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At least 19 recordsLinked to original sources

PubMed1999

Comparative analysis of embryonic gene expression defines potential interaction sites for Xenopus EphB4 receptors with ephrin-B ligands.

The Eph family of receptor tyrosine kinases and their ligands, the ephrins, act as signaling molecules regulating the migratory behavior of neurons and neural crest cells, and are implicated in tissue patterning, blood vessel formation, and tumorigenesis. On the basis of structural similarities and overlapping binding specificities, Eph receptors as well as their ligands can be divided into A and B subfamilies with orthologues found in all vertebrates. We describe here the isolation of cDNAs encoding Xenopus EphB4 receptors and show that embryonic expression is prominently associated with the developing vasculature, newly forming somites, the visceral arches, and non-neuronal tissues of the embryonic head. In a screen to identify potential ligands for EphB4 in Xenopus embryos, we isolated cDNAs for the Xenopus ephrin-B2 and -B3, which demonstrates that the Xenopus genome harbors genes encoding orthologues to all three currently known mammalian ephrin-B genes. We next performed in situ hybridizations to identify tissues and organs where EphB4 receptors may encounter ephrin-B ligands during embryonic development. Our analysis revealed distinct, but overlapping patterns of ephrin-B gene expression. Interestingly, each ephrin-B ligand displayed expression domains either adjacent to or within EphB4-expressing tissues. These findings indicate that EphB4 receptors may interact in vivo with multiple B-class ephrins. The expression patterns also suggest that EphB4 receptors and their ligands may be involved in visceral arch formation, somitogenesis, and blood vessel development.

Alleles↗

PubMed2002

Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase.

We have previously documented the cell-type-specific and hormone-dependent expression of the EphB4 receptor in the mouse mammary gland. To investigate its role in the biology of the mammary gland, we have established transgenic mice bearing the EphB4 receptor under the control of the MMTV-LTR promoter, which represents the first transgenic mouse model to investigate the effect(s) of unscheduled expression of EphB4 in adult organisms. Transgene expression in the mammary epithelium was induced at puberty, increased during pregnancy, culminated at early lactation and persisted until day three of post-lactational involution. In contrast, expression of the endogenous EphB4 gene is downregulated during pregnancy, is essentially absent during lactation and is re-induced after day three of post-lactational involution. The unscheduled expression of EphB4 led to a delayed development of the mammary epithelium at puberty and during pregnancy. During pregnancy, less lobules were formed, these however exhibited more numerous but smaller alveolar units. Transgenic mammary glands were characterized by a fragile, irregular morphology at lactation; however, sufficient functionality was maintained to nourish the young. Transgenic mammary glands exhibited untimely epithelial apoptotic cell death during pregnancy and abnormal epithelial DNA synthesis at early post-lactational involution, indicating a disturbed response to proliferative/apoptotic signals. Mammary tumours were not observed in the EphB4 transgenic animals; however, in double transgenic animals expressing both EphB4 and the neuT genes, tumour appearance was significantly accelerated and, in contrast to neuT-only animals, metastases were observed in the lung. These results implicate EphB4 in the regulation of tissue architecture, cellular growth response and establishment of the invasive phenotype in the adult mammary gland.

Animals↗

PubMed2005

Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma.

BACKGROUND: The EphB4 receptor tyrosine kinase has been reported as increased in tumours originating from several different tissues and its expression in a prostate cancer xenograft model has been reported. METHODS: RT-PCR, western blotting and immunohistochemical techniques were used to examine EphB4 expression and protein levels in human prostate cancer cell lines LNCaP, DU145 and PC3. Immunohistochemistry was also used to examine localisation of EphB4 in tissue samples from 15 patients with prostate carcinomas. RESULTS: All three prostate cancer cell lines expressed the EphB4 gene and protein. EphB4 immunoreactivity in vivo was significantly greater in human prostate cancers as compared with matched normal prostate epithelium and there appeared to be a trend towards increased expression with higher grade disease. CONCLUSION: EphB4 is expressed in prostate cancer cell lines with increased expression in human prostate cancers when compared with matched normal tissue. EphB4 may therefore be a useful anti-prostate cancer target.

Antineoplastic Agents↗

PubMed2006

EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival.

We sought to evaluate the biological function of the receptor tyrosine kinase EphB4 in bladder cancer. All of the nine bladder cancer cell lines examined express EphB4 and the receptor could be phosphorylated following stimulation with its cognate ligand, EphrinB2. Out of the 15 fresh bladder cancer specimens examined, 14 expressed EphB4 with a mean sevenfold higher level of expression compared to adjacent normal urothelium. EphB4 expression was regulated by several mechanisms: EPHB4 gene locus was amplified in 27% tumor specimens and 33% cell lines studied; inhibition of EGFR signaling downregulated EphB4 levels; and forced expression of wild-type p53 reduced EphB4 expression. EphB4 knockdown using specific siRNA and antisense oligodeoxynucleotides molecules led to a profound inhibition in cell viability associated with apoptosis via activation of caspase-8 pathway and downregulation of antiapoptotic factor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibited tumor cell migration and invasion. EphB4 knockdown in an in vivo murine tumor xenograft model led to a nearly 80% reduction in tumor volume associated with reduced tumor proliferation, increased apoptosis and reduced tumor microvasculature. EphB4 is thus a potential candidate as a predictor of disease outcome in bladder cancer and as target for novel therapy.

Base Sequence↗

PubMed2006

The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway.

Recent evidence supports a role for EphB receptor tyrosine kinases as tumour suppressors in colorectal and prostate cancer. However, it is unclear how these receptors inhibit cancer cell tumorigenicity - an activity that is highly unusual for a family of receptor tyrosine kinases. Here, we report that the EphB4 receptor can behave as a tumour suppressor in a mouse xenograft model of breast cancer when stimulated by its ligand, ephrin-B2. In breast cancer cells, EphB4 activates an antioncogenic pathway involving Abl family tyrosine kinases and the Crk adaptor protein. This Abl-Crk pathway inhibits breast cancer cell viability and proliferation in addition to motility and invasion, and also downregulates the pro-invasive matrix metalloprotease, MMP-2. Consistent with these effects, EphB4 and the Abl-Crk pathway are constitutively active in non-transformed mammary epithelial cells. These findings identify a novel Eph receptor signalling pathway with tumour-suppressor activity and predict that therapeutic intervention to activate EphB4 signalling will inhibit tumour progression.

Animals↗

PubMed2003

EphB4 receptor tyrosine kinase transgenic mice develop glomerulopathies reminiscent of aglomerular vascular shunts.

We have established transgenic mice over-expressing the EphB4 receptor tyrosine kinase in the kidney. The EphB4 protein was localised to the developing tubular system of both control and transgenic newborn mice. In transgenic adults, transgene expression persisted in the proximal tubules and the Bowman's capsules, structures, which were not stained in control kidneys. The glomeruli of control animals consisted of regular, round vascular baskets with clearly discernable afferent and efferent arterioles. In contrast, approximately 40% of the transgenic glomeruli had an irregular shrivelled appearance and many exhibited fused, horse shoe-like afferent and efferent arterioles bypassing the glomerulus. These abnormal glomerular structures are very reminiscent of aglomerular vascular shunts, a human degenerative glomerulopathy of unknown aetiology.

Animals↗

PubMed2004

[Detecting protein expression of EphrinB2 ligand and its receptor EphB4 in astrocytoma using confocal laser scanning microscopy].

BACKGROUND & OBJECTIVE: EphrinB2 is a novel angiogenic factor. EphrinB2 and its receptor EphB4 express in several kinds of tumor cells,and correlate with tumorigenesis and neoangiogenesis. This study was designed to explore the characteristics of EphB4 and EphrinB2 protein expression in astrocytomas. METHODS: Double labelling immunofluorescence was used to detect co-expression of EphB4/EphrinB2 with glial fibrilary acid protein (GFAP)or CD34 protein in 35 fresh glioma specimens, and 2 kinds of human glioma cell lines (CHG-5,and SHG-44). RESULTS: EphB4/EphrinB2 and CD34 proteins co-expressed in some tumor stromal microvessels, and mainly localizing in endothelial cells. Co-expression of EphB4/EphrinB2 and GFAP proteins was also noticed in tumor cells,and 2 glioma cell lines. In poorly-differentiated SHG-44 cells, the average fluorescence intensity of EphB4 was 72.48+/-33.78,and that of EphrinB2 was 96.80+/-36.98, both higher than those in well-differentiated CHG-5 cells (56.7+/-21.7, and 53.6+/-18.8). But the green fluorescence intensity of GFAP in SHG-44 cells was 22.3+/-15.3, while in CHG-5 cells was 47.5+/-16.7. CONCLUSION: Expressions of EphB4 and EphrinB2 proteins may be related to differentiation degree of tumor cells.

Antigens, CD34↗

PubMed2004

Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation.

Homeobox genes (Hox) encode for transcription factors, which regulate cell proliferation and migration and play an important role in the development of the cardiovascular system during embryogenesis. In this study, we investigated the role of HoxA9 for endothelial cell migration and angiogenesis in vitro and identified a novel target gene, the EphB4 receptor. Inhibition of HoxA9 expression decreased endothelial cell tube formation and inhibited endothelial cell migration, suggesting that HoxA9 regulates angiogenesis. Because Eph receptor tyrosine kinases importantly contribute to angiogenesis, we examined whether HoxA9 may transcriptionally regulate the expression of EphB4. Downregulation of HoxA9 reduced the expression of EphB4. Chromatin-immunoprecipitation revealed that HoxA9 interacted with the EphB4 promoter, whereas a deletion construct of HoxA9 without DNA-binding motif (Delta(aa) 206-272) did not bind. Consistently, HoxA9 wild-type overexpression activated the EphB4 promoter as determined by reporter gene expression. HoxA9 binds to the EphB4 promoter and stimulates its expression resulting in an increase of endothelial cell migration and tube forming activity. Thus, modulation of EphB4 expression may contribute to the proangiogenic effect of HoxA9 in endothelial cells.

Cell Movement↗

PubMed2003

Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels.

Differentiation of pluripotent embryonic stem (ES) cells is associated with expression of fate-specifying gene products. Coordinated development, however, must involve modifying factors that enable differentiation and growth to adjust in response to local microenvironmental determinants. We report here that the ephrin receptor, EphB4, known to be spatially restricted in expression and critical for organized vessel formation, modifies the rate and magnitude of ES cells acquiring genotypic and phenotypic characteristics of mesodermal tissues. Hemangioblast, blood cell, cardiomyocyte, and vascular differentiation was impaired in EphB4-/- ES cells in conjunction with decreased expression of mesoderm-associated, but not neuroectoderm-associated, genes. Therefore, EphB4 modulates the response to mesoderm induction signals. These data add differentiation kinetics to the known effects of ephrin receptors on mammalian cell migration and adhesion. We propose that modifying sensitivity to differentiation cues is a further means for ephrin receptors to contribute to tissue patterning and organization.

Animals↗

PubMed2002

A role of EphB4 receptor and its ligand, ephrin-B2, in erythropoiesis.

Erythropoiesis is regulated not only by erythropoietin but also by microenvironments which are composed of transmembrane molecules. We have previously shown that a receptor tyrosine kinase EphB4 is predominantly expressed on human erythroid progenitors in bone marrow. EphB4 is expressed in approximately 45% of hematopoietic progenitor cells, which are CD34-positive and c-Kit-positive in human umbilical cord blood (hUCB). The transmembrane ligand for EphB4 or ephrin-B2 is expressed on bone marrow stromal cells and arterial endothelial cells. When such EphB4-positive hematopoietic progenitor cells were co-cultured with stromal cells which express ephrin-B2, they were immediately detached from stromal cells and differentiated to mature erythroid cells. At that time, expression of EphB4 immediately down-regulated. In contrast, on ephrin-B2 non-expressing stromal cells, they remained EphB4-positive cells and the generated number of mature erythroid cells was less than that on ephrin-B2 expressing stromal cells. Additionally, ephrin-B2 expression on endothelial cells up-regulated under hypoxic condition. Taken together, we propose that one of the molecular cues that regulate erythropoiesis is ephrin-B2 on stromal cells.

Cell Division↗

PubMed2006

EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling.

The complex molecular mechanisms that drive endothelial cell movement and the formation of new vessels are poorly understood and require further investigation. Eph receptor tyrosine kinases and their membrane-anchored ephrin ligands regulate cell movements mostly by cell-cell contact, whereas the G-protein-coupled receptor CXCR4 and its unique SDF-1 chemokine ligand regulate cell movement mostly through soluble gradients. By using biochemical and functional approaches, we investigated how ephrinB and SDF-1 orchestrate endothelial cell movement and morphogenesis into capillary-like structures. We describe how endogenous EphB2 and EphB4 signaling are required for the formation of extracellular matrix-dependent capillary-like structures in primary human endothelial cells. We further demonstrate that EphB2 and EphB4 activation enhance SDF-1-induced signaling and chemotaxis that are also required for extracellular matrix-dependent endothelial cell clustering. These results support a model in which SDF-1 gradients first promote endothelial cell clustering and then EphB2 and EphB4 critically contribute to subsequent cell movement and alignment into cord-like structures. This study reveals a requirement for endogenous Eph signaling in endothelial cell morphogenic processes, uncovers a novel link between EphB forward signaling and SDF-1-induced signaling, and demonstrates a mechanism for cooperative regulation of endothelial cell movement.

Cell Movement↗

PubMedDate not supplied

Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast.

Members of the Eph family of receptor tyrosine kinase have been implicated in cell-cell communication and tissue integrity during embryogenesis. We have previously demonstrated cell type specific and hormone dependent EphB4 expression in the mouse mammary parenchyma suggesting involvement in the homeostasis of this organ. Since disruption of tissue organization is crucial for metastatic dissemination, we have investigated the expression of EphB4 during carcinogenesis of the human breast. Immunohistochemical analysis of 24 normal human breast samples and 124 consecutive breast carcinomas was correlated with tumor characteristics (stage, histology, grade, lymph node involvement) and the expression of ER, PR, Ki-67, p53 and HER2. In normal breast tissue, the EphB4 protein was expressed exclusively in parenchymal cells. Strikingly, a drastic reduction in the number of EphB4 protein expressing cells was observed in almost all invasive carcinomas analyzed, irrespective of the tumor type (p<0.0001). Furthermore, we found a highly significant correlation between EphB4 positivity and low histological grading of the tumor cells (p=0.002) suggesting that in breast cancer, EphB4 expression is not compatible with tumor progression. This raises the possibility that EphB4 could represent a potent tool for therapeutic intervention.

Breast↗

PubMed1999

Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development.

Ephrin-B2 is a transmembrane ligand that is specifically expressed on arteries but not veins and that is essential for cardiovascular development. However, ephrin-B2 is also expressed in nonvascular tissues and interacts with multiple EphB class receptors expressed in both endothelial and nonendothelial cell types. Thus, the identity of the relevant receptor for ephrin-B2 and the site(s) where these molecules interact to control angiogenesis were not clear. Here we show that EphB4, a specific receptor for ephrin-B2, is exclusively expressed by vascular endothelial cells in embryos and is preferentially expressed on veins. A targeted mutation in EphB4 essentially phenocopies the mutation in ephrin-B2. These data indicate that ephrin-B2-EphB4 interactions are intrinsically required in vascular endothelial cells and are consistent with the idea that they mediate bidirectional signaling essential for angiogenesis.

Animals↗

PubMed2001

Gridlock signalling pathway fashions the first embryonic artery.

Arteries and veins are morphologically, functionally and molecularly very different, but how this distinction is established during vasculogenesis is unknown. Here we show, by lineage tracking in zebrafish embryos, that angioblast precursors for the trunk artery and vein are spatially mixed in the lateral posterior mesoderm. Progeny of each angioblast, however, are restricted to one of the vessels. This arterial-venous decision is guided by gridlock (grl), an artery-restricted gene that is expressed in the lateral posterior mesoderm. Graded reduction of grl expression, by mutation or morpholino antisense, progressively ablates regions of the artery, and expands contiguous regions of the vein, preceded by an increase in expression of the venous marker EphB4 receptor (ephb4) and diminution of expression of the arterial marker ephrin-B2 (efnb2). grl is downstream of notch, and interference with notch signalling, by blocking Su(H), similarly reduces the artery and increases the vein. Thus, a notch-grl pathway controls assembly of the first embryonic artery, apparently by adjudicating an arterial versus venous cell fate decision.

Animals↗

PubMed2006

The EphB4 receptor-tyrosine kinase promotes the migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization.

Several studies have reported the up-regulation of EphB receptor-tyrosine kinases and ephrin-B ligands in a variety of tumors, suggesting a functional relation between EphB/ephrin-B signaling and tumor progression. The ability of the EphB receptors to regulate cell migration and promote angiogenesis likely contributes to tumor progression and metastasis. Here we show that EphB receptors, and especially EphB4, regulate the migration of murine melanoma cells. Highly malignant melanoma cells express the highest levels of EphB4 receptor and migrate faster than less malignant melanoma cells. Furthermore, inhibition of EphB receptor forward signaling by overexpression of a form of EphB4 lacking the cytoplasmic portion or by treatment with competitively acting soluble EphB2-Fc results in slower melanoma cell migration. In contrast, overexpression of active EphB4 significantly enhances cell migration. The effects of EphB4 receptor on cell migration and cell morphology require its kinase activity because the inhibition of EphB4 kinase activity by overexpression of kinase dead EphB4 inhibits cell migration and affects the organization of actin cytoskeleton. Activation of EphB4 receptor with its ligand ephrin-B2-Fc enhances the migratory ability of melanoma cells and increases RhoA activity, whereas inhibiting EphB receptor forward signaling decreases RhoA activity. Moreover, expression of dominant negative RhoA blocks the effects of active EphB4 on cell migration and actin organization. These data suggest that EphB4 forward signaling contributes to the high migratory ability of invasive melanoma cells by influencing RhoA-mediated actin cytoskeleton reorganization.

Actins↗

PubMedDate not supplied

Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer.

The protein kinases includes many oncogenes and growth-factor receptors, as well as genes that are involved in cell cycle regulation. EphB4 receptors are a subfamily of receptor tyrosine kinases that are activated by ephrin-B2 ligands and are thought to play an important role in the development and oncogenesis of various tissues. However, very little experimental evidence exists to support this hypothesis. To elucidate the involvement of EphB4 and ephrin-B2 in endometrial carcinogenesis, we used fluorescent immunohistochemistry to analyze serial frozen sections of 20 endometrial carcinomas and 20 normal endometria for EphB4 and ephrin-B2 protein expression. We analyzed the relationship between the patient's characteristics and the percentages of EphB4- and ephrin-B2-stained cells. EphB4 expression was significantly associated with histological grade (p < 0.001) and certain clinical stages. Ephrin-B2 Expression was significantly associated with the presence of invasion to > 1/2 myometrium (p = 0.002). Our results demonstrate that increased EphB4 and ephrin-B2 expression may reflect or induce in endometrial carcinomas increased potential for growth and tumorigenicity. Furthermore, these results suggest that EphB4 receptor kinase may modulate the biological behavior of endometrial carcinomas through autocrine and/or paracrine activation, which is caused by ephrin-B2 ligands that are expressed in the same or neighbouring cells by immunohistochemistry.

Adenocarcinoma↗

PubMed2004

Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development.

Vascular development begins with the formation of a primary vascular plexus that is rapidly remodeled by angiogenesis into the interconnected branched patterns characteristic of mature vasculature. Several receptor tyrosine kinases and their ligands have been implicated to control early development of the vascular system. These include the vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2) that bind VEGF, the Tie-1 and Tie-2 receptors that bind the angiopoietins, and the EphB4 receptor that binds the membrane-anchored ligand ephrin-B2. Targeted mutations in the mouse germline have revealed essential functions for these molecules in vascular development. In particular, protein-null mutations that delete either EphB4 or ephrin-B2 from the mouse have been shown to result in early embryonic lethality due to failed angiogenic remodeling. The venous expression of EphB4 and arterial expression of ephrin-B2 has lead to the speculation that the interaction of these two molecules leads to bidirectional signaling into both the receptor-expressing cell and the ligand-expressing cell, and that both forward and reverse signals are required for proper development of blood vessels in the embryo. Indeed, targeted removal of the ephrin-B2 carboxy-terminal cytoplasmic tail by another group was shown to perturb vascular development and result in the same early embryonic lethality as the null mutation, leading the authors to propose that ephrin-B2 reverse signaling directs early angiogenic remodeling of the primary vascular plexus [Cell 104 (2001) 57]. However, we show here that the carboxy-terminal cytoplasmic domain of ephrin-B2, and hence reverse signaling, is not required during early vascular development, but it is necessary for neonatal survival and functions later in cardiovascular development in the maturation of cardiac valve leaflets. We further show that ephrin-B2 reverse signaling is required for the pathfinding of axons that form the posterior tract of the anterior commissure. Our results thus indicate that ephrin-B2 functions in the early embryo as a typical instructive ligand to stimulate EphB4 receptor forward signaling during angiogenic remodeling and that later in embryonic development ephrin-B2 functions as a receptor to transduce reverse signals involved in cardiac valve maturation and axon pathfinding.

Animals↗

PubMed2000

The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis.

The cues and signaling systems that guide the formation of embryonic blood vessels in tissues and organs are poorly understood. Members of the Eph family of receptor tyrosine kinases and their cell membrane-anchored ligands, the ephrins, have been assigned important roles in the control of cell migration during embryogenesis, particularly in axon guidance and neural crest migration. Here we investigated the role of EphB receptors and their ligands during embryonic blood vessel development in Xenopus laevis. In a survey of tadpole-stage Xenopus embryos for EphB receptor expression, we detected expression of EphB4 receptors in the posterior cardinal veins and their derivatives, the intersomitic veins. Vascular expression of other EphB receptors, including EphB1, EphB2 or EphB3, could however not be observed, suggesting that EphB4 is the principal EphB receptor of the early embryonic vasculature of Xenopus. Furthermore, we found that ephrin-B ligands are expressed complementary to EphB4 in the somites adjacent to the migratory pathways taken by intersomitic veins during angiogenic growth. We performed RNA injection experiments to study the function of EphB4 and its ligands in intersomitic vein development. Disruption of EphB4 signaling by dominant negative EphB4 receptors or misexpression of ephrin-B ligands in Xenopus embryos resulted in intersomitic veins growing abnormally into the adjacent somitic tissue. Our findings demonstrate that EphB4 and B-class ephrins act as regulators of angiogenesis possibly by mediating repulsive guidance cues to migrating endothelial cells.

Animals↗