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  • DKFZ Publication Database  (8)
  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; tumor ; CELL ; Germany ; IN-VIVO ; VIVO ; DISEASE ; DISTINCT ; DIFFERENTIATION ; ACTIVATION ; LIGAND ; MECHANISM ; MARKER ; CONTRAST ; mechanisms ; culture ; MUSCLE ; SMOOTH-MUSCLE CELLS ; T-LYMPHOCYTES ; BODY ; REGULATOR ; VEGF ; CELL-DIFFERENTIATION ; JUNCTIONS ; RE ; endothelial cells ; cell differentiation ; neovascularization ; in vivo ; ENDOTHELIAL-CELL ; regulatory mechanism ; VASCULAR MORPHOGENESIS ; JUNCTION ; CONTACT ; ARTERIAL-VENOUS DIFFERENTIATION ; CARDIOVASCULAR DEVELOPMENT ; EPH ; SMOOTH-MUSCLE-CELLS ; EphB4 ; ephrinB2 ; smooth muscle cells
    Abstract: Objective-The EphB ligand ephrinB2 has been identified as a critical determinant of arterial endothelial differentiation and as a positive regulator of invading endothelial cells during angiogenesis. This study was aimed at identifying determinants of endothelial cell ephrinB2 expression. Methods and Results-Arteriovenous asymmetrical endothelial cell ephrinB2 expression in vivo is lost on transfer into culture with aortic endothelial cells becoming partially ephrinB2-negative and saphenous vein endothelial cells becoming partially ephrinB2-positive. Contact with smooth muscle cells and angiogenic stimulation by vascular endothelial growth factor lead to an increased endothelial cell ephrinB2 expression. Quiescent, smooth muscle-contacting endothelial cells express ephrinB2 uniformly on their luminal surface. In contrast, monolayer endothelial cells translocate ephrinB2 to interendothelial cell junctions, which is strongly enhanced by EphB4-Fc-mediated receptor body activationed. Junctional ephrinB2 colocalizes and coimmunoprecipitates with CD31. Conclusions-This study identifies distinct regulatory mechanisms of endothelial ephrinB2 expression and cellular distribution in quiescent and activated endothelial cells. The data demonstrate that endothelial cell ephrinB2 expression is controlled by microenvironmental determinants rather than being an intrinsic endothelial cell differentiation marker
    Type of Publication: Journal article published
    PubMed ID: 16357318
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  • 2
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; CELL ; Germany ; MICROSCOPY ; MOLECULES ; COMPLEX ; LIGAND ; COMPLEXES ; FLOW ; BIOLOGY ; MOLECULE ; antibodies ; antibody ; ADHESION ; RECRUITMENT ; leukocyte ; INTERFACE ; ATOMIC-FORCE MICROSCOPY ; CELL-SURFACE ; RECEPTORS ; SMOOTH-MUSCLE ; RE ; TUMOR-GROWTH ; endothelial cells ; interaction ; TYROSINE KINASES ; EVENTS ; ENGLAND ; endothelium ; VASCULAR MORPHOGENESIS ; CARDIOVASCULAR DEVELOPMENT ; NOV ; FULL-LENGTH ; interactions ; CELL BIOLOGY ; transmigration ; EphB4 receptor ; Ephrin-B2 ligand ; MOLECULAR DISTINCTION ; SH2 DOMAIN
    Abstract: The vascular endothelium is a crucial interface that controls the recruitment of circulating leukocytes. Based on the luminal expression of the ephrin-B2 ligand by endothelial cells (ECs) and the expression of EphB receptors (EphBRs) by circulating monocytes, we hypothesized that EphBR-ephrinB interactions are involved in monocyte adhesion. Adhesion experiments with monocytic cells were performed on ECs that overexpressed either full-length ephrin-B2 or cytoplasmically truncated ephrin-B2 (Delta C-ephrin-B2). Atomic force microscopy confirmed similar adhesive strengths of EphBR-expressing J774 cells to ECs that either overexpressed full-length ephrin-B2 or truncated Delta C-ephrin-B2 (1-minute interaction). Yet, adhesion experiments under static or flow conditions for 30 minutes demonstrated the preferential adhesion of monocytic cells to ECs that overexpressed full-length ephrin-B2 but not to Delta C-ephrin-B2 or to ECs that had been mock transduced. Adhesion was blocked by ephrin-B2-specific and EphBR-specific antibodies. Correspondingly, adhesion of EphB4-receptor-overexpressing monocytes to ephrin-B2-positive ECs was further augmented. Trafficking experiments of cell-surface molecules revealed that, prior to internalization, the resulting EphB4-receptor-ephrin-B2 complex translocated from the luminal surface to inter-endothelial junctions. Lastly, full-length ephrin-B2 in ECs was also involved in monocyte transmigration. Collectively, our study identifies a role of EphBR-ephrinB interactions as a new step in the cascade of events leading to monocyte adhesion and transmigration through the vascular endothelium
    Type of Publication: Journal article published
    PubMed ID: 18957513
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  • 3
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; IN-VIVO ; INHIBITION ; MIGRATION ; ADHESION MOLECULE ; MORPHOGENESIS ; RECEPTOR-TYROSINE KINASE ; BREAST-CANCER METASTASIS ; LUNG METASTASIS
    Abstract: The tyrosine kinase receptor EphB4 interacts with its ephrinB2 ligand to act as a bidirectional signaling system that mediates adhesion, migration, and guidance by controlling attractive and repulsive activities. Recent findings have shown that hematopoietic cells expressing EphB4 exert adhesive functions towards endothelial cells expressing ephrinB2. We therefore hypothesized that EphB4/ephrinB2 interactions may be involved in the preferential adhesion of EphB4-expressing tumor cells to ephrinB2-expressing endothelial cells. Screening of a panel of human tumor cell lines identified EphB4 expression in nearly all analyzed tumor cell lines. Human A375 melanoma cells engineered to express either full-length EphB4 or truncated EphB4 variants which lack the cytoplasmic catalytic domain (Delta C-EphB4) adhered preferentially to ephrinB2-expressing endothelial cells. Force spectroscopy by atomic force microscopy confirmed, on the single cell level, the rapid and direct adhesive interaction between EphB4 and ephrinB2. Tumor cell trafficking experiments in vivo using sensitive luciferase detection techniques revealed significantly more EphB4-expressing A375 cells but not Delta C-EphB4-expressing or mock-transduced control cells in the lungs, the liver, and the kidneys. Correspondingly, ephrinB2 expression was detected in the microvessels of these organs. The specificity of the EphB4-mediated tumor homing phenotype was validated by blocking the EphB4/ephrinB2 interaction with soluble EphB4-Fc. Taken together, these experiments identify adhesive EphB4/ephrinB2 interactions between tumor cells and endothelial cells as a mechanism for the site-specific metastatic dissemination of tumor cells.
    Type of Publication: Journal article published
    PubMed ID: 21047731
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  • 4
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; THERAPY ; TYROSINE KINASE ; SYSTEM ; SYSTEMS ; PROTEIN ; MOLECULES ; LIGAND ; FAMILY ; BLOOD-FLOW ; DENDRITIC CELLS ; blood flow ; FLOW ; DOWN-REGULATION ; FIELD ; MOLECULE ; METASTASIS ; TRAFFICKING ; ADHESION ; RECEPTORS ; ESTABLISHMENT ; VESSELS ; REGULATOR ; PERMEABILITY ; VEGF ; signaling ; RE ; FAMILIES ; GUIDANCE ; assembly ; TYROSINE KINASES ; ROLES ; function ; ENDOTHELIAL-CELL ; endothelium ; receptor tyrosine kinase ; TIE2 ; VASCULAR MORPHOGENESIS ; CARDIOVASCULAR DEVELOPMENT ; EPH RECEPTOR ; RECEPTOR TYROSINE KINASES ; VASCULAR-PERMEABILITY ; LIGAND ANGIOPOIETIN-2 ; NEURAL DEVELOPMENT ; TUMOR ENDOTHELIUM
    Abstract: Vascular receptor tyrosine kinases (RTK) have been identified as critical regulatory signaling molecules of developmental and adult vascular morphogenic processes [vascular endothelial growth factor (VEGF) receptors=sprouting; EphB receptors=assembly; Tie2 receptor=maturation and quiescence]. It is intriguing that the same molecules that control the growth of blood and lymphatic vessels play critical roles in the adult to regulate maintenance functions related to vascular homeostasis. VEGF is among the most potent inducers of vascular permeability. The second vascular RTK system, the interaction of paracrine-acting Angiopoietin-1 with its cognate receptor Tie2, acts as an endothelial maintenance and survival-mediating molecular system, which stabilizes the vessel wall and controls endothelial cell quiescence. The third vascular RTK system, the interaction of Eph receptors with their Eph family receptor-interacting protein (ephrin) ligands, transduces positional guidance cues on outgrowing vascular sprouts, which are critical for proper arteriovenous assembly and establishment of blood flow. As such, Eph-ephrin interactions act as an important regulator of cell-cell interactions, exerting propulsive and repulsive functions on neighboring cells and mediating adhesive functions. This review summarizes recent findings related to the roles of the Angiopoietin-Tie and the Eph-ephrin systems as regulators of cell trafficking in the vascular system. The recognition of vascular homeostatic functions of vascular RTKs marks an important change of paradigm in the field of angiogenesis research as it relates angiogenesis-inducing molecules to vascular maintenance functions in the adult. This may also broaden the scope of vascular RTK-targeted therapies. J. Leukoc. Biol. 80: 719-726;2006
    Type of Publication: Journal article published
    PubMed ID: 16864601
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  • 5
    Abstract: The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to maintain glycemia below the diabetes definition threshold (HbA1c 〈 6.5%) still develop diabetic complications. This suggests additional insulin- and glucose-independent mechanisms could be involved in T2D progression and/or initiation. T2D patients have elevated levels of the metabolite methylglyoxal (MG). We show here, using Drosophila glyoxalase 1 knockouts, that animals with elevated methylglyoxal recapitulate several core aspects of T2D: insulin resistance, obesity, and hyperglycemia. Thus elevated MG could constitute one root cause of T2D, suggesting that the molecular causes of elevated MG warrant further study.
    Type of Publication: Journal article published
    PubMed ID: 29551588
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  • 6
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; VIVO ; SITE ; SITES ; PROTEIN ; TISSUE ; TUMORS ; MICE ; COMPLEX ; LIGAND ; MECHANISM ; MARKER ; TISSUES ; mechanisms ; BINDING ; BIOLOGY ; fibroblasts ; MOLECULAR-BIOLOGY ; GLYCOPROTEIN ; NO ; PROGRESSION ; PATTERNS ; EXPRESSION ANALYSIS ; UP-REGULATION ; TUMOR PROGRESSION ; METASTASIS ; EXTRACELLULAR-MATRIX ; ADHESION ; CELL-ADHESION ; LIGANDS ; NORMAL TISSUE ; MOLECULAR-CLONING ; molecular biology ; molecular ; PATTERN ; fibroblast ; analysis ; USA ; FRAGMENT ; tumor stroma ; endothelium ; host ; outcome ; interactions ; CELL BIOLOGY ; PARTNER ; activated fibroblasts ; C-ASSOCIATED PROTEIN ; CYCLOPHILIN-C ; MAC-2-BINDING PROTEIN ; mural cells ; PERICYTES ; STROMAL FIBROBLASTS
    Abstract: Tumor development involves complex bidirectional interactions between tumor cells and host stromal cells. Endosialin (Tem1) has been identified as a highly O-glycosylated transmembrane glycoprotein, which is specifically expressed by tumor vessel-associated pericytes and stromal fibroblasts of a wide range of human tumors. Recent experiments in endosialin-deficient mice have unraveled a critical role of endosialin in site-specific tumor progression and metastasis. To molecularly understand the mechanisms of endosialin function, we aimed to identify extracellular endosialin ligands and identified Mac-2 BP/90K as a specific interaction partner. Detailed biochemical analyses identified a C-terminal fragment of Mac-2 BP/90K, which was shown to contain binding sites for galectin- 3, and collagens as the structures responsible for endosialin binding. Subsequent expression analysis of Mac-2 BP/90K in vivo revealed weak or no expression in most normal tissues and strong up-regulation in tumor cells of human neoplastic tissues. Intriguingly, the expression patterns of Mac-2 BP/90K and endosialin were mutually exclusive in all human tissues. Correspondingly, loss-of-function adhesion experiments of Mac-2 BP/90K-expressing tumor cells on endosialin-expressing fibroblasts revealed a repulsive outcome of the Mac-2 BP/90K interaction. Taken together, the experiments identify a novel repulsive interaction between endosialin on stromal fibroblasts and Mac-2 BP/90K on tumor cells
    Type of Publication: Journal article published
    PubMed ID: 18490383
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  • 7
    Keywords: ACTIVATION, ADULT, ANGIOGENESIS, ARTERY, ARTERY GROWTH ARTERIOGENESIS, BLOOD, CARDIOVASCULAR DEVELOP
    Abstract: Expression of the arterial marker molecule ephrinB2 in endothelial cells is a prerequisite for adequate remodeling processes of the developing or angiogenic vasculature. Although its role in these processes has been extensively studied, the impact of ephrinB2 on the remodeling of adult arteries is largely unknown. To this end, we analyzed its expression during a biomechanically induced arteriolar remodeling process known as arteriogenesis and noted a significant increase in ephrinB2 expression under these conditions. By examining those biomechanical forces presumed to drive arteriogenesis, we identified cyclic stretch as a critical inducer of ephrinB2 expression in endothelial cells. Subsequent functional analyses in vitro revealed that endothelial cells expressing ephrinB2 limit the migration of smooth muscle cells, thereby enhancing segregation of both cell types. Moreover, MCP-1 induced transmigration of monocytes through a monolayer of endothelial cells overexpressing a truncated variant of ephrinB2 was clearly impeded. Taken together, these data suggest that expression of ephrinB2 in adult endothelial cells is upregulated during arterial remodeling and controlled by cyclic stretch, a well-known inducer of such processes. This stretch-induced ephrinB2 expression may be pivotal for arteriogenesis as it limits smooth muscle cell migration within defined borders and controls monocyte extravasation
    Type of Publication: Journal article published
    PubMed ID: 18445690
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  • 8
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