May 5, 2022): 5171. http://dx.doi.org/10.3390/ijms23095171.
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Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell–cell and cell–substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas.
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Xu, Yan, Dorothea Robev, Nayanendu Saha, Bingcheng Wang, Matthew B. Dalva, Kai Xu, Juha P. Himanen, and Dimitar B. Nikolov. "The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism." International Journal of Molecular Sciences 22, no. 19 (September 28, 2021): 10473. http://dx.doi.org/10.3390/ijms221910473.
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The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph–Eph interfaces. One Eph–Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor–receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.
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Beauchamp, Amanda, and Waldemar Debinski. "Ephs and ephrins in cancer: Ephrin-A1 signalling." Seminars in Cell & Developmental Biology 23, no. 1 (February 2012): 109–15. http://dx.doi.org/10.1016/j.semcdb.2011.10.019.
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Zhou, Xuan, Liu Xiaoli, Na Xu, Lin Li, Qisi Lu, Jinfang Zhang, Bintao Huang, and Qingfeng Du. "EphrinB2/EphB4 Interaction Promotes Myeloid Leukemia Cell Invasion through RhoA-Mediated Mechanism." Blood 124, no. 21 (December 6, 2014): 1018. http://dx.doi.org/10.1182/blood.v124.21.1018.1018.
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Abstract Background and Objective: Several studies have reported the up-regulation of EphB receptor-tyrosine kinases and ephrinB ligands in a variety of tumors, suggesting a functional relation between EphB/ephrinB signaling and tumor progression. However, how they regulate the invasiveness of myeloid leukemia cells were still unknown. Our previously study suggested that EphB4 were highly expressed in patients with extramedullary leukemia compared with patients without extramedullary leukemia, which indicated that the expression of EphB4 was related with myeloid leukemia cell invasion. To address the molecular mechanism, we aimed to characterize the role of EphB4 and ephrinB2 ligands in the interaction of myeloid leukemia cells. Methods: To clarify the question, myeloid leukemia cell lines (K562 cells and THP-1 cells) treated with clustered ephrinA1–Fc proteins, ephrinB2–Fc proteins and Fc proteins were cultured in vitro, then migration and invasion were determined by transwell assay according to different time. Pulldown western immunoblot analysis were used to detect the level of GTP-RhoA and total RhoA; the phosphorylation of EphB4 and MMP9 expression were also determined by immunoblot analysis before and after the treatment of different clustered Fc proteins. Results: The results showed that after ephrinB2–Fc stimulation, the numbers of K562 cells migrating through transwell chamber were significantly enhanced compared to Fc proteins stimulation (1.85-fold, P=0.033), meanwhile, the numbers of K562 cells invading the matrigel also enhanced (1.46 -fold, P=0.025). However, the numbers of K562 cells migrating through transwell chamber after ephrinA1–Fc stimulation didn’t significantly increase compared to Fc proteins stimulation (P=0.411), and the numbers of K562 cells invading the matrigel also didn’t enhanced (P=0.072) after ephrinA1–Fc stimulation. Moreover, after ephrinB2–Fc stimulation, the numbers of THP-1 cells migrating through transwell chamber were significantly enhanced compared to Fc proteins stimulation (2.25-fold, P<0.01), meanwhile, the numbers of THP-1 cells invading the matrigel also enhanced (1.66 -fold, P<0.01). However, the numbers of THP-1 cells migrating through transwell chamber and the numbers of THP-1 cells invading the matrigel didn’t significantly enhanced (P>0.05, P>0.05) after ephrinA1–Fc stimulation. Furthermore, EphB4 immunoprecipitation followed by immunoblotting with anti-phosphotyrosine antibody revealed that EphB4 is phosphorylated on tyrosine in K562 cells after ephrinB2–Fc stimulation. Additionally, the level of active RhoA (GTP-RhoA) and MMP9 in K562 cells were both significantly increased in response to EphB4 receptor activation with its ligand ephrin-B2-Fc ( P<0.05). Conclusions: These findings suggested that EphB4/EprinB2 signaling played an important role in myeloid leukemia cells progression by promoting their migratory ability, activating RhoA activity and increasing MMP9 expression. Our findings reveal a novel regulation of this intriguing receptor/ligand family that contributes to the cell invasiveness of myeloid leukemia cells. Disclosures No relevant conflicts of interest to declare.