Academic literature on the topic 'Eph-receptor A4'

Ephrin-A4 is a ligand for the erythropoietin-producing hepatocellular (Eph) receptor family of tyrosine kinases. We have identified a secreted form of ephrin-A4, denoted ephrin-A4 (s), which is encoded by an alternatively spliced mRNA and is produced by in vivo activated B cells in tonsils. Blood B cells secrete ephrin-A4 (s) upon stimulation via the B-cell antigen receptor. A subpopulation of tonsil cells in the crypts with a dendritic cell phenotype was shown to express EphA2, an Eph receptor tyrosine kinase that was found to be capable of binding an ephrin-A4 immunoglobulin chimeric protein. We conclude that ephrin-A4 (s) may play a role in the interaction between activated B lymphocytes and dendritic cells in human tonsils. (Blood. 2000;95:221-230)

Abstract Ephrin-A4 is a ligand for the erythropoietin-producing hepatocellular (Eph) receptor family of tyrosine kinases. We have identified a secreted form of ephrin-A4, denoted ephrin-A4 (s), which is encoded by an alternatively spliced mRNA and is produced by in vivo activated B cells in tonsils. Blood B cells secrete ephrin-A4 (s) upon stimulation via the B-cell antigen receptor. A subpopulation of tonsil cells in the crypts with a dendritic cell phenotype was shown to express EphA2, an Eph receptor tyrosine kinase that was found to be capable of binding an ephrin-A4 immunoglobulin chimeric protein. We conclude that ephrin-A4 (s) may play a role in the interaction between activated B lymphocytes and dendritic cells in human tonsils. (Blood. 2000;95:221-230)

Abstract Abstract 4819 The Eph receptors are found in a wide range of cancers and correlate with metastasis. However, their precise role in cancer has only started to be addressed. In this study, we investigated the role of Eph-A4 receptor in metastasis and invasive activity of myeloid leukemia cells. We fisr tested the expression of Eph-A4 in eight primary myeloid leukemias imclulding four with extramedullary metastasis and four without it, and leukemia cell line K562 by Real-time PCR and western blotting, then found that Eph- A4 was wildly expressed in myeloid Leukemia cells, especially in myeloid leukemia cells with high invasive activity. To further clarified the question, the stable over-expressing Eph-A4 cell line (K562-EphA4) based the wild K562 cell and pGC lentivirus vector were established to declare the metastasis and invasive activity in myeloid leukemia cells in vitro by trans-well migration assay. The results indicated that the mRNA level and protein expression of Eph-A4 were significantly increased in myeloid leukemias with extramedullary metastasis and K562 cells compared to those without it (P<0.05).After we successfully established the stable over-expressing Eph-A4 cell line, we verified its mRNA level and protein expression were both significantly increased ((P<0.05).Furthermore, RhoA and Rac1/cdc42, which are important adhesion molecules and related to metastasis and invasive activity were both highly expressed in K562-EphA4 cells compared to wild K562 cells (P<0.05). Moreover, the trans-well migration assay showed that cells that migrated to lower chambers and matrigel hydrogel were both increased in K562-EphA4 cells compared to wild K562 cells (5.22±2.11*104/ml vs 13.56±2.70*104 /ml P<0.000;18.07±3.15/cm2 vs 28.53±2.50/cm2P<0.000 respectively). Our findings suggest that Eph- A4 is likely to play an important role in the regulation the of myeloid Leukemia through the control of RhoA and Rac1/cdc42 associated signaling, migration and invasive activity, and therefore may represent a novel target for cancer treatment. Disclosures: No relevant conflicts of interest to declare.

Expression of the ephrin-A4 ligand, a family member of ligands binding the Eph receptor tyrosine kinases, is induced after an antigen–receptor stimulation of lymphocytes. To understand the transcription regulation of the ephrin-A4 gene, its promoter was identified and regulating elements were characterized. The ephrin-A4 promoter contains cis elements directing the cell-specific expression. By deletion studies, three specific regions, which were contributing to the transcription activity in lymphoid cells, were localized. In one of these regions, an inverted CCAAT box was identified and shown to bind the transcription activator nuclear factor-Y (NF-Y). The importance of NF-Y binding for the ephrin-A4 promoter activity is shown by a total abrogation of promoter activity after destruction of its binding site. NF-Y binding and activity are also crucially dependent on the integrity of the surrounding sequence. In addition, electrophoretic mobility-shift assay and serial-mutation analysis of the two remaining regulating regions revealed cis regulatory elements contributing to the transcription activity of the ephrin-A4 promoter.

Eph receptors and their ephrin ligands are involved in normal hematopoietic development and tumorigenesis. Using methylated CpG island amplification/DNA promoter microarray, we identified several EPH receptor and EPHRIN genes as potential hypermethylation targets in acute lymphoblastic leukemia (ALL). We subsequently studied the DNA methylation status of the Eph/ephrin family by bisulfite pyrosequencing. Hypermethylation of EPHA2, -A4, -A5, -A6, -A7, -A10, EPHB1, -B2, -B3, -B4, EFNA1, -A3, -A5, and EFNB1 and -B2 genes was detected in leukemia cell lines and primary ALL bone marrow samples. Expression analysis of EPHB4, EFNB2, and EFNA5 genes demonstrated that DNA methylation was associated with gene silencing. We cloned the promoter region of EPHB4 and demonstrated that promoter hypermethylation can result in EPHB4 transcriptional silencing. Restoration of EPHB4 expression by lentiviral transduction resulted in reduced proliferation and apoptotic cell death in Raji cells in which EPHB4 is methylated and silenced. Finally, we demonstrated that phosphorylated Akt is down-regulated in Raji cells transduced with EPHB4. These results suggest that epigenetic silencing by hypermethylation of EPH/EPHRIN family genes contributes to ALL pathogenesis and that EPHB4 can function as a tumor suppressor in ALL.

Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion–mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin-dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion–mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion–mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma.

Actually, there is a strong incidence of psychiatric diseases, representing a 13% of total burden diseases and 450 million of people affected. The etiology of psychiatric diseases remains unknown. However, scientific evidences suggest a maldevelopment of nervous system (NS). The diagnosis is inaccurate, and international manuals (ICD-10 and DSM-IV) identify pathologies according to a list of symptoms but no underlying biological cause of disease. The aim of the thesis is to identify potential biomarkers -related to the development of NS- in peripheral blood of psychiatric patients diagnosed as different mental diseases, such as autism spectrum disorders (ASD), schizophrenia and bipolar disorders. It is intended to contribute with the improvement of diagnostic, prognostic and treatment of subjects. The thesis is divided into 4 chapters: 1) study of neurotrophins in ASD, where the results show the relationship of this family of molecules with the disease, 2) study of Latrophilin-3 (LPHN3) in the TEA, which was obtained in association with lower cognitive level of ASD, 3) study of the Eph-receptor A4 in the pathology of schizophrenia and bipolar disorder, results of which show no association, and finally 4) study of Ankyrin-3 (ANK3) in schizophrenia and bipolar disorder, which shown a relationship with bipolar disorder but not with schizophrenia.
Actualment, hi ha una forta incidència de les patologies psiquiàtriques, representant un 13% del total de les malalties i 450 milions de persones afectades. L’etiologia de les patologies psiquiàtriques és desconeguda. Tot i així, evidències científiques suggereixen un mal desenvolupament del sistema nerviós (SN). El diagnòstic és poc precís, i els manuals internacionals (ICD-10 i DSM-IV) identifiquen les patologies d’acord a un llistat de símptomes, però sense cap causa biològica subjacent de la patologia. L’objectiu de la tesi és la identificació de biomarcadors potencials –relacionats en el desenvolupament del SN- en sang perifèrica de pacients diagnosticats amb diferents patologies mentals, com ara els trastorns de l’espectre autista (TEA), esquizofrènia i desordres bipolars. És pretén contribuir amb la millora del diagnòstic, el pronòstic i el tractament de les persones que les pateixen. La tesi s’estructura en 4 capítols: 1) estudi de les neurotrofines en els TEA, on els resultats evidencien la relació d’aquesta família de molècules amb la patologia, 2) estudi de la Latrofilina-3 (LPHN3) en els TEA, on s’ha obtingut associació amb el nivell cognitiu més baix dels TEA, 3) estudi del receptor EPH A4 en les patologies d’esquizofrènia i desordres bipolars, resultats del qual no mostren associació i, per últim 4) estudi de la Ankirina-3 (ANK3) en l’esquizofrènia i els desordres bipolars, en el qual si que es troba una relació amb els desordres bipolars, però no amb l’esquizofrènia.
Actualmente, hay una fuerte incidencia de las patologías psiquiátricas, representando un 13% del total de las enfermedades y 450 millones de personas afectadas. La etiología de las patologías psiquiátricas es desconocida. Aún así, evidencias científicas sugieren un mal desarrollo del sistema nervioso (NS). El diagnóstico es poco preciso, y los manuales internacionales (ICD-10 y DSM-IV) identifican las patologías de acuerdo a un listado de síntomas, pero sin ninguna causa biológica subyacente de la patología. El objetivo de la tesis es la identificación de biomarcadores potenciales –relacionados con el desarrollo del SN- en sangre periférica de pacientes diagnosticados con diferentes patologías mentales, como son los trastornos del espectro autista (TEA), esquizofrenia y desordenes bipolares. Se pretende contribuir en la mejora del diagnóstico, el pronóstico i el tratamiento de las personas que las padecen. La tesis se estructura en 4 capítulos: 1) estudio de las neurotrofinas en los trastornos del espectro autista (TEA), en el cual los resultados evidencian la relación de esta familia de moléculas con la patología, 2) estudio de la Latrofilina-3 (LPHN3) en los TEA, donde se ha obtenido una asociación con el nivel cognitivo más bajo de los TEA, 3) estudio del receptor EPH A4 en las patologías de la esquizofrenia y los desordenes bipolares, resultados del cual no muestran asociación y, por último 4) estudio de la Ankirina-3 (ANK3) en la esquizofrenia y los desordenes bipolares, en el cual si que se ha encontrado una relación con los desordenes bipolares, pero no con la esquizofrenia.