Journal articles: 'EphrinA5'

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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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Pensold, Daniel, Julia Gehrmann, Georg Pitschelatow, Asa Walberg, Kai Braunsteffer, Julia Reichard, Amin Ravaei, et al. "The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling." International Journal of Molecular Sciences 22, no. 3 (January 29, 2021): 1332. http://dx.doi.org/10.3390/ijms22031332.

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The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

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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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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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Liu, Hui, Kavi Devraj, Kerstin Möller, Stefan Liebner, Markus Hecker, and Thomas Korff. "EphrinB-mediated reverse signalling controls junctional integrity and pro-inflammatory differentiation of endothelial cells." Thrombosis and Haemostasis 112, no. 07 (2014): 151–63. http://dx.doi.org/10.1160/th13-12-1034.

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SummaryThe EphB/ephrinB receptor-ligand system is pivotal for the development of the embryonic vasculature and for angiogenesis in the adult organism. We observed that (i) the expression of ephrinB2 and ephrinB1 is up-regulated in capillaries during inflammation, that (ii) these ligands are localised on the luminal endothelial surface, and that (iii) they interact with the ephrinB-receptor EphB2 on monocyte/macrophages. This study delineates the impact of ephrinB-mediated reverse signalling on the integrity and proinflammatory differentiation of the endothelium. To this end, in vitro analyses with human cultured endothelial cells reveal that knockdown of ephrinB2 or ephrinB1 impairs monocyte transmigration through the endothelium. While ephrinB2 but not ephrinB1 interacts with PECAM-1 (CD31) in this context, reverse signalling by ephrinB1 but not ephrinB2 elicits a c-Jun N-terminal kinase (JNK)-dependent up-regulation of E-selectin expression. Furthermore, treatment of endothelial cells with soluble EphB2 receptor bodies or EphB2-overexpressing mouse myeloma cells links ephrinB2 to PECAM-1 and induces its Src-dependent phosphorylation while diminishing Src homology phosphotyrosyl phosphatase-2 (SHP-2) activity and increasing endothelial cell permeability. We conclude that extravasation of EphB2 positive leukocyte populations is facilitated by lowering the integrity of endothelial cell junctions and enhancing the pro-inflammatory phenotype of the endothelium through activation of ephrinB ligands.

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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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Ghosh Moulick, Ranjita, Gregor Panaitov, Liping Du, Dirk Mayer, and Andreas Offenhäusser. "Neuronal adhesion and growth on nanopatterned EA5-POPC synthetic membranes." Nanoscale 10, no. 11 (2018): 5295–301. http://dx.doi.org/10.1039/c7nr08520f.

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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.

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Wang, Ting, Jing Chen, Chuan-Xi Tang, Xiao-Yan Zhou, and Dian-Shuai Gao. "Inverse Expression Levels of EphrinA3 and EphrinA5 Contribute to Dopaminergic Differentiation of Human SH-SY5Y Cells." Journal of Molecular Neuroscience 59, no. 4 (May 23, 2016): 483–92. http://dx.doi.org/10.1007/s12031-016-0759-y.

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Sullivan, Chelsea S., Vishwa Mohan, Paul B. Manis, Sheryl S. Moy, Young Truong, Bryce W. Duncan, and Patricia F. Maness. "Developmental Regulation of Basket Interneuron Synapses and Behavior through NCAM in Mouse Prefrontal Cortex." Cerebral Cortex 30, no. 8 (April 6, 2020): 4689–707. http://dx.doi.org/10.1093/cercor/bhaa074.

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Abstract Parvalbumin (PV)-expressing basket interneurons in the prefrontal cortex (PFC) regulate pyramidal cell firing, synchrony, and network oscillations. Yet, it is unclear how their perisomatic inputs to pyramidal neurons are integrated into neural circuitry and adjusted postnatally. Neural cell adhesion molecule NCAM is expressed in a variety of cells in the PFC and cooperates with EphrinA/EphAs to regulate inhibitory synapse density. Here, analysis of a novel parvalbumin (PV)-Cre: NCAM F/F mouse mutant revealed that NCAM functions presynaptically in PV+ basket interneurons to regulate postnatal elimination of perisomatic synapses. Mutant mice exhibited an increased density of PV+ perisomatic puncta in PFC layer 2/3, while live imaging in mutant brain slices revealed fewer puncta that were dynamically eliminated. Furthermore, EphrinA5-induced growth cone collapse in PV+ interneurons in culture depended on NCAM expression. Electrophysiological recording from layer 2/3 pyramidal cells in mutant PFC slices showed a slower rise time of inhibitory synaptic currents. PV-Cre: NCAM F/F mice exhibited impairments in working memory and social behavior that may be impacted by altered PFC circuitry. These findings suggest that the density of perisomatic synapses of PV+ basket interneurons is regulated postnatally by NCAM, likely through EphrinA-dependent elimination, which is important for appropriate PFC network function and behavior.

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Carvalho, Ricardo F., Martin Beutler, Katharine J. M. Marler, Bernd Knöll, Elena Becker-Barroso, R. Heintzmann, Tony Ng, and Uwe Drescher. "Silencing of EphA3 through a cis interaction with ephrinA5." Nature Neuroscience 9, no. 3 (February 19, 2006): 322–30. http://dx.doi.org/10.1038/nn1655.

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Lee, Haeryung, Eunjeong Park, Yujin Kim, and Soochul Park. "EphrinA5-EphA7 complex induces apoptotic cell death via TNFR1." Molecules and Cells 35, no. 5 (May 2013): 450–55. http://dx.doi.org/10.1007/s10059-013-0072-3.

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Oliver Millner, Thomas, Barbara Ricci, Xinyu Zhang, Nicola Pomella, and Silvia Marino. "Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma." Neuro-Oncology 21, Supplement_4 (October 2019): iv1—iv2. http://dx.doi.org/10.1093/neuonc/noz167.004.

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Abstract Introduction The epigenetic regulator Bmi1 is essential for the self-renewal of neural stem cells (NSC), and highly expressed in glioblastoma (GBM) stem/initiating cells (GIC), where knockdown significantly reduces tumour growth in xenograft models. We have used a combined genome-wide and target gene-driven approach to identify EphrinA5 (EfnA5) as a mediator of Bmi1 function in mouse and human GIC. Methods and results We compared mGIC, from a PTEN/p53 deletion mouse model, to matched NSC. Combined ChIPSeq and RNASeq showed a differential redistribution of the repressive PRC mark H3K27me3 in mGIC, and that transcriptional regulation is Bmi1-dependent in a proportion of H3K27me3 marked genes. Subsequently, using shRNA knockdown, we show that Bmi1 regulates cell morphology, proliferation and migration/invasion via repression of EfnA5 in mGIC, and that the same mechanism is essential for GBM development in an allograft model. To confirm the translational potential of the BMI1/EFNA5 pathway we examined published RNA microarray, RNAseq and single-cell RNAseq datasets and found a significant inverse relationship between BMI1 and EFNA5. Finally, we show that BMI1 also regulates cell proliferation via repression of EFNA5 in primary human GIC in vitro. Conclusions We present evidence from a mouse model, human expression datasets and human primary cells showing that the Bmi1-EfnA5 pathway plays a prominent regulatory role in GIC. As the anti-proliferative role of BMI1 silencing is mediated by de-repression of EFNA5 in hGIC, precision targeting of Ephrin signalling, for example with agents that mimic EFNA5 action, could be an effective therapeutic tool in human GBM overexpressing BMI1.

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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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Weinl, Christine, Nadine Becker, and Juergen Loeschinger. "Responses of temporal retinal growth cones to ephrinA5-coated beads." Journal of Neurobiology 62, no. 2 (2004): 219–30. http://dx.doi.org/10.1002/neu.20101.

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Ricci, Barbara, Thomas O. Millner, Nicola Pomella, Xinyu Zhang, Loredana Guglielmi, Sara Badodi, Dario Ceric, et al. "Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma." Oncogene 39, no. 12 (January 27, 2020): 2523–38. http://dx.doi.org/10.1038/s41388-020-1161-3.

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BONG, Yong-Sik, Yeon-Hwa PARK, Hyun-Shik LEE, Kathleen MOOD, Akihiko ISHIMURA, and Ira O. DAAR. "Tyr-298 in ephrinB1 is critical for an interaction with the Grb4 adaptor protein." Biochemical Journal 377, no. 2 (January 15, 2004): 499–507. http://dx.doi.org/10.1042/bj20031449.

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The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, are thought to play a role in the regulation of cell adhesion and migration during development by mediating cell-to-cell signalling events. The transmembrane ephrinB protein is a bidirectional signalling molecule that sends a forward signal through the activation of its cognate receptor tyrosine kinase residing on another cell. The reverse signal is transduced into the ephrinB-expressing cell via tyrosine phosphorylation of its conserved C-terminal cytoplasmic domain. Previous work from our laboratory has implicated the activated FGFR1 (fibroblast growth factor receptor 1) as a regulator of a de-adhesion signal that results from overexpression of ephrinB1. In the present study, we report the isolation of Xenopus Grb4 (growth-factor-receptor-bound protein 4), an ephrinB1-interacting protein, and we show that when expressed in Xenopus oocytes, ephrinB1 interacts with Grb4 in the presence of an activated FGFR1. Amino acid substitutions were generated in Grb4, and the resulting mutants were expressed along with ephrinB1 and an activated FGFR in Xenopus oocytes. Co-immunoprecipitation analysis shows that the FLVR motif within the Src homology 2 domain of Xenopus Grb4 is vital for this phosphorylation-dependent interaction with ephrinB1. More importantly, using deletion and substitution analysis we identify the tyrosine residue at position 298 of ephrinB1 as being required for the physical interaction with Grb4, whereas Tyr-305 and Tyr-310 are dispensable. Moreover, we show that the region between amino acids 301 and 304 of ephrinB1 is also required for this critical tyrosine-phosphorylation-dependent event.

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Shin, Jongdae, Changkyu Gu, Eunjeong Park, and Soochul Park. "Identification of Phosphotyrosine Binding Domain-Containing Proteins as Novel Downstream Targets of the EphA8 Signaling Function." Molecular and Cellular Biology 27, no. 23 (September 17, 2007): 8113–26. http://dx.doi.org/10.1128/mcb.00794-07.

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ABSTRACT Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-1b and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA-1b and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required for this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells. Taken together, our findings support a possible function for Anks family proteins as scaffolding proteins of the EphA8 signaling pathway.

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Kitamura, Takuya, Yukihito Kabuyama, Akihisa Kamataki, Miwako K. Homma, Hideo Kobayashi, Shigeo Aota, Shin-ichi Kikuchi, and Yoshimi Homma. "Enhancement of lymphocyte migration and cytokine production by ephrinB1 system in rheumatoid arthritis." American Journal of Physiology-Cell Physiology 294, no. 1 (January 2008): C189—C196. http://dx.doi.org/10.1152/ajpcell.00314.2007.

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Although the etiology of early events in rheumatoid arthritis (RA) remains undefined, an anomaly in T cell homeostasis and hyperproliferation of synovial-lining cells are involved in the disease process. Since it has been reported that the ephrin/Eph receptor system plays important signaling roles in inflammation processes, we attempted to examine ephrinB molecules in T cells and synovial cells derived from RA in this study. The expression level of ephrinB1 was significantly high in synovial fibroblasts and CD3-positive exudate lymphocytes in synovial tissues derived from patients with RA compared with those in osteoarthritis (OA). Protein and mRNA levels of ephrinB1 were also higher in peripheral blood lymphocytes (PBLs) prepared from patients with RA than those from normal controls. Similar results were obtained from an animal model of human RA, collagen antibody-induced arthritis mice. Moreover, a recombinant ephrinB1/Fc fusion protein stimulated normal PBLs to exhibit enhanced migration and production of TNF-α. EphrinB1/Fc also activated synovial cells established from patients with RA to produce IL-6. Tyrosine phosphorylation of EphB1 was induced in these cells by ephrinB1/Fc. The CpG islands in the 5′ upstream regulatory region of the ephrinB1 gene were hypomethylated in RA patients compared with those of normal donors. These results suggest that ephrinB1 and EphB1 receptors play an important role in the inflammatory states of RA, especially by affecting the population and function of T cells. Inhibition of the ephrinB/EphB system might be a novel target for the treatment of RA.

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Wang, Tong-Hong, Kwai-Fong Ng, Ta-Sen Yeh, Yu-Ling Wang, Kung-Hao Liang, Chau-Ting Yeh, and Tse-Ching Chen. "Peritumoral Small EphrinA5 Isoform Level Predicts the Postoperative Survival in Hepatocellular Carcinoma." PLoS ONE 7, no. 7 (July 30, 2012): e41749. http://dx.doi.org/10.1371/journal.pone.0041749.

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Lee, Jangwoo, Amy Corcoran, Manjong Han, David M. Gardiner, and Ken Muneoka. "Dlx5 and Msx2 regulate mouse anterior neural tube closure through ephrinA5-EphA7." Development, Growth & Differentiation 55, no. 3 (February 21, 2013): 341–49. http://dx.doi.org/10.1111/dgd.12044.

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Liu, Yixin, Heidi Kaljunen, Ana Pavić, Tuulia Saarenpää, Juha P. Himanen, Dimitar B. Nikolov, and Adrian Goldman. "Binding of EphrinA5 to RET receptor tyrosine kinase: An in vitro study." PLOS ONE 13, no. 6 (June 11, 2018): e0198291. http://dx.doi.org/10.1371/journal.pone.0198291.

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Negrete, Oscar A., David Chu, Hector C. Aguilar, and Benhur Lee. "Single Amino Acid Changes in the Nipah and Hendra Virus Attachment Glycoproteins Distinguish EphrinB2 from EphrinB3 Usage." Journal of Virology 81, no. 19 (July 25, 2007): 10804–14. http://dx.doi.org/10.1128/jvi.00999-07.

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ABSTRACT The henipaviruses, Nipah virus (NiV) and Hendra virus (HeV), are lethal emerging paramyxoviruses. EphrinB2 and ephrinB3 have been identified as receptors for henipavirus entry. NiV and HeV share similar cellular tropisms and likely use an identical receptor set, although a quantitative comparison of receptor usage by NiV and HeV has not been reported. Here we show that (i) soluble NiV attachment protein G (sNiV-G) bound to cell surface-expressed ephrinB3 with a 30-fold higher affinity than that of sHeV-G, (ii) NiV envelope pseudotyped reporter virus (NiVpp) entered ephrinB3-expressing cells much more efficiently than did HeV pseudotyped particles (HeVpp), and (iii) NiVpp but not HeVpp entry was inhibited efficiently by soluble ephrinB3. These data underscore the finding that NiV uses ephrinB3 more efficiently than does HeV. Henipavirus G chimeric protein analysis implicated residue 507 in the G ectodomain in efficient ephrinB3 usage. Curiously, alternative versions of published HeV-G sequences show variations at residue 507 that can clearly affect ephrinB3 but not ephrinB2 usage. We further defined surrounding mutations (W504A and E505A) that diminished ephrinB3-dependent binding and viral entry without compromising ephrinB2 receptor usage and another mutation (E533Q) that abrogated both ephrinB2 and -B3 usage. Our results suggest that ephrinB2 and -B3 binding determinants on henipavirus G are distinct and dissociable. Global expression analysis showed that ephrinB3, but not ephrinB2, is expressed in the brain stem. Thus, ephrinB3-mediated viral entry and pathology may underlie the severe brain stem neuronal dysfunction seen in fatal Nipah viral encephalitis. Characterizing the determinants of ephrinB2 versus -B3 usage will further our understanding of henipavirus pathogenesis.

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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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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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Wang, Tong-Hong, Junn-Liang Chang, Jar-Yi Ho, Hsiao-Chun Wu, and Tse-Ching Chen. "EphrinA5 suppresses colon cancer development by negatively regulating epidermal growth factor receptor stability." FEBS Journal 279, no. 2 (November 30, 2011): 251–63. http://dx.doi.org/10.1111/j.1742-4658.2011.08419.x.

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Wong, Eric V., Julie A. Kerner, and Daniel G. Jay. "Convergent and divergent signaling mechanisms of growth cone collapse by ephrinA5 and slit2." Journal of Neurobiology 59, no. 1 (March 1, 2004): 66–81. http://dx.doi.org/10.1002/neu.10342.

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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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Zhou, Xuan, Liu Xiaoli, Na Xu, Yajuan Xiao, Jinfang Zhang, Bintao Huang, and Qingfeng Du. "Activation Of EphrinB2/EphB4 Influences Myeloid Leukemia Cell Migration and Invasion." Blood 122, no. 21 (November 15, 2013): 1360. http://dx.doi.org/10.1182/blood.v122.21.1360.1360.

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Abstract Eph receptors and ephrin ligands are cell-surface molecules capable of bidirectional signaling that control cell-cell interactions, migration and invasion. However, their role and regulation in myeloid leukemia cells remain to be defined. To address the hypothesis that Ephrin/EphB is an important regulator of myeloid leukemia cell migration and invasion, we first screened the mRNA levels of 23 eph and ligand ephrin RTK family members in myeloid leukemia cells (K562, HL-60, THP-1) and mononuclear cells from healthy donors, then found that EphB4, EphA5, EfnA1 highly expressed in most myeloid leukemia cells compared to healthy donors(P<0.05). Both the mRNA and protein levels of EphB4 and EphA5 were detected in 13 primary myeloid leukemia cells (5 from patients with extramedullary leukemia among 13 cases) and 10 mononuclear cells from healthy donors by real-time RT-PCR and Immunoblot analysis. The results showed that both the mRNA and protein levels of EphB4 and EphA5 were higher in 13 primary myeloid leukemia cells relative to the 10 healthy donors (P=0.046). Moreover, the EphB4 were highly expressed in 5 patients with extramedullary leukemia compared with 8 patients without extramedullary leukemia. These findings indicated that EphB4 and EphA5 expression were correlated with the development of myeloid leukemia cells, moreover, EphB4 may be closely related with myeloid leukemia cell migration or invasion. To further clarified the question, migration were determined in leukemia cell lines (K562 cells) which were treated with clustered ephrinA1–Fc proteins, ephrinB2–Fc proteins and Fc proteins by transwell migration assay. Invasion were also determined by matrigel invasion assay. 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 (1.8 to 2.5-fold, P<0.05), meanwhile, the numbers of K562 cells invading the matrigel also enhanced (1.2 to 1.8-fold, P<0.05). However, after ephrinA1–Fc stimulation, the numbers of K562 cells migrating through transwell chamber didn’t signiﬁcantly increase compared to Fc proteins stimulation (P>0.05), and the numbers of K562 cells invading the matrigel also didn’t enhanced (P>0.05). These findings indicated that ephrinB2–Fc could activate EphB4, leading to the change of myeloid leukemia cell migration and invasion. Further study may help to assess a promising potential of this protein to be used as a prognostic marker or as a target for a molecular therapy. Disclosures: No relevant conflicts of interest to declare.

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Peuckert, Christiane, Evelin Wacker, Jürgen Rapus, Pat Levitt, and Jürgen Bolz. "Adaptive changes in gene expression patterns in the somatosensory cortex after deletion of ephrinA5." Molecular and Cellular Neuroscience 39, no. 1 (September 2008): 21–31. http://dx.doi.org/10.1016/j.mcn.2008.05.011.

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Slape, Christopher I. "EphA3 Is Expressed on Leukemia Stem Cells, and Eph/Ephrin Signalling Features in the Remodelling of the Leukemia Stem Cell Niche." Blood 124, no. 21 (December 6, 2014): 4783. http://dx.doi.org/10.1182/blood.v124.21.4783.4783.

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Abstract EphA3 is a member of the Eph receptor tyrosine kinase family, the largest such family in the human genome. The bi-directional signalling of Eph receptors and their ligands (the ephrins) is responsible for correct migration and positioning of cells during development, as well as adult processes such as angiogenesis and neurogenesis. EphA3 was first discovered as a receptor expressed on the surface of LK63, a B-cell leukemia cell line. It is not expressed on normal human hematopoietic cells, but expression has been noted on the cell surface of leukemic blasts from a high percentage of patients with hematopoietic neoplasia of all lineages. It is particularly commonly expressed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), where it is present in approximately 50% of patients. A therapeutic antibody against EphA3 has been developed and is in Phase II clinical trials for MDS and AML. Consistent with data from human MDS patients, the NUP98-HOXD13 (NHD13) mouse model of MDS spontaneously expresses EphA3 on a percentage of cells from all populations throughout the hematopoietic compartment. The proportion of positive cells varies from mouse to mouse, but the proportion positively correlates with disease severity, indicating a possible causative relationship. Studies crossing the NHD13 transgene onto an EphA3 knockout background are ongoing and will definitively answer this question. Recent studies have demonstrated the alteration (or “remodelling”) of the hematopoietic stem cell (HSC) micro-environment (or “niche”) by malignant hematopoietic cells, and the role that this plays in maintaining the leukemia stem cell (LSC) population. This self-reinforcing niche remodelling is critical to the maintenance of hematopoietic disease, particularly during a course of chemotherapy. These niche changes have also been shown to be sufficient to drive malignancy, and are therefore an attractive target for the design of disruptive therapeutics. EphA3 and other Eph/ephrin family members are expressed on normal mesenchymal stem/stromal cells (MSCs) and other stromal component cells of the HSC niche. EfnA5 (EphrinA5) is the high-affinity ligand for EphA3, and we observed an increased expression of EfnA5 on stromal cells in the NHD13 mice, indicating that the EphA3-EfnA5 interaction in these mice may facilitate LSC maintenance in the LSC niche. More broadly, it appears that Eph/Ephrin signalling may be a component of the remodelling of the niche to favour LSCs over normal HSCs. Possible indirect means by which this remodelling may occur include production of the cytokines CCL3 (decreased in NHD13 mice) or CXCL12 (variably decreased in NHD13 mice, and its receptor CXCR4 is increased on the cell surface of NHD13 HSCs). Imaging studies confirm preferential homing of EphA3-positive LSCs to niche locations, including co-localisation with CXCL12. It is therefore likely that the remodelled stem cell niche maintains stemness and leukemogenicity of the LSCs via interaction of the Eph/ephrin family members abnormally expressed on the LSCs and stromal cells, respectively. Disclosures No relevant conflicts of interest to declare.

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Teng, Teng, Afsaneh Gaillard, Aude Muzerelle, and Patricia Gaspar. "EphrinA5 Signaling Is Required for the Distinctive Targeting of Raphe Serotonin Neurons in the Forebrain." eneuro 4, no. 1 (January 2017): ENEURO.0327–16.2017. http://dx.doi.org/10.1523/eneuro.0327-16.2017.

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Deschamps, C., M. Faideau, M. Jaber, A. Gaillard, and L. Prestoz. "Expression of ephrinA5 during development and potential involvement in the guidance of the mesostriatal pathway." Experimental Neurology 219, no. 2 (October 2009): 466–80. http://dx.doi.org/10.1016/j.expneurol.2009.06.020.

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Li, J.-J., D.-P. Liu, G.-T. Liu, and D. Xie. "EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor." Oncogene 28, no. 15 (March 9, 2009): 1759–68. http://dx.doi.org/10.1038/onc.2009.15.

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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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Szepietowska, B., T. L. Horvath, and R. S. Sherwin. "Role of Synaptic Plasticity and EphA5-EphrinA5 Interaction Within the Ventromedial Hypothalamus in Response to Recurrent Hypoglycemia." Diabetes 63, no. 3 (November 12, 2013): 1140–47. http://dx.doi.org/10.2337/db13-1259.

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Noh, Hyuna, Eunjeong Park, and Soochul Park. "In Vivo Expression of EphrinA5-Fc in Mice Results in Cephalic Neural Crest Agenesis and Craniofacial Abnormalities." Molecules and Cells 37, no. 1 (January 27, 2014): 59–65. http://dx.doi.org/10.14348/molcells.2014.2279.

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Worku, Tesfaye, Kai Wang, Duncan Ayers, Di Wu, Zia Ur Rehman, Hao Zhou, and Liguo Yang. "Regulatory roles of ephrinA5 and its novel signaling pathway in mouse primary granulosa cell apoptosis and proliferation." Cell Cycle 17, no. 7 (April 3, 2018): 892–902. http://dx.doi.org/10.1080/15384101.2018.1456297.

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Wang, Tong-Hong, Chau-Ting Yeh, Jar-Yi Ho, Kwai-Fong Ng, and Tse-Ching Chen. "OncomiR miR-96 and miR-182 promote cell proliferation and invasion through targeting ephrinA5 in hepatocellular carcinoma." Molecular Carcinogenesis 55, no. 4 (February 8, 2015): 366–75. http://dx.doi.org/10.1002/mc.22286.

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Gu, Jin-Mo, David J. Wang, Jennifer M. Peterson, Jonathan Shintaku, Sandya Liyanarachchi, Vincenzo Coppola, Ashley E. Frakes, Brian K. Kaspar, Dawn D. Cornelison, and Denis C. Guttridge. "An NF-κB - EphrinA5-Dependent Communication between NG2+ Interstitial Cells and Myoblasts Promotes Muscle Growth in Neonates." Developmental Cell 36, no. 2 (January 2016): 215–24. http://dx.doi.org/10.1016/j.devcel.2015.12.018.

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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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Gervais, Manon, Gwenaël Labouèbe, Alexandre Picard, Bernard Thorens, and Sophie Croizier. "EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis." PLOS Biology 18, no. 11 (November 30, 2020): e3000680. http://dx.doi.org/10.1371/journal.pbio.3000680.

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Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

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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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Szepietowska, B., W. Zhu, J. Czyzyk, T. Eid, and R. S. Sherwin. "EphA5-EphrinA5 Interactions Within the Ventromedial Hypothalamus Influence Counterregulatory Hormone Release and Local Glutamine/Glutamate Balance During Hypoglycemia." Diabetes 62, no. 4 (December 28, 2012): 1282–88. http://dx.doi.org/10.2337/db12-0982.

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Kimura, K., T. Hikida, S. Yawata, T. Yamaguchi, and S. Nakanishi. "Pathway-specific engagement of ephrinA5-EphA4/EphA5 system of the substantia nigra pars reticulata in cocaine-induced responses." Proceedings of the National Academy of Sciences 108, no. 24 (May 31, 2011): 9981–86. http://dx.doi.org/10.1073/pnas.1107592108.

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Mohd-Zin, Siti W., Nor-Linda Abdullah, Aminah Abdullah, Nicholas D. E. Greene, Pike-See Cheah, King-Hwa Ling, Hadri Yusof, et al. "Identification of the genomic mutation in Epha4rb-2J/rb-2J mice." Genome 59, no. 7 (July 2016): 439–48. http://dx.doi.org/10.1139/gen-2015-0142.

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The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4rb-2J/rb-2J, is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or “hopping gait” phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4rb-2J corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4rb-2J allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein–protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.

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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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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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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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Yoo, Sooyeon, Jongdae Shin, and Soochul Park. "EphA8-ephrinA5 signaling and clathrin-mediated endocytosis is regulated by Tiam-1, a Rac-specific guanine nucleotide exchange factor." Molecules and Cells 29, no. 6 (May 22, 2010): 603–9. http://dx.doi.org/10.1007/s10059-010-0075-2.

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Journal articles on the topic 'EphrinA5'

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