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1
Helbling, P. M., D. M. Saulnier, and A. W. Brandli. "The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis." Development 127, no. 2 (January 15, 2000): 269–78. http://dx.doi.org/10.1242/dev.127.2.269.
Повний текст джерелаАнотація:
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.
2
Yang, Nai-Ying, Elena B. Pasquale, Laurie B. Owen, and Iryna M. Ethell. "The EphB4 Receptor-tyrosine Kinase Promotes the Migration of Melanoma Cells through Rho-mediated Actin Cytoskeleton Reorganization." Journal of Biological Chemistry 281, no. 43 (August 31, 2006): 32574–86. http://dx.doi.org/10.1074/jbc.m604338200.
Повний текст джерелаАнотація:
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.
3
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.
Повний текст джерелаАнотація:
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.
4
ter Elst, Arja, Kim R. Kampen, Sander H. Diks, Steven M. Kornblau, Guillermo Garcia-Manero, and Evelina S. De Bont. "EphrinB1 Activation As a Potential New Treatment Option in AML." Blood 118, no. 21 (November 18, 2011): 5235. http://dx.doi.org/10.1182/blood.v118.21.5235.5235.
Повний текст джерелаАнотація:
Abstract Abstract 5235 Aberrant Ephrin signaling has been shown to be an important pathway that contributes to the pathogenesis of many solid tumors (Surawska et al. Cytokine & Growth factor reviews 2004). Deregulated ephrin receptor (Eph) and ligand (Efn) expression is often associated with poor prognosis in solid tumors. Ephrin receptor and ligand overexpression can result in tumorigenesis through induced tumor growth, tumor cell survival, angiogenesis and metastasis (Surawska et al. Cytokine & Growth Factor Reviews 2004; Campbell et al. Curr. Isues Mol. Biol. 2008; Chen et al. Cancer Research 2008). In normal cells Eph receptors and ligands play key roles in vascular patterning, where they function in endothelial cell migration, and proliferation (Adams et al, Genes Dev. 1999; Zhang et al., Blood 2001). Thus far particularly EphB4 receptor and ephrin-B2 ligand have been implicated in the process of normal angiogenesis. In acute myeloid leukemia (AML) patients it was found that bone marrow biopsies at diagnosis exhibited enhanced microvessel density (MVD) (de Bont ES et al., BJH 2001; Byrd JC et al., Blood 2002; Padro et al., Blood 2000). Normal hematopoietic stem cells (HSCs) express the following mRNA transcripts ephrin receptors EphA1, EphA2, EphB2, and EphB4 and ephrin ligands EfnA3, EfnA4, and EfnB2. Moreover, overexpression of EphB4 receptor in HSCs (from cord blood) resulted in enhanced differentiation towards megakaryocytes (Wang et al. Blood 2002). In AML cell lines there is a common co-expression on protein level observed between EphB4 receptor and ephrin-B2 ligand. Recently, an aberrant DNA methylation of ephrin receptors and ligands was described in acute lymphocytic and myelocytic leukemia cell lines (Kuang et al. Blood 2010). In addition, restoration of EphB4 expression in an acute lymphoid leukemia cell line resulted in reduced proliferation and apoptotic cell death. These data suggests that the ephrin signaling pathway might play an important role in leukemia. In a previous study we have found high kinase activity of EphB receptors and high phosphorylation levels of EphB receptors in AML samples, as measured using kinase arrays and proteome profiler arrays. In this study, we have found extensive membrane expression of EphB1 on AML cell lines and primary AML blasts. To identify the role of Ephrin signaling in AML, two AML cell lines THP-1 and HL60 with an EphB1 membrane expressing cell percentage of 70% and 20% respectively were chosen for stimulation with Ephrin-B1 ligand. Treatment of these cell lines with Ephrin-B1 ligand resulted in a decreased proliferation 30% in THP-1 cells versus 22% in HL60 cells and increased apoptosis 23% in THP-1 cells and 4% in HL60 cells. Of note, the most prominent effect of Ephrin-B1 stimulation was found in THP-1 cells, this cell line contained a higher percentage of EphB1 membrane expressing cells. We further investigated the mechanism through which EphB1 reduces leukemic cell growth and induces leukemic cell death in THP-1 cells. Westernblot analysis of cell cycle regulators showed that expression of the anti-apoptotic protein BCL2 is reduced upon Ephrin-B1 ligand stimulation and the expression of the pro-apoptotic protein BAX is induced. In addition, mRNA expression of the cell cycle inhibitor of cell cycle progression p21 was found to be 2,5 fold upregulated in ephrin-B1 ligand treated cells compared to untreated control cells. MGG stainings of Ephrin-B1 treated cells revealed multiple cells with two nuclei in both THP-1 and HL60 cells. These results indicate that a high percentage of AML cells express EphB1 receptor on the membrane and that stimulation of these cells with Ephrin-B1 ligand results in reduced leukemic growth and increased cell death. EphrinB1 activation in AML deserves further investigation considering EphB1 as a putative new treatment option for AML patients. Disclosures: No relevant conflicts of interest to declare.
5
Lee, Kyeong, Hossam Nada, Hyun Jung Byun, Chang Hoon Lee, and Ahmed Elkamhawy. "Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies." Pharmaceuticals 14, no. 12 (November 30, 2021): 1247. http://dx.doi.org/10.3390/ph14121247.
Повний текст джерелаАнотація:
EphB3 is a major key player in a variety of cellular activities, including cell migration, proliferation, and apoptosis. However, the exact role of EphB3 in cancer remains ambiguous. Accordingly, new EphB3 inhibitors can increase the understanding of the exact roles of the receptor and may act as promising therapeutic candidates. Herein, a hybrid approach of structure-based design and virtual combinatorial library generated 34 quinazoline sulfonamides as potential selective EphB3 inhibitors. A molecular docking study over EphB3 predicted the binding affinities of the generated library, and the top seven hit compounds (3a and 4a–f), with GlideScore ≥ −6.20 Kcal/mol, were chosen for further MM-GBSA calculations. Out of the seven top hits, compound 4c showed the highest MM-GBSA binding free energy (−74.13 Kcal/mol). To validate these predicted results, compounds 3a and 4a–f were synthesized and characterized using NMR, HRMS, and HPLC. The biological evaluation revealed compound 4c as a potent EphB3 inhibitory lead (IC50 = 1.04 µM). The screening of 4c over a mini-panel of kinases consisting of EGFR, Aurora A, Aurora B, CDK2/cyclin A, EphB1, EphB2, EphB4, ERBB2/HER2, and KDR/VEGFR2, showed a promising selective profile against EphB3 isoform. A dose-dependent assay of compound 4c and a molecular docking study over the different forms of EphB provided insights into the elicited biological activities and highlighted reasonable explanations of the selectivity.
6
Kawano, Hiroki, Yoshio Katayama, Kentaro Minagawa, Manabu Shimoyama, Mark Henkemeyer, and Toshimitsu Matsui. "A Novel Feedback Mechanism by Ephrin-B1/B2 In T Cell Activation: Concentration-Dependent Switch From Costimulation to Inhibition." Blood 116, no. 21 (November 19, 2010): 277. http://dx.doi.org/10.1182/blood.v116.21.277.277.
Повний текст джерелаАнотація:
Abstract Abstract 277 Eph is the largest known family of receptor tyrosine kinases, and bind to a cell surface-associated ligand, ephrin on neighboring cells upon direct cell-cell contact. The ensuing bidirectional signals have been recognized as a major form of contact-dependent cell communications, such as cell attraction and repulsion to control accurate spatial and temporal patterning in the development of the central nervous system. EphBs, EphB6 in particular, are expressed in T cells and its specific ligand, ephrin-B2 has been shown to act as a costimulatory molecule for the T cell receptor (TCR)-mediated cell proliferation. Recently, another remarkable feature of ephrins, a concentration-dependent transition from promotion to inhibition in axon growth has emerged in ephrin-As. Thus, we postulated that this type of ligand concentration dependent functional transition would be suitable for the delicate tuning of immune responses to avoid reckless drive. To figure this out, we carefully evaluated the costimulatory effects of ephrin-Bs by using murine primary T cells. Interestingly, low doses of solid phase ephrin-B1 as well as ephrin-B2 (at up to 5μ g/ml) costimulated, to the comparable level with anti-CD28, T cell proliferation induced by suboptimal concentration of immobilized anti-CD3 antibody, but high concentrations of ephrin-B1/B2 inhibited the TCR-mediated proliferation significantly (by approximately 70% reduction from the baseline at 20μ g/ml). The similar concentration-dependent transition from coactivation to inhibition was also observed under the optimal CD3 stimulation. The concentration-dependent biphasic effects, positively at low concentration and negatively at high concentration, by ephrin-B1/B2 in T cell activation were confirmed in the cytokine production such as TNF-α, IL-2, and IFN-γ. In contrast, ephrin-B3 showed steadily increasing stimulatory effect even in higher concentrations in proliferation and cytokine production. We speculated that these unique modulations were partly mediated by EphB6 because EphB6 transfected in HEK293T cells has been shown to exert biphasic effects in cell adhesion and migration in response to different concentrations of ephrin-B2. T cell derived from Ephb6 -/- mice showed decreased CD3-stimulated cell proliferation as reported previously. However, the unique comodulatory pattern by each ephrin-B was virtually preserved in Ephb6 -/- T cells. Since the functions of Eph family could be redundant, we further investigated by generating multiple EphB knockout mice lacking four genes, Ephb1, Ephb2, Ephb3 and Ephb6. Surprisingly, no further alteration was observed in T cells from the quadruple knockout mice compared to the Ephb6 single deficiency. We also confirmed that EphA4, an exception in EphA receptor family which binds ephrin-Bs, was not expressed in T cells by RT-PCR. Taken together with the fact that EphB5 does not exist in mammals, the unique comodification by ephrin-Bs might be regulated by EphB4. Next, we examined the cross-talk of EphB forward signaling with TCR pathway. The inhibitor of p38MAPK and p44/42MAPK significantly reduced the TCR-mediated proliferation, but did conserve the concentration-dependent effects of ephrin-B1/B2, suggesting the interference with EphB signaling in TCR signal transduction at the upstream of MAPKs which are important for cell growth and survival. Immuno-blot analyses revealed that high concentrations of ephrin-B1/B2, but not ephrin-B3, clearly inhibited the anti-CD3 induced phosphorylation of Lck and its downstream signaling molecules such as ZAP70, c-Raf, MEK1/2, Erk, and Akt, although the phosphorylation of CD3ζ was not inhibited by high concentrations of any ephrin-Bs. These data suggest that Eph signaling upon stimulation by high concentrations of ephrin-B1/B2 may engage in negative feedback to TCR signals via Lck. The present studies demonstrate that TCR-mediated primary T cell activation may be highly governed by EphB/ephrin-B axis with a complexity determined by the combination as well as the concentration of different ephrin-Bs expressed in immunological microenvironments. EphB-involved in negative feedback of T cell activation could be a novel therapeutic target to inhibit the most proximal TCR signaling molecule, Lck. The generation of strong signaling molecule which mimics ephrin-B1/B2 would be an effective strategy to control T cell mediated immune disorders. Disclosures: No relevant conflicts of interest to declare.
7
Salvucci, Ombretta, Maria de la Luz Sierra, Jose A. Martina, Peter J. McCormick, and Giovanna Tosato. "EphB2 and EphB4 receptors forward signaling promotes SDF-1–induced endothelial cell chemotaxis and branching remodeling." Blood 108, no. 9 (November 1, 2006): 2914–22. http://dx.doi.org/10.1182/blood-2006-05-023341.
Повний текст джерелаАнотація:
Abstract 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.
8
Wagner, Melany J., Marilyn S. Hsiung, Gerald D. Gish, Rick D. Bagshaw, Sasha A. Doodnauth, Mohamed A. Soliman, Claus Jørgensen, Monika Tucholska, and Robert Rottapel. "The Shb scaffold binds the Nck adaptor protein, p120 RasGAP, and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2." Journal of Biological Chemistry 295, no. 12 (February 14, 2020): 3932–44. http://dx.doi.org/10.1074/jbc.ra119.009276.
Повний текст джерелаАнотація:
Eph receptors are a family of receptor tyrosine kinases that control directional cell movement during various biological processes, including embryogenesis, neuronal pathfinding, and tumor formation. The biochemical pathways of Eph receptors are context-dependent in part because of the varied composition of a heterotypic, oligomeric, active Eph receptor complex. Downstream of the Eph receptors, little is known about the essential phosphorylation events that define the context and instruct cell movement. Here, we define a pathway that is required for Eph receptor B2 (EphB2)–mediated cell sorting and is conserved among multiple Eph receptors. Utilizing a HEK293 model of EphB2+/ephrinB1+ cell segregation, we found that the scaffold adaptor protein SH2 domain–containing adaptor protein B (Shb) is essential for EphB2 functionality. Further characterization revealed that Shb interacts with known modulators of cytoskeletal rearrangement and cell mobility, including Nck adaptor protein (Nck), p120-Ras GTPase-activating protein (RasGAP), and the α- and β-Chimaerin Rac GAPs. We noted that phosphorylation of Tyr297, Tyr246, and Tyr336 of Shb is required for EphB2–ephrinB1 boundary formation, as well as binding of Nck, RasGAP, and the chimaerins, respectively. Similar complexes were formed in the context of EphA4, EphA8, EphB2, and EphB4 receptor activation. These results indicate that phosphotyrosine-mediated signaling through Shb is essential in EphB2-mediated heterotypic cell segregation and suggest a conserved function for Shb downstream of multiple Eph receptors.
9
Li, Wenqing, Lai Wen, Bhavisha Rathod, Anne-Claude Gingras, Klaus Ley, and Ho-Sup Lee. "Kindlin2 enables EphB/ephrinB bi-directional signaling to support vascular development." Life Science Alliance 6, no. 3 (December 27, 2022): e202201800. http://dx.doi.org/10.26508/lsa.202201800.
Повний текст джерелаАнотація:
Direct contact between cells expressing either ephrin ligands or Eph receptor tyrosine kinase produces diverse developmental responses. Transmembrane ephrinB ligands play active roles in transducing bi-directional signals downstream of EphB/ephrinB interaction. However, it has not been well understood how ephrinB relays transcellular signals to neighboring cells and what intracellular effectors are involved. Here, we report that kindlin2 can mediate bi-directional ephrinB signaling through binding to a highly conserved NIYY motif in the ephrinB2 cytoplasmic tail. We show this interaction is important for EphB/ephrinB-mediated integrin activation in mammalian cells and for blood vessel morphogenesis during zebrafish development. A mixed two-cell population study revealed that kindlin2 (in ephrinB2-expressing cells) modulates transcellular EphB4 activation by promoting ephrinB2 clustering. This mechanism is also operative for EphB2/ephrinB1, suggesting that kindlin2-mediated regulation is conserved for EphB/ephrinB signaling pathways. Together, these findings show that kindlin2 enables EphB4/ephrinB2 bi-directional signal transmission.
10
Kuang, Shao-Qing, Hao Bai, Zhi-Hong Fang, Gonzalo Lopez, Hui Yang, Weigang Tong, Zack Z. Wang, and Guillermo Garcia-Manero. "Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia." Blood 115, no. 12 (March 25, 2010): 2412–19. http://dx.doi.org/10.1182/blood-2009-05-222208.
Повний текст джерелаАнотація:
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.
11
Henkemeyer, Mark, Olga S. Itkis, Michelle Ngo, Peter W. Hickmott, and Iryna M. Ethell. "Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus." Journal of Cell Biology 163, no. 6 (December 22, 2003): 1313–26. http://dx.doi.org/10.1083/jcb.200306033.
Повний текст джерелаАнотація:
Here, using a genetic approach, we dissect the roles of EphB receptor tyrosine kinases in dendritic spine development. Analysis of EphB1, EphB2, and EphB3 double and triple mutant mice lacking these receptors in different combinations indicates that all three, although to varying degrees, are involved in dendritic spine morphogenesis and synapse formation in the hippocampus. Hippocampal neurons lacking EphB expression fail to form dendritic spines in vitro and they develop abnormal spines in vivo. Defective spine formation in the mutants is associated with a drastic reduction in excitatory glutamatergic synapses and the clustering of NMDA and AMPA receptors. We show further that a kinase-defective, truncating mutation in EphB2 also results in abnormal spine development and that ephrin-B2–mediated activation of the EphB receptors accelerates dendritic spine development. These results indicate EphB receptor cell autonomous forward signaling is responsible for dendritic spine formation and synaptic maturation in hippocampal neurons.
12
Noren, Nicole K., Nai-Ying Yang, Morgan Silldorff, Ravi Mutyala, and Elena B. Pasquale. "Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor." Biochemical Journal 422, no. 3 (August 27, 2009): 433–42. http://dx.doi.org/10.1042/bj20090014.
Повний текст джерелаАнотація:
Receptor tyrosine kinases of the Eph family become tyrosine phosphorylated and initiate signalling events upon binding of their ligands, the ephrins. Eph receptors such as EphA2 and EphB4 are highly expressed but poorly tyrosine phosphorylated in many types of cancer cells, suggesting a limited interaction with ephrin ligands. Nevertheless, decreasing the expression of these receptors affects the malignant properties of cancer cells, suggesting that Eph receptors may influence cancer cells independently of ephrin stimulation. Ligand-independent activities of Eph receptors in cancer, however, have not been demonstrated. By using siRNA (small interfering RNA) to downregulate EphB4 in MCF7 and MDA-MB-435 cancer cells, we found that EphB4 inhibits integrin-mediated cell substrate adhesion, spreading and migration, and reduces β1-integrin protein levels. Low expression of the EphB4 preferred ligand, ephrin-B2, and minimal contact between cells in these assays suggest that cell contact-dependent stimulation of EphB4 by the transmembrane ephrin-B2 ligand does not play a role in these effects. Indeed, inhibitors of ephrin-B2 binding to endogenous EphB4 did not influence cell substrate adhesion. Increasing EphB4 expression by transient transfection inhibited cell substrate adhesion, and this effect was also independent of ephrin stimulation because it was not affected by single amino acid mutations in EphB4 that impair ephrin binding. The overexpressed EphB4 was tyrosine phosphorylated, and we found that EphB4 kinase activity is important for inhibition of integrin-mediated adhesion, although several EphB4 tyrosine phosphorylation sites are dispensable. These findings demonstrate that EphB4 can affect cancer cell behaviour in an ephrin-independent manner.
13
Zhang, Xiu-Qin, Nobuyuki Takakura, Yuichi Oike, Tomohisa Inada, Nicholas W. Gale, George D. Yancopoulos, and Toshio Suda. "Stromal cells expressing ephrin-B2 promote the growth and sprouting of ephrin-B2+ endothelial cells." Blood 98, no. 4 (August 15, 2001): 1028–37. http://dx.doi.org/10.1182/blood.v98.4.1028.
Повний текст джерелаАнотація:
Ephrin-B2 is a transmembrane ligand that is specifically expressed on arterial endothelial cells (ECs) and surrounding cells and interacts with multiple EphB class receptors. Conversely, EphB4, a specific receptor for ephrin-B2, is expressed on venous ECs, and both ephrin-B2 and EphB4 play essential roles in vascular development. The bidirectional signals between EphB4 and ephrin-B2 are thought to be specific for the interaction between arteries and veins and to regulate cell mixing and the making of particular boundaries. However, the molecular mechanism during vasculogenesis and angiogenesis remains unclear. Manipulative functional studies were performed on these proteins in an endothelial cell system. Using in vitro stromal cells (OP9 cells) and a paraaortic splanchnopleura (P-Sp) coculture system, these studies found that the stromal cells expressing ephrin-B2 promoted vascular network formation and ephrin-B2+ EC proliferation and that they also induced the recruitment and proliferation of α-smooth muscle actin (α-SMA)–positive cells. Stromal cells expressing EphB4 inhibited vascular network formation, ephrin-B2+ EC proliferation, and α-SMA+ cell recruitment and proliferation. Thus, these data suggest that ephrin-B2 and EphB4 mediate reciprocal interactions between arterial and venous ECs and surrounding cells to form each characteristic vessel.
14
Mimche, Patrice, Lauren Brady, Daniel Cox, and Tracey Lamb. "The Eph/Ephrin molecules are modulated in organs of parasitized red blood cells sequestration and may contribute to disease pathogenesis in rodent malaria. (P3059)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 187.5. http://dx.doi.org/10.4049/jimmunol.190.supp.187.5.
Повний текст джерелаАнотація:
Abstract Eph receptors and their Ephrin ligands are the largest family of receptor tyrosine kinases. Beyond their role in cell trafficking/adhesion and cancer, nothing is known about their activation during malaria infection. We explored the regulation of Eph/Ephrin in malaria using the rodent malaria model P. berghei ANKA, a parasite that causes experimental cerebral malaria in C57BL/6 mice. Infection with P. berghei ANKA leads to modulation of transcription for some members of the Eph/Ephrin in C57BL/6 mouse brain and spleen. This may be driven by inflammatory cytokines upregulated in these organs in response to sequestration of iRBCs because TNFR2-/- mice which are known to be resistant from death by ECM did not display any upregulation of Eph/Ephrin. To further examine their modulation, subsets of antigen presenting cells and T cells were FACS sorted from splenocytes at different time points post infection. Transcription was found to be modulated between days 2 and 3, particularly for EphB2 on CD11b+ macrophage/neutrophil subset. To support the modulation of transcription in the brain during ECM, mouse primary brain microvascular endothelial cells were isolated from naïve mice and stimulated with inflammatory cytokines and lysates of iRBCs. We observed an increase in the transcription of EphB4 and EphB6 in response to inflammatory cytokine signaling and an increase in the protein expression of EphB4 in response to iRBC lysates. The implications of these results will be discussed.
15
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.
Повний текст джерелаАнотація:
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, Zhengyu, Nobuyuki Miura, Andres Bonelli, Pamela Mole, Nadia Carlesso, Douglas P. Olson, and David T. Scadden. "Receptor tyrosine kinase, EphB4 (HTK), accelerates differentiation of select human hematopoietic cells." Blood 99, no. 8 (April 15, 2002): 2740–47. http://dx.doi.org/10.1182/blood.v99.8.2740.
Повний текст джерелаАнотація:
Abstract EphB4 (HTK) and its ligand, ephrinB2, are critical for angiogenesis and result in fatal abnormalities of capillary formation in null mice. EphB4 was originally identified in human bone marrow CD34+cells by us and has since been reported to be expressed in erythroid progenitors, whereas the ligand ephrinB2 is expressed in bone marrow stromal cells. Reasoning that the developmental relationship between angiogenesis and hematopoiesis implies common regulatory molecules, we assessed whether EphB4 signaling influences the function and phenotype of primitive human hematopoietic cells. Ectopically expressed EphB4 in cell lines of restricted differentiation potential promoted megakaryocytic differentiation, but not granulocytic or monocytic differentiation. Primary cord blood CD34+ cells transduced with EphB4 resulted in the elevated expression of megakaryocytic and erythroid specific markers, consistent with EphB4 selectively enhancing some lineage-committed progenitors. In less mature cells, EphB4 depleted primitive cells, as measured by long-term culture-initiating cells or CD34+CD38− cell numbers, and increased progenitor cells of multiple cell types. Effects of ectopic EphB4 expression could be abrogated by either targeted mutations of select tyrosine residues or by the tyrosine kinase inhibitor, genistein. These data indicate that EphB4 accelerates the differentiation of primitive cells in a nonlineage-restricted manner but alters only select progenitor populations, influencing lineages linked by common ancestry with endothelial cells. EphB4 enforces preferential megakaryocytic and erythroid differentiation and may be a molecular bridge between angiogenesis and hematopoiesis.
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Xiaoli, Liu, Jinfang Zhang, Qingfeng Du, Na Xu, Lulu Xu, Xiaozhen Xiao, and Xuan Zhou. "Overexpression of the EphB4 Receptor Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Through Regulating Mlcp and VAV1." Blood 120, no. 21 (November 16, 2012): 4421. http://dx.doi.org/10.1182/blood.v120.21.4421.4421.
Повний текст джерелаАнотація:
Abstract Abstract 4421 Objective: To study the role of EphB4 in imatinib (IM) resistant chronic myeloid leukemia (CML) and investigate the mechanism. Methods: We derived IM-resistant cells, K562-R cells, from wild K562 cells under gradually increasing IM concentrations. We analysed expression level of EphB4 in CML patients, wild K562 and K562-R cell lines by real-time reverse transcription PCR and Western blot analysis. Then we established stable under-expressing EphB4 cell (K562-R-EphB4-sh) lines. We analysed the sensitive for IM of K562, K562-R, K562-R-EphB4-sh cell lines by CCK8 assay. Microarray analysis was used to screen differential expression genes between K562-R and K562-R-EphB4-sh cell lines. Results: The mRNA and protein of EphB4 were significantly increased in IM resistant CML patients compared to IM sensitive CML patients (p<0.05). The Similar results were observed in K562-R and K562 cells (p<0.01). To analyze the role of EphB4 in IM resistance, EphB4 was knocked down with shRNA expressed by pLL3.7 lentivirus vector. We established stable under-expressing EphB4 cell line K562-R-EphB4-sh. RT-PCR and western blot analysis showed that mRNA and protein expression of EphB4 in K562-R-EphB4-sh cells were reduced (p<0.05). CCK8 assay found K562 cells (IC50 0.1207±0.0234μM), K562-R-EphB4-sh cells (IC50 0.7228±0.04752μM) were sensitive to IM but K562-R (IC50 2.8101±0.04674μM) still showed IM resistance (p<0.05). Those suggested K562-R-EphB4-sh cells resensitize to IM when the expression of EphB4 was down regulated. However, these cells were still less sensitive than K562 cells. Microarray analysis between K562-R and K562-R-EphB4-sh cell lines found 641 differential expression genes, most of them were related to cell adhesion and cell cytoskeleton. We confirmed MLCP and VAV1 were down regulated in K562-R-EphB4-sh cells compared to K562-R cell lines by western blot analysis. Conclusion: Our study suggest EphB4 receptor contributes to IM-resistant in CML through regulating cell adhesion molecular MLCP and VAV1, which may provide new biomarkers and contribute to] developping new drugs for the disease. Disclosures: No relevant conflicts of interest to declare.
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Birgbauer, E., C. A. Cowan, D. W. Sretavan, and M. Henkemeyer. "Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina." Development 127, no. 6 (March 15, 2000): 1231–41. http://dx.doi.org/10.1242/dev.127.6.1231.
Повний текст джерелаАнотація:
Optic nerve formation requires precise retinal ganglion cell (RGC) axon pathfinding within the retina to the optic disc, the molecular basis of which is not well understood. At CNS targets, interactions between Eph receptor tyrosine kinases on RGC axons and ephrin ligands on target cells have been implicated in formation of topographic maps. However, studies in chick and mouse have shown that both Eph receptors and ephrins are also expressed within the retina itself, raising the possibility that this receptor-ligand family mediates aspects of retinal development. Here, we more fully document the presence of specific EphB receptors and B-ephrins in embryonic mouse retina and provide evidence that EphB receptors are involved in RGC axon pathfinding to the optic disc. We find that as RGC axons begin this pathfinding process, EphB receptors are uniformly expressed along the dorsal-ventral retinal axis. This is in contrast to the previously reported high ventral-low dorsal gradient of EphB receptors later in development when RGC axons map to CNS targets. We show that mice lacking both EphB2 and EphB3 receptor tyrosine kinases, but not each alone, exhibit increased frequency of RGC axon guidance errors to the optic disc. In these animals, major aspects of retinal development and cellular organization appear normal, as do the expression of other RGC guidance cues netrin, DCC, and L1. Unexpectedly, errors occur in dorsal but not ventral retina despite early uniform or later high ventral expression of EphB2 and EphB3. Furthermore, embryos lacking EphB3 and the kinase domain of EphB2 do not show increased errors, consistent with a guidance role for the EphB2 extracellular domain. Thus, while Eph kinase function is involved in RGC axon mapping in the brain, RGC axon pathfinding within the retina is partially mediated by EphB receptors acting in a kinase-independent manner.
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Angmalisang, Elvin C. "Peran Sinyal Ephrin-B2/EPH-B4 pada Angiogenesis Postnatal." Jurnal Biomedik:JBM 12, no. 2 (July 12, 2020): 77. http://dx.doi.org/10.35790/jbm.12.2.2020.29161.
Повний текст джерелаАнотація:
Abstract: Angiogenesis is the process of developing new blood vessels that play an important role in embryogenesis as well as postnatal period. The postnatal angiogenesis is regulated by pro- and anti-angiogenic factors and several signals, one of which is the ephrin/Eph signal. Ephrin-B2 and its receptor EphB4 are transmembrane tyrosine kinase (RTKs) receptors which have an important role in angiogenesis inter alia promoting angiogenesis sprouting and participating in blood vessel maturation (remodeling and stabilization).Keywords: angiogenesis, Ephrin-B2, EphB4, EphrinB2/EphB4 signaling Abstrak: Angiogenesis adalah proses perkembangan pembuluh darah baru yang berperan penting pada embriogenesis, dan juga saat postnatal. Proses postnatal angiogenesis diregulasi oleh faktor-faktor pro- dan anti-angiogenik serta sinyal-sinyal, salah satunya ialah sinyal ephrin/Eph. Ephrin-B2 dan reseptornya EphB4 merupakan reseptor tirosin kinase (RTKs) transmembran yang berperan penting pada angiogenesis, yaitu untuk memromosikan angio-genesis sprouting, serta berpartisipasi dalam pematangan pembuluh darah (remodeling dan stabilisasi).Kata kunci: angiogenesis, Ephrin-B2, EphB4, sinyal EphrinB2/EphB4
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Liang, Lung-Yu, Michael Roy, Christopher R. Horne, Jarrod J. Sandow, Minglyanna Surudoi, Laura F. Dagley, Samuel N. Young, et al. "The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs." Biochemical Journal 478, no. 17 (September 14, 2021): 3351–71. http://dx.doi.org/10.1042/bcj20210572.
Повний текст джерелаАнотація:
EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell–cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulation is strongly linked to proliferative diseases. However, unlike active Eph receptors, whose catalytic activities are thought to initiate an intracellular signalling cascade, EphB6 and EphA10 are classified as catalytically dead, raising the question of how non-catalytic functions contribute to Eph receptor signalling homeostasis. In this study, we have characterised the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane (JM) region, pseudokinase and SAM domains. Using small-angle X-ray scattering and cross-linking-mass spectrometry, we observed high flexibility within their intracellular regions in solution and a propensity for interaction between the component domains. We identified tyrosine residues in the JM region of EphB6 as EphB4 substrates, which can bind the SH2 domains of signalling effectors, including Abl, Src and Vav3, consistent with cellular roles in recruiting these proteins for downstream signalling. Furthermore, our finding that EphB6 and EphA10 can bind ATP and ATP-competitive small molecules raises the prospect that these pseudokinase domains could be pharmacologically targeted to counter oncogenic signalling.
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Li, Chaohao, Nadia A. Lanman, Yifan Kong, Daheng He, Fengyi Mao, Elia Farah, Yanquan Zhang, et al. "Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance." Journal of Biological Chemistry 295, no. 16 (March 17, 2020): 5470–83. http://dx.doi.org/10.1074/jbc.ra119.011385.
Повний текст джерелаАнотація:
Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.
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Wang, Zhengyu, Kenneth Cohen, Ying Shao, Pamela Mole, David Dombkowski, and David T. Scadden. "Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels." Blood 103, no. 1 (January 1, 2004): 100–109. http://dx.doi.org/10.1182/blood-2003-04-1063.
Повний текст джерелаАнотація:
Abstract 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.
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Peng, Hsien-Yu, Gin-Den Chen, Cheng-Hung Lai, Kwong-Chung Tung, Junn-Liang Chang, and Tzer-Bin Lin. "Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B." American Journal of Physiology-Renal Physiology 298, no. 1 (January 2010): F109—F117. http://dx.doi.org/10.1152/ajprenal.00287.2009.
Повний текст джерелаАнотація:
Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in spinal pain-related neural plasticity has been identified. To test whether Src-family non-receptor tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor (NMDAR) NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate cross-organ sensitization between the colon and the urethra, external urethra sphincter electromyogram activity evoked by pelvic nerve stimulation and protein expression in the lumbosacral (L6–S2) dorsal horn were studied before and after intracolonic mustard oil (MO) instillation. We found MO instillation produced colon-urethra reflex sensitization along with an upregulation of endogenous ephrinB2 expression as well as phosphorylation of EphB1/2, Src-family kinase, and NR2B tyrosine residues. Intrathecal immunoglobulin fusion protein of EphB1 and EphB2 as well as PP2 reversed the reflex sensitization and NR2B phosphorylation caused by MO. All these results suggest that EphBR-ephrinB interactions, which provoke Src-family kinase-dependent NMDAR NR2B phosphorylation at the lumbosacral spinal cord level, are involved in cross-organ sensitization, contributing to the development of viscero-visceral referred pain between the bowel and the urethra.
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Ge, Yu-Wei, Kai Feng, Xiao-Liang Liu, Hong-Fang Chen, Zhen-Yu Sun, Cai-Feng Wang, Zhi-Qing Liu, et al. "The Recombinant Protein EphB4-Fc Changes the Ti Particle-Mediated Imbalance of OPG/RANKL via EphrinB2/EphB4 Signaling Pathway and Inhibits the Release of Proinflammatory Factors In Vivo." Oxidative Medicine and Cellular Longevity 2020 (June 6, 2020): 1–15. http://dx.doi.org/10.1155/2020/1404915.
Повний текст джерелаАнотація:
Aseptic loosening caused by wear particles is one of the common complications after total hip arthroplasty. We investigated the effect of the recombinant protein ephB4-Fc (erythropoietin-producing human hepatocellular receptor 4) on wear particle-mediated inflammatory response. In vitro, ephrinB2 expression was analyzed using siRNA-NFATc1 (nuclear factor of activated T-cells 1) and siRNA-c-Fos. Additionally, we used Tartrate-resistant acid phosphatase (TRAP) staining, bone pit resorption, Enzyme-linked immunosorbent assay (ELISA), as well as ephrinB2 overexpression and knockdown experiments to verify the effect of ephB4-Fc on osteoclast differentiation and function. In vivo, a mouse skull model was constructed to test whether the ephB4-Fc inhibits osteolysis and inhibits inflammation by micro-CT, H&E staining, immunohistochemistry, and immunofluorescence. The gene expression of ephrinB2 was regulated by c-Fos/NFATc1. Titanium wear particles activated this signaling pathway to the promoted expression of the ephrinB2 gene. However, ephrinB2 protein can be activated by osteoblast membrane receptor ephB4 to inhibit osteoclast differentiation. In in vivo experiments, we found that ephB4 could regulate Ti particle-mediated imbalance of OPG/RANKL, and the most important finding was that ephB4 relieved the release of proinflammatory factors. The ephB4-Fc inhibits wear particle-mediated osteolysis and inflammatory response through the ephrinB2/EphB4 bidirectional signaling pathway, and ephrinB2 ligand is expected to become a new clinical drug therapeutic target.
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Piffko, Andras, Thomas Broggini, Christoph Harms, Ralf Heinrich Adams, Peter Vajkoczy, and Marcus Czabanka. "Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2–EphB4 Signaling in Melanoma Metastatic Spine Disease." International Journal of Molecular Sciences 22, no. 15 (July 27, 2021): 8028. http://dx.doi.org/10.3390/ijms22158028.
Повний текст джерелаАнотація:
Tumor–endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2–EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2–EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.
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Pennisi, Angela, Wen Ling, Xin Li, Sharmin Khan, John D. Shaughnessy, Bart Barlogie, and Shmuel Yaccoby. "The ephrinB2/EphB4 axis is dysregulated in osteoprogenitors from myeloma patients and its activation affects myeloma bone disease and tumor growth." Blood 114, no. 9 (August 27, 2009): 1803–12. http://dx.doi.org/10.1182/blood-2009-01-201954.
Повний текст джерелаАнотація:
Myeloma bone disease is caused by uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Bidirectional signaling between the cell-surface ligand ephrinB2 and its receptor, EphB4, is involved in the coupling of osteoblastogenesis and osteoclastogenesis and in angiogenesis. EphrinB2 and EphB4 expression in mesenchymal stem cells (MSCs) from myeloma patients and in bone cells in myelomatous bones was lower than in healthy counterparts. Wnt3a induced up-regulation of EphB4 in patient MSCs. Myeloma cells reduced expression of these genes in MSCs, whereas in vivo myeloma cell-conditioned media reduced EphB4 expression in bone. In osteoclast precursors, EphB4-Fc induced ephrinB2 phosphorylation with subsequent inhibition of NFATc1 and differentiation. In MSCs, EphB4-Fc did not induce ephrinB2 phosphorylation, whereas ephrinB2-Fc induced EphB4 phosphorylation and osteogenic differentiation. EphB4-Fc treatment of myelomatous SCID-hu mice inhibited myeloma growth, osteoclastosis, and angiogenesis and stimulated osteoblastogenesis and bone formation, whereas ephrinB2-Fc stimulated angiogenesis, osteoblastogenesis, and bone formation but had no effect on osteoclastogenesis and myeloma growth. These chimeric proteins had similar effects on normal bone. Myeloma cells expressed low to undetectable ephrinB2 and EphB4 and did not respond to the chimeric proteins. The ephrinB2/EphB4 axis is dysregulated in MM, and its activation by EphB4-Fc inhibits myeloma growth and bone disease.
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Munarini, Nadia, Richard Jäger, Susanne Abderhalden, Gisela Zuercher, Valeria Rohrbach, Saemi Loercher, Brigitte Pfanner-Meyer, Anne-Catherine Andres, and Andrew Ziemiecki. "Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase." Journal of Cell Science 115, no. 1 (January 1, 2002): 25–37. http://dx.doi.org/10.1242/jcs.115.1.25.
Повний текст джерелаАнотація:
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.
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Kertesz, Nathalie, Valery Krasnoperov, Ramachandra Reddy, Lucy Leshanski, S. Ram Kumar, Sergey Zozulya, and Parkash S. Gill. "The soluble extracellular domain of EphB4 (sEphB4) antagonizes EphB4-EphrinB2 interaction, modulates angiogenesis, and inhibits tumor growth." Blood 107, no. 6 (March 15, 2006): 2330–38. http://dx.doi.org/10.1182/blood-2005-04-1655.
Повний текст джерелаАнотація:
AbstractThe receptor tyrosine kinase EphB4 and its ligand EphrinB2 play a crucial role in vascular development during embryogenesis. The soluble monomeric derivative of the extracellular domain of EphB4 (sEphB4) was designed as an antagonist of EphB4/EphrinB2 signaling. sEphB4 blocks activation of EphB4 and EphrinB2; suppresses endothelial cell migration, adhesion, and tube formation in vitro; and inhibits the angiogenic effects of various growth factors (VEGF and bFGF) in vivo. sEphB4 also inhibits tumor growth in murine tumor xenograft models. sEphB4 is thus a therapeutic candidate for vascular proliferative diseases and cancer.
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Liu, Tingting, Xianwei Zeng, Fangling Sun, Hongli Hou, Yunqian Guan, Deyu Guo, Houxi Ai, Wen Wang, and Guojun Zhang. "EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro." Cellular Physiology and Biochemistry 41, no. 2 (2017): 819–34. http://dx.doi.org/10.1159/000459693.
Повний текст джерелаАнотація:
Background/Aims: EphB4 belongs to the largest family of Eph receptor tyrosine kinases. It contributes to a variety of pathological progresses of cancer malignancy. However, little is known about its role in neural stem cells (NSCs). This study examined whether EphB4 is required for proliferation and differentiation of human embryonic neural stem cells (hNSCs) in vitro. Methods: We up- and down-regulated EphB4 expression in hNSCs using lentiviral over-expression and shRNA knockdown constructs and then investigated the influence of EphB4 on the properties of hNSCs. Results: Our results show that shRNA-mediated EphB4 reduction profoundly impaired hNSCs self-renewal and proliferation. Furthermore, detection of differentiation revealed that knockdown of EphB4 inhibited hNSCs differentiation towards a neuronal lineage and promoted hNSCs differentiation to glial cells. In contrast, EphB4 overexpression promoted hNSCs self-renewal and proliferation, further induced hNSCs differentiation towards a neuronal lineage and inhibited hNSCs differentiation to glial cells. Moreover, we found that EphB4 regulates cell proliferation mediated by the Abl-CyclinD1 pathway. Conclusion: These studies provide strong evidence that fine tuning of EphB4 expression is crucial for the proliferation and neuronal differentiation of hNSCs, suggesting that EphB4 might be an interesting target for overcoming some of the therapeutic limitations of neuronal loss in brain diseases.
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McCall, Jamie L., Drew Gehring, Beth K. Clymer, Kurt W. Fisher, Binita Das, David L. Kelly, Hyunseok Kim, Michael A. White та Robert E. Lewis. "KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors". Molecular and Cellular Biology 36, № 17 (6 червня 2016): 2246–61. http://dx.doi.org/10.1128/mcb.00087-16.
Повний текст джерелаАнотація:
Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producinghepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.
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Nanamiya, Ren, Ryoko Saito-Koyama, Yasuhiro Miki, Chihiro Inoue, Teeranut Asavasupreechar, Jiro Abe, Ikuro Sato, and Hironobu Sasano. "EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer." International Journal of Molecular Sciences 22, no. 16 (August 7, 2021): 8522. http://dx.doi.org/10.3390/ijms22168522.
Повний текст джерелаАнотація:
Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.
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Yuan, Kuo, Tse-Ming Hong, Jeremy J. W. Chen, Wan Hua Tsai, and Ming T. Lin. "Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis." Blood 104, no. 4 (August 15, 2004): 1025–33. http://dx.doi.org/10.1182/blood-2003-09-3334.
Повний текст джерелаАнотація:
AbstractEphrinB2 and EphB4, its cognate receptor, are important in the vascular development of the mouse embryo. Their roles in human inflammatory angiogenesis, however, are not well understood. By examining hyperinflammatory lesions, we saw that ephrinB2 was predominantly expressed in macrophage-like cells and EphB4 in small venules. Because macrophages usually transmigrate through postcapillary venules during inflammation, we wanted to explore the downstream effects of EphB4 after binding to ephrinB2. By using cDNA microarray technique and following reverse transcriptase–polymerase chain reaction (RT-PCR), we found that syntenin and syndecan-1 were up-regulated in EphB4-positive endothelial cells dose dependently and time dependently after stimulation with preclustered ephrinB2. In vitro, ephrinB2 suppressed the angiogenic effects of basic fibroblast growth factor (bFGF) on EphB4-positive endothelial cells, partially due to syndecan-1's competition with fibroblast growth factor receptor (FGFR) for bFGF. However, ephrinB2 exhibited angiogenic effects in vivo, possibly due to an inflammation-associated enzyme—heparanase. The enzymes could convert the inhibitory effect of ephrinB2 on EphB4-positive endothelial cells to an activating effect by removing poorly sulfated side chains of up-regulated syndecan-1 ectodomain. Depending on the presence of heparanases, the roles of syndecan-1 may be opposite in different physiological settings.
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Wu, Hsi-Chin, Chao-Hsiang Chang, Hsien-Yu Peng, Gin-Den Chen, Cheng-Yuang Lai, Ming-Chun Hsieh, and Tzer-Bin Lin. "EphrinB2 induces pelvic-urethra reflex potentiation via Src kinase-dependent tyrosine phosphorylation of NR2B." American Journal of Physiology-Renal Physiology 300, no. 2 (February 2011): F403—F411. http://dx.doi.org/10.1152/ajprenal.00520.2010.
Повний текст джерелаАнотація:
Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in pain-related neural plasticity at the spinal cord level have been identified. To test whether Src-family tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate pelvic-urethra reflex potentiation, we recorded external urethra sphincter electromyogram reflex activity and analyzed protein expression in the lumbosacral (L6-S2) dorsal horn in response to intrathecal ephrinB2 injections. When compared with vehicle solution, exogenous ephrinB2 (5 μg/rat it)-induced reflex potentiation, in associated with phosphorylation of EphB1/2, Src-family kinase, NR2B Y1336 and Y1472 tyrosine residues. Both intrathecal EphB1 and EphB2 immunoglobulin fusion protein (both 10 μg/rat it) prevented ephrinB2-dependent reflex potentiation, as well as protein phosphorylation. Pretreatment with PP2 (50 μM, 10 μl it), an Src-family kinase antagonist, reversed the reflex potentiation, as well as Src kinase and NR2B phosphorylation. Together, these results suggest the ephrinB2-dependent EphBR activation, which subsequently provokes Src kinase-mediated N-methyl-d-aspartate receptor NR2B phosphorylation in the lumbosacral dorsal horn, is crucial for the induction of spinal reflex potentiation contributing to the development of visceral pain and/or hyperalgesia in the pelvic area.
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Li, Lin, Na Xu, Xuan Zhou, Yuling Li, Qisi Lu, Ziyuan Lu, Jixian Huang, et al. "EphB4/EphrinB2 Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Involved in Cytoskeletal Proteins." Blood 126, no. 23 (December 3, 2015): 5135. http://dx.doi.org/10.1182/blood.v126.23.5135.5135.
Повний текст джерелаАнотація:
Abstract Background and Objective: Through the introduction ofthe tyrosine kinase inhibitor(TKI) significantly improves the prognosis, drug resistance is still a major obstacle to cure chronic myelogenous leukaemia (CML).Many documents have suggested aberrant activation of EphB4/ephrin B2 participate in imatinib-resistant CML patients but the role and mechanism have largely remained elusive. Our previous study found that Homoharringtonine overcome imatinib resistance by blocking the EphB4/RhoA pathway in K562. Then, we established IM resistance CML cell line (K562-R) and EphB4 knock down IM resistance CML cell line (K562-R-EphB4-sh). Furthermore, we performed the experiment to address the hypothesis that aberrant over expressed of EphB4 might play an important role in of Imatinib-resistant chronic myeloid leukemia cells. Methods and Results: EphB4 receptor was over expressed in CML -Blast Crisis (BC) patients and resistant cell lines by western blot (P <0.05) and mRNA(P <0.01).We evaluated the imatinib response in 22 CML-CP patients (400mg/d or 600mg/d).EphB4 mRNA levels in cancer cells correlated with the corresponding BCR-ABL transcript level of at 3 months in each case (y=24.461x-2.3491 R2 =0.8756, P<0.0001).These patients were then equally divided into two groups according to relative EphB4 mRNA median level (0.979217).The level of EphB4 receptor expression was significantly associated with 12-month CCyR(The 12-month CCyR rate in low EphB4 group was 72.7% VS36.3% in high EphB4 groups (P<0.01)).Cell invasive ability decreased in K562-R-EphB4-sh cells (K562-R13.56±2.70;K562-R-EphB4-sh 5.78±2.54 n=3) meanwhile cells restored sensitivity(IC50μM: K562-R 2.7621±0.0154; K562-R-EphB4-sh0.6908±0.0623; K562 0.1179±0.0379) to IM in vitro and in vivo (tumor volume after IM treatment (mm3):K562-R 2301.25±555.76; K562-R-EphB4-sh1630.16±412.01; K562 806.15±202.31);The apoptosis rate of K562-R-EphB4-sh (25.27±1.27)had been showed much higher than that ofK562-R (7.23±1.97). In addition, the proportion of cells in G0/G1 phase was significantly decreased in K562-R-EphB4-sh cells (13.58%)than K562-R( 29.30%), but higher than K562( 6.37%).When co-cultured cells with ephrinB2 ligand, restored sensitivity to IM was observed in K562-R cells( IC50μM : ephrinB2-Fc1.071±0.039; IgG-Fc2.697±0.145; Blank control 2.663±0.102), apoptosis rate (ephrin B2-Fc(42.72 ± 0.95) %;was higher than IgG Fc group (28.77 ± 1.64) % or the control group (28.93 ± 1.49) % (P <0.001) with group treated with IM (2.7 µg/ml, 24 hours), along with significantly increased level of phospho-EphB4 (450nm absorbance:ephrinB2-Fc0.920±0.031;IgG-Fc0.379±0.008; blank control0.381±0.005) and decreased phosphorylation level of cytoskeletal proteins RhoA, Rac1, Cdc42(P <0.05). Conclusion: Our study illustrated that aberrant activation EphB4/ EphrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins. Disclosures No relevant conflicts of interest to declare.
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Abéngozar, María Angeles, Sergio de Frutos, Sergio Ferreiro, Joaquím Soriano, Manuel Perez-Martinez, David Olmeda, Marco Marenchino, et al. "Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth." Blood 119, no. 19 (May 10, 2012): 4565–76. http://dx.doi.org/10.1182/blood-2011-09-380006.
Повний текст джерелаАнотація:
Abstract Membrane-anchored ephrinB2 and its receptor EphB4 are involved in the formation of blood and lymphatic vessels in normal and pathologic conditions. Eph/ephrin activation requires cell-cell interactions and leads to bidirectional signaling pathways in both ligand- and receptor-expressing cells. To investigate the functional consequences of blocking ephrinB2 activity, 2 highly specific human single-chain Fv (scFv) Ab fragments against ephrinB2 were generated and characterized. Both Ab fragments suppressed endothelial cell migration and tube formation in vitro in response to VEGF and provoked abnormal cell motility and actin cytoskeleton alterations in isolated endothelial cells. As only one of them (B11) competed for binding of ephrinB2 to EphB4, these data suggest an EphB-receptor–independent blocking mechanism. Anti-ephrinB2 therapy reduced VEGF-induced neovascularization in a mouse Matrigel plug assay. Moreover, systemic administration of ephrinB2-blocking Abs caused a drastic reduction in the number of blood and lymphatic vessels in xenografted mice and a concomitant reduction in tumor growth. Our results show for the first time that specific Ab-based ephrinB2 targeting may represent an effective therapeutic strategy to be used as an alternative or in combination with existing antiangiogenic drugs for treating patients with cancer and other angiogenesis-related diseases.
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Barneh, Farnaz, Mona Moshayedi, Hamid Mirmohammadsadeghi, Shaghayegh Haghjooy-Javanmard, Ali Mohammad Sabzghabaee, and Shirinsadat Badri. "EphB4 Tyrosine Kinase Stimulation Inhibits Growth of MDA-MB-231 Breast Cancer Cells in a Dose and Time Dependent Manner." Disease Markers 35 (2013): 933–38. http://dx.doi.org/10.1155/2013/857895.
Повний текст джерелаАнотація:
Background. EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc.Methods. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence.Results. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel.Conclusion. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.
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Pennisi, Angela, Wen Ling, Xin Li, Jianmei Chen, Sharmin Khan, and Shmuel Yaccoby. "The EphrinB2/EphB4 Axis Is Dysregulated in Osteoprogenitors from Myeloma Patients and Its Activation by EphrinB2-Fc or EhpB4-Fc Affects Myeloma Bone Disease and Tumor Growth in Vivo." Blood 112, no. 11 (November 16, 2008): 844. http://dx.doi.org/10.1182/blood.v112.11.844.844.
Повний текст джерелаАнотація:
Abstract Induction of osteolytic bone lesions in myeloma (MM) is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Recent studies indicate that in addition to role in cell adhesion, repulsion and neovascularization, bidirectional signaling between the cell surface molecules EphrinB2 and EphB4 also mediates the coupling between osteoblasts and osteoblasts. While mesenchymal stem cells (MSCs) and osteoblasts express the ligand EphrinB2 land its receptor, EphB4, osteoclasts and their precursors mainly express EphrinB2. Forward signaling in MSCs promotes osteogenic differentiation and reverse signaling in osteoclast precursors inhibits their differentiation. The aims of the study were to investigate whether the EphrinB2/Eph4 axis is dysregulated in MM osteoprogenitors and whether activation of this axis in myelomatous bone by EphrinB2-Fc or EphB4-Fc affects MM bone disease, angiogenesis and tumor growth. MSCs were generated from bone marrow of healthy donors (n=5) and patients with MM (n=13). Gene expression was determined by qRT-PCR. MSCs from MM patients had reduced expression of EphrinB2 (EFNB2) by 61±6% (p<0.02) and EphB4 by 60±10% (p<0.02) than expression levels of these molecules in MSCs from healthy donors. Expression of other EFN and EPH B genes were detected and similarly expressed in patients and donors MSCs. Differentiation of MSCs from MM patients into osteoblasts resulted in upregulation of EFNB2 and downregulation of EPHB4. MM cell lines and primary MM plasma cells expressed low to undetectable levels of this family of genes. We exploited our SCID-hu system for primary MM to study the consequences of activation of forward signaling by EphrinB2-Fc or reverse signaling by EphB4-Fc on MM-induced bone disease and MM growth. Twelve SCID-hu mice were engrafted with MM cells from a patient with active MM. Upon detection of MM growth (by human Ig ELISA) and bone disease (radiographically), hosts were locally treated with Fc (control), EphrinB2-Fc or EPHB4 (4 mice/group) for 4 weeks using Alzet pump that continually released 0.11 μg/hour of each compound. While in Fc-treated hosts BMD of the implanted bone was reduced by 8±3% from pretreatment levels, it was increased by EphrinB2-Fc and EPhB4-Fc by 15±8% (p<0.03 vs. Fc) and 2±1% (p<0.02 vs. Fc) from pretreatment levels, respectively. At experiment’s end levels of human Ig in mice sera were increased by 308±99% and 244±86% from pretreatment levels in Fc- and EphrinB2- Fc groups, respectively, while were reduced by 92±1% (p<0.02 vs. Fc) from pretreatment levels in EphB4-Fc group. In myelomatous bones, EphB4-Fc and EphrinB2-Fc increased the numbers of osteoblasts by >3 folds (p<0.004) while EphB4-Fc, but not EphrinB2-Fc, reduced osteoclast numbers by 5 folds (p<0.01 vs. Fc group). The numbers of CD34-reactive neovessels were reduced by 2 folds following treatment with EphB4-Fc (p<0.03) and were increased by 2.5 folds following treatment with EphrinB2-Fc (p<0.05). Our study suggests that downregulation of EphrinB2 and EhpB4 in MSCs from MM patients contributes to their impaired osteogenic differentiation and that treatment with EphrinB2-Fc or EphB4-Fc helps restore coupling of bone remodeling in myelomatous bones. The results also indicate that EphB4-Fc treatment is an effective approach to simultaneously inhibit MM and its associated bone disease.
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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.
Повний текст джерелаАнотація:
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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Renuse, Santosh, Vijay S. Madamsetty, Dong-Gi Mun, Anil K. Madugundu, Smrita Singh, Savita Udainiya, Kiran K. Mangalaparthi, et al. "Tyrosine Phosphoproteomics of Patient-Derived Xenografts Reveals Ephrin Type-B Receptor 4 Tyrosine Kinase as a Therapeutic Target in Pancreatic Cancer." Cancers 13, no. 14 (July 7, 2021): 3404. http://dx.doi.org/10.3390/cancers13143404.
Повний текст джерелаАнотація:
Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, the discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in the treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in mice serve as potentially valuable preclinical models as they maintain the histological and molecular heterogeneity of the original human tumor. Here, we employed high-resolution mass spectrometry combined with immunoaffinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in the identification of 1199 tyrosine-phosphorylated sites mapping to 704 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Preclinical studies confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.
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de Saint-Vis, Blandine, Caroline Bouchet, Grégory Gautier, Jenny Valladeau, Christophe Caux, and Pierre Garrone. "Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin." Blood 102, no. 13 (December 15, 2003): 4431–40. http://dx.doi.org/10.1182/blood-2003-02-0500.
Повний текст джерелаАнотація:
AbstractEph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34+ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. EphB3 was specifically expressed by Langerhans cells, and EphA2 and EphA7 were expressed by both Langerhans- and interstitial-type DCs. EphA and EphB protein expression on DCs generated in vitro was confirmed by staining with ephrin-A3-Fc and ephrin-B3-Fc fusion proteins that bind to different Eph members, in particular EphA2 and EphB3. Immunostaining with anti-EphA2 antibodies demonstrated the expression of EphA2 by immature DCs and by skin Langerhans cells isolated ex vivo. Interestingly, ephrin expression was detected in epidermal keratinocytes and also in DCs. Adhesion of CD34+-derived DCs to fibronectin, but not to poly-l-lysine, was increased in the presence of ephrin-A3-Fc, a ligand of EphA2, through a β1 integrin activation pathway. As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking. (Blood. 2003;102:4431-4440)
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de Muijnck, Cansu, Yoren van Gorkom, Maurice van Duijvenvoorde, Mina Eghtesadi, Geeske Dekker-Ensink, Shadhvi S. Bhairosingh, Alessandra Affinito, Peter J. K. Kuppen, Alexander L. Vahrmeijer, and Cornelis F. M. Sier. "Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer." Pharmaceuticals 13, no. 8 (July 30, 2020): 172. http://dx.doi.org/10.3390/ph13080172.
Повний текст джерелаАнотація:
Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible targets for image-guided surgery of breast cancer, with mixed results. Methods: In this study we have evaluated tyrosine kinase receptor EphB4, a member from the Eph tyrosine kinase receptor family, as a possible target for image-guided surgery of breast cancers. Two independent tissue micro arrays, consisting of matched sets of tumor and normal breast tissue, were stained for EphB4 by immunohistochemistry. The intensity of staining and the percentage of stained cells were scored by two independent investigators. Results: Immunohistochemical staining for EphB4 shows that breast cancer cells display enhanced membranous expression compared to adjacent normal breast tissue. The enhanced tumor staining is not associated with clinical variables like age of the patient or stage or subtype of the tumor, including Her2-status. Conclusion: These data suggest that EphB4 is a promising candidate for targeted image-guided surgery of breast cancer, especially for Her2 negative cases.
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Gong, T., J. Xu, B. Heng, S. Qiu, B. Yi, Y. Han, E. C. M. Lo, and C. Zhang. "EphrinB2/EphB4 Signaling Regulates DPSCs to Induce Sprouting Angiogenesis of Endothelial Cells." Journal of Dental Research 98, no. 7 (April 24, 2019): 803–12. http://dx.doi.org/10.1177/0022034519843886.
Повний текст джерелаАнотація:
Dental pulp stem cells (DPSCs) are capable of facilitating angiogenesis resembling pericytes when located adjacent to endothelial cells (ECs). Nevertheless, the precise mechanisms orchestrating their proangiogenic functions remain unclear. Using a 3-dimensional (3-D) fibrin gel model, we aimed to investigate whether EphrinB2/EphB4 signaling in DPSCs plays a role in supporting vascular morphogenesis mediated by ECs, together with the underlying mechanism involved. The EphrinB2/EphB4 signaling was inhibited either by a pharmacological inhibitor of EphB4 receptor or by knocking down the expressions of EphrinB2 and EphB4 using lentiviral small hairpin RNA (shRNA). DPSCs were either encapsulated in fibrin gel together with human umbilical vein endothelial cells (HUVECs) or cultured as a monolayer on top of HUVECs to investigate both paracrine and juxtacrine interactions simultaneously. Following 10 d of direct coculture, we found that pharmacological inhibition of EphrinB2/EphB4 signaling severely impaired vessel formation and laminin deposition. When directly cocultured with HUVECs, knockdown of EphrinB2 or EphB4 in DPSCs significantly inhibited endothelial sprouting, resulting in less capillary sprouts with reduced vessel length ( P < 0.05). By contrast, when DPSCs were not in direct contact with HUVECs, attenuation of EphrinB2 or EphB4 expression levels in DPSCs did not exert any significant effects on capillary morphogenesis. Noticeably, exogenous stimulation with soluble EphrinB2-Fc or EphB4-Fc (1 µg/mL) enhanced vascular endothelial growth factor (VEGF) secretion from DPSCs, thereby moderately promoting angiogenic cascades in the fibrin matrix. This study, for the first time, reveals a crucial role of EphrinB2/EphB4 signaling in regulating the capacity of DPSCs to induce sprouting angiogenesis. These findings advance our understanding of postnatal angiogenesis and may have future regenerative medicine applications.
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Fehnel, Katie Pricola, David L. Penn, Micah Duggins-Warf, Maxwell Gruber, Steven Pineda, Julie Sesen, Alexander Moses-Gardner, et al. "Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients." Experimental & Molecular Medicine 52, no. 4 (April 2020): 658–71. http://dx.doi.org/10.1038/s12276-020-0414-0.
Повний текст джерелаАнотація:
Abstract We investigated (1) EphrinB2 and EphB4 receptor expression in cerebral AVMs, (2) the impact of an altered EphrinB2:EphB4 ratio on brain endothelial cell function and (3) potential translational applications of these data. The following parameters were compared between AVM endothelial cells (AVMECs) and human brain microvascular endothelial cells (HBMVECs): quantified EphrinB2 and EphB4 expression, angiogenic potential, and responses to manipulation of the EphrinB2:EphB4 ratio via pharmacologic stimulation/inhibition. To investigate the clinical relevance of these in vitro data, Ephrin expression was assessed in AVM tissue (by immunohistochemistry) and urine (by ELISA) from pediatric patients with AVM (n = 30), other cerebrovascular disease (n = 14) and control patients (n = 29), and the data were subjected to univariate and multivariate statistical analyses. Compared to HBMVECs, AVMECs demonstrated increased invasion (p = 0.04) and migration (p = 0.08), impaired tube formation (p = 0.06) and increased EphrinB2:EphB4 ratios. Altering the EphrinB2:EphB4 ratio (by increasing EphrinB2 or blocking EphB4) in HBMVECs increased invasion (p = 0.03 and p < 0.05, respectively). EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients. Using the optimal urinary cutoff value (EphrinB2 > 25.7 pg/μg), AVMs were detected with high accuracy (80% vs. controls) and were distinguished from other cerebrovascular disease (75% accuracy). Post-treatment urinary EphrinB2 levels normalized in an index patient. In summary, AVMECs have an EphrinB2:EphB4 ratio that is increased compared to that of normal HBMVECs. Changing this ratio in HBMVECs induces AVMEC-like behavior. EphrinB2 is clinically relevant, and its levels are increased in AVM tissue and patient urine. This work suggests that dysregulation of the EphrinB2:EphB4 signaling cascade and increases in EphrinB2 may play a role in AVM development, with potential utility as a diagnostic and therapeutic target.
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Scalia, Pierluigi, Stephen J. Williams, and Antonio Giordano. "Core Element Cloning, Cis-Element Mapping and Serum Regulation of the Human EphB4 Promoter: A Novel TATA-Less Inr/MTE/DPE-Like Regulated Gene." Genes 10, no. 12 (December 2, 2019): 997. http://dx.doi.org/10.3390/genes10120997.
Повний текст джерелаАнотація:
The EphB4 gene encodes for a transmembrane tyrosine kinase receptor involved in embryonic blood vessel differentiation and cancer development. Although EphB4 is known to be regulated at the post-translational level, little is known about its gene regulation. The present study describes the core promoter elements’ identification and cloning, the cis-regulatory elements’ mapping and the serum regulation of the human EphB4 gene promoter region. Using bioinformatic analysis, Sanger sequencing and recombinant DNA technology, we analyzed the EphB4 gene upstream region spanning +40/−1509 from the actual transcription start site (TSS) and proved it to be a TATA-less gene promoter with dispersed regulatory elements characterized by a novel motif-of-ten element (MTE) at positions +18/+28, and a DPE-like motif and a DPE-like-repeated motif (DRM) spanning nt +27/+30 and +32 +35, respectively. We also mapped both proximal (multiple Sp1) and distal (HoxA9) trans-activating/dispersed cis-acting transcription factor (TF)-binding elements on the region we studied and used a transient transfection reporter assay to characterize its regulation by serum and IGF-II using EphB4 promoter deletion constructs with or without the identified new DNA-binding elements. Altogether, these findings shed new light on the human EphB4 promoter structure and regulation, suggesting mechanistic features conserved among Pol-II TATA-less genes phylogenetically shared from Drosophila to Human genomes.
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Qingfeng, DU, Xu Lulu, Zhang Jinfang, Xu Na, Huang Bintao, Luo Xujing, Xiao Xiaozhen, and Liu Xiaoli. "EphB4 Expression and Biological Significance in Drug Resistance of Myeloid Leukemia." Blood 118, no. 21 (November 18, 2011): 4725. http://dx.doi.org/10.1182/blood.v118.21.4725.4725.
Повний текст джерелаАнотація:
Abstract Abstract 4725 Chemotherapy is widely used in treatment of myeloid leukemia, the efficancy of which, however, is often hampered by the development of intrinsic and acquired multidrug resistance(MDR), the exact mechanism of which is still unclear. Overexpression and deregulated activation of protein tyrosine kinase(PTK) are frequently observed in several types of hematologic malignancies, the abnormally signal cascade transducted by which has been demonstrated to play an important role in antiapoptosis, differentiation block, enhancing autonomous proliferation, and also in inducing drug resistance. EphB4 is also a protein tyrosine kinase, a member of the largest family of receptor tyrosine kinase, which has been found with abnormally upregulated expression or activity in many types of cancer especially solid tumor types, such as mammary adenocarcinoma, colon carcinoma, ovarian cancer and prostatic carcinoma. Here the aim of our study was to examine the expression and biological role of EphB4 in drug resistance of myeloid leukemia. Using RT-PCR assay and western blot, we tested the mRNA level in 35 myeloid leukemia patients including 4 cases of acute myeloid leukemia(AML) with primary multiple drug-resistance(MDR), 3 cases of AML which have relapsed, 5 cases of newly diagnosed AML, 5 cases of AML which got (complete remission) CR at the first chemotherapy treatment, 9 cases of chronic myeloid leukemia in chronic phase(CML-CP), and 9 cases of CML in blast crisis(CML-BC). The results showed the EphB4 mRNA level was significantly upregulated in AML bearing relapse(EphB4/β-actin ratio:0.962±0.114) or MDR(EphB4/β-actin ratio: 0.993±0.047) and also in CML-BC(EphB4/β-actin ratio: 1.001±0.060) compared with newly diagnosed AML(EphB4/β-actin ratio: 0.332±0.014), AML with CR(EphB4/β-actin ratio:0.401±0.015) and CML-CP(EphB4/β-actin ratio: 0.432±0.020). Subsequently, we examined both the transcriptional and translational level of EphB4 in several myeloid leukemia cell lines including K562, HL60,U937,KG1α and an adriamycin-resistant cell line—HL60/ADM, and drug-resistant capacity of the five cell lines was also tested by CCK-8 assay. Finally EphB4 protein expression is found to be upregulated at both transcriptional and translational level in K562, KG1αand HL60/ADM, which showed stronger capacity of resistance to gradient concentrations of adriamycin(IC50 of K562:0.451±0.037ug/ml,KG1α:0.217±0.017ug/ml, HL60/ADM: 2.663±0.102ug/ml) compared with that of HL60 and U937(IC50 of HL60:0.040±0.001ug/ml, U937:0.040±0.005ug/ml) in which little or no expression of EphB4 mRNA or protein was observed. And the most noteworthy is that HL60/ADM, which shows the strongest drug resistant capability. also bears the most amount of EphB4 at both transcriptional level (EphB4 /β-actin ratio: 1.002±0.017), and translational level (EphB4 /β-actin ratio: 0.975±0.051). These data supports a role for EphB4 in inducing drug resistance and raise the possibility that therapeutic intervention to EphB4 expression or signaling might inhibit or even reverse drug resistande in meyloid leukemia. Disclosures: No relevant conflicts of interest to declare.
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Masood, Rizwan, Guangbin Xia, D. Lynne Smith, Piergips Scalia, Jonathan G. Still, Anil Tulpule, and Parkash S. Gill. "Ephrin B2 expression in Kaposi sarcoma is induced by human herpesvirus type 8: phenotype switch from venous to arterial endothelium." Blood 105, no. 3 (February 1, 2005): 1310–18. http://dx.doi.org/10.1182/blood-2004-03-0933.
Повний текст джерелаАнотація:
Abstract Kaposi sarcoma (KS) is an angioproliferative tumor derived from endothelial cells in which tumor cells form aberrant vascular structures. Ephrin B2 and ephrin B4 (EphB4) are artery- and vein-specific proteins, respectively, with critical roles in vessel maturation. We investigated whether the disorganized KS vasculature was due to unbalanced expression of ephrin B2 and EphB4. Secondly, we wished to determine if human herpesvirus type 8 (HHV-8), the viral agent associated with KS, regulates ephrin B2 and EphB4. An arterial phenotype was observed in KS tissue and cell lines, as shown by abundant expression of ephrin B2 with little or no EphB4. Infection of venous endothelial cells with HHV-8 resulted in a phenotype switch from EphB4 to ephrin B2, similar to that seen with vascular endothelial growth factor (VEGF). The HHV-8 effect on ephrin B2 expression was reproduced with the HHV-8-specific viral G-protein-coupled receptor. We also showed that ephrin B2 expression is required for KS cell viability by knock down with siRNA. KS is the first example of a human tumor with a predominantly arterial phenotype. This predominance can be attributed to expression of HHV-8 proteins and their downstream effects. Ephrin B2 is thus an important novel factor in KS biology and a potential target for therapy.
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Burns, Michael C., Vinay Sagar, Borko Jovanovic, Alicia K. Morgans, David James VanderWeele, David I. Quinn, Walter Michael Stadler, Sarki Abdulkadir, and Maha H. A. Hussain. "A phase II study of sEphB4-HSA in metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): TPS274. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.tps274.
Повний текст джерелаАнотація:
TPS274 Background: The EphB4/EphrinB2 pathway is a promising therapeutic target for patients with mCRPC. EphB4 expression is increased in prostate cancer tissue and cell lines, and retained in castration resistant states. EphB4 crosstalks with the PI3K/AKT and MAPK pathways to regulate cell survival and proliferation, and its interaction with the transmembrane ligand EphrinB2 leads to T-cell suppression and immune evasion. A soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) binds to EphrinB2 and blocks interaction with the cell surface EphB4 receptor to promote immune infiltration and induce tumor cell death. Here we report an ongoing phase II study exploring the preliminary efficacy and safety of sEphB4-HSA in patients with progressive disease after frontline therapy for mCRPC. Methods: Eligibility criteria include mCRPC with disease progression after second generation AR targeted therapy (i.e., abiraterone or enzalutamide), ECOG PS ≤ 2, and adequate renal, hepatic and hematological functions. Pts having received 4 or more prior treatment therapies for mCRPC are excluded. The primary objective is efficacy as reflected by PSA response using PCWG3 criteria. Secondary objectives include safety and tolerability by CTCAE v 5.0, time to PSA progression, overall response by RECIST 1.1 and PCWG3 (bone) criteria, and rPFS. Translational endpoints include expression of EphB4 and EphrinB2 in metastatic tumor samples by immunohistochemistry and correlation with alterations in MYC, PTEN/PI3K, AR, and p53 pathways. sEphB4-HSA is administered as IV infusion over 60 min every 14 days with spacing to every 21 days after 6 cycles. Therapy will continue till disease progression, unacceptable toxicity, treatment delay ≥4 weeks, or patient withdrawal. Preliminary efficacy will be assessed using PSA response rate (PR and CR) with a Simon two stage minimax trial design assuming the undesirable overall response rate (null hypothesis) to be approximately 10% or less, and the alternate hypothesis suggesting success to be approximately 30% or more. Toxicity will be evaluated by the DSMC after the first stage including 15 patients. If 2 or more respond, then an additional 10 patients will be added. Clinical trial information: NCT04033432.
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Chen, Yinnan, Hongmei Zhang, and Yanmin Zhang. "Targeting receptor tyrosine kinase EphB4 in cancer therapy." Seminars in Cancer Biology 56 (June 2019): 37–46. http://dx.doi.org/10.1016/j.semcancer.2017.10.002.
Повний текст джерела
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Piffko, Andras, Christian Uhl, Peter Vajkoczy, Marcus Czabanka, and Thomas Broggini. "EphrinB2–EphB4 Signaling in Neurooncological Disease." International Journal of Molecular Sciences 23, no. 3 (January 31, 2022): 1679. http://dx.doi.org/10.3390/ijms23031679.
Повний текст джерелаАнотація:
EphrinB2–EphB4 signaling is critical during embryogenesis for cardiovascular formation and neuronal guidance. Intriguingly, critical expression patterns have been discovered in cancer pathologies over the last two decades. Multiple connections to tumor migration, growth, angiogenesis, apoptosis, and metastasis have been identified in vitro and in vivo. However, the molecular signaling pathways are manifold and signaling of the EphB4 receptor or the ephrinB2 ligand is cancer type specific. Here we explore the impact of these signaling pathways in neurooncological disease, including glioma, brain metastasis, and spinal bone metastasis. We identify potential downstream pathways that mediate cancer suppression or progression and seek to understand it´s role in antiangiogenic therapy resistance in glioma. Despite the Janus-faced functions of ephrinB2–EphB4 signaling in cancer Eph signaling remains a promising clinical target.
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Noren, Nicole K., and Elena B. Pasquale. "Paradoxes of the EphB4 Receptor in Cancer: Figure 1." Cancer Research 67, no. 9 (May 1, 2007): 3994–97. http://dx.doi.org/10.1158/0008-5472.can-07-0525.
Повний текст джерела