Ephrin b2 and its receptor ephb4 were first discovered to play a role in arterial vein specification and angiogenic remodeling during embryonic development. One clone, encoding human ephrin b2 efnb2, was found capable of rendering helausu cells permissive for hev and nivmediated cell fusion as well as infection by live virus. The involvement of ephrinb2 in a range of physiological systems has been described, including vascular, lymphatic, neuronal, and renal development, neurotransmission, synaptic plasticity, and tumor metastasis. All ligands share a conserved extracellular sequence, which most likely corresponds to the receptor binding domain. Diabetic ephrinb2stimulated peripheral blood mononuclear. Ephrinb2 ligand is a functional receptor for hendra virus.
Our results indicate that the role of ephrin b2 and ephb receptors in these processes involves crkpcas signaling and suggest that ephrin b2 has some cellcellcontactindependent. Author summary the activity of proteins can be finely and reversibly tuned by posttranslational modifications. Ephrin b2 is a transmembrane ligand that is specifically expressed on arteries but not veins and that is essential for cardiovascular development. Identification of ephrin b2 and ephrin b3 as hostcell receptors. Ephrins are naturally divided into two structural groups. The present study investigated ephrin b2 as a prognostic factor and therapeutic target for gastric cancer. Following binding of an ephrin ligand to the extracellular globular domain of an eph receptor, tyrosine and serine residues in the juxtamembrane region of the eph become phosphorylated allowing the intracellular tyrosine kinase to convert into its active form and subsequently activate or repress downstream signaling cascades. Epha and ephb receptors preferentially bind ephrin a and ephrin b ligands, respectively, but epha4 is exceptional for its ability to bind all ephrins. The association between ephrinb2 and gastric cancer prognosis and the potential of ephrinb2 as a therapeutic target in gastric cancer treatment remains unknown. Here, we show that of all known ephrins ephrina1a5. Marsh, linfa wang, in the role of animals in emerging viral diseases, 2014. Stimulation of ephrinb2 reverse signaling by ephb4 promotes.
Recombinant mouse ephrinb2 fc chimera protein, cf 496eb. Binds promiscuously eph receptors residing on adjacent cells, leading to contactdependent bidirectional signaling into neighboring cells. Guidance molecules in cancer and tumor angiogenesis. Thus, the identity of the relevant receptor for ephrin b2 and the sites where. Ephrin b2 was tyrosinephosphorylated in the b2 wt cells, but not in the b2 5f cells as was expected.
Recombinant human ephrinb2 fc chimera protein, cf 7397eb. Mechanisms of ephrineph signalling in development, physiology and disease. Optimal dilutions should be determined by each laboratory for each application. Ephrinb2 controls cell motility and adhesion during blood. Fcalcfobs for 10% of the data not used at any stage of structural refinement. Moreover, ephrinb2fc inhibited cedvpp entry into chob1 cells fig 5d, left panel. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma. Torres r, firestein bl, dong h, staudinger j, olson en, huganir rl, bredt ds, gale nw. All ligands share a conserved extracellular sequence, which most likely corresponds to the receptorbinding domain. Here, we report the crystal structure of the epha4 ligandbinding domain in complex with ephrin b2, which represents the first structure of an epha ephrin b interclass complex. S11 b, supplementary material online, and besides, its ephrin b3 does not have the leu and trp residues needed for the binding to the receptor, and its ephrin b2 ortholog lacks the region of interaction. Our ephrin b2 antibodies can be used in a variety of model species.
Symmetrical mutant phenotypes of the receptor ephb4 and its. For each mouse, two different solutions purified patient iggs and ephrinb2 ligand or purified control igg and ephrinb2 ligand were injected in either the right or left hemisphere. Hev and niv virions attach to host cell surfaces through the identified receptor molecules ephrin b2 and ephrin b3, which are expressed on a large number of different cell types bonaparte et al. The ephrins and ephrelated receptors comprise the largest. Thus, we examined whether other ephrins might serve as alternative receptors for niv. B2 5f cells contain 5 phenylalanine residues instead of tyrosines in the carboxyterminal domain, which renders the protein unable to transduce phosphotyrosinedependentreverse signaling see antibodies, sirnas and vectors. A threeday infusion of the ectodomain of either ephb2 or ephrinb2 into the lateral ventricle disrupted migration of neuroblasts and increased cell proliferation. Ephrin b2 encodes a member of the ephrin eph family. Ephrin b2 and ephb4 selectively mark arterial and venous. A key region of molecular specificity orchestrates unique. Jul 26, 2005 available expression vectors containing the first 10 genes were obtained and individually transfected into helausu cells. B family of transmembrane ligands that bind and induce the tyrosine autophosphorylation of eph receptors. Differential expression patterns of eph receptors and ephrin.
Inhibition of ephb4ephrinb2 signaling enhances response to. B2 was detected in immersion fixed rat hippocampal neurons using 2 gml goat antihumanmouserat ephrin. This conserved sequence consists of approximately 125 amino acids and includes four invariant cysteines. Use the list below to choose the ephrin b2 antibody which is most appropriate for your research. Oct 08, 2019 the interface between cedv g protein and ephrinb2 or ephrinb1 buries surface areas of 1,412 a 2 and 1,425 a 2, respectively. In this paper, proteome analyses showed that ephrin b2 fc significantly activates multiple signaling pathways related to cell proliferation, survival, and migration and suppresses apoptosis and cell death. However, ephrin b2 is also expressed in nonvascular tissues and interacts with multiple ephb class receptors expressed in both endothelial and nonendothelial cell types.
This gene encodes a member of the ephrin eph family. Ephb4 ephrin b2 is involved in embryonic vessel development, vascular remodelling and pathological vessel formation in adults including tumour angiogenesis. Additionally, interactions between ephb4 and ephrinb2 on bone marrow sinusoids and. Ephb2 ephrin typeb receptor 2 precursor homo sapiens.
While the existence of extracellular phosphoproteins has been known, the functional significance of extracellular phosphorylation is poorly understood. Ephb4 and ephrin b2 are known for their roles in dorsal aorta and cardinal veins. Ephrinb2 and its receptor ephb4 were first discovered to play a role in arterial vein specification. Great efforts were spent on identifying the functional receptors for henipavirus. Structural and functional analyses reveal promiscuous and. Disrupted surface crosstalk between nmda and ephrinb2. Ephrinb2, a transmembrane ligand of ephb receptor tyrosine kinases. Emerging roles for eph receptors and ephrin ligands in. Structure and thermodynamic characterization of the ephb4ephrin. Ephrin b2 is a protein that in humans is encoded by the efnb2 gene. Mice were recovered and perfused 57 h after injection with 4% paraformaldehyde pentobarbital anaesthesia. In addition, both ephrin b2 and its receptor ephb4 are expressed in mature monocytes and lymphocytes and regulate their motility, adhesion, transmigration, and the secretion of inflammatory mediators. Based on their structures and sequence relationships, ephrins are divided into the ephrin a efna class, which are. Ephrinb2 regulates vegfr2 function in developmental and.
Ephrinb2 and ephrinb3 as functional henipavirus receptors. Further, ephrin b2 expression was induced by hhv8 and also by the hhv8specific vgpcr in ks and endothelial cell lines. Pdf ephrinb2 controls vegfinduced angiogenesis and. Ks tumor cells were found to express the ephrin b2 arterial marker.
Disease description a malignancy originating in tissues of the prostate. Ephephrin signaling and biology of mesenchymal stromal. A hydrophobic core and a hydrophilic rim, which were observed in other henipavirusephrin interfaces 18, 38, were also found in the cedv gephrin b1b2 interfaces. Ephrin b2 expression in kaposi sarcoma is induced by human. Disruption of ephephrin signaling affects migration and. Alternative names ephrelated receptor tyrosine kinase ligand 5. Cell surface transmembrane ligand for eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and ep.
Ephrin b2 is a potential target for treatment of ks because inhibition of ephrin b2 expression or signaling was detrimental to ks cell viability and function. Likewise, degradation of the ephrin b2 icd results in src dephosphorylation and deactivation. The signaling pathway downstream of the receptor is. In the current study, we investigated the involvement of ephb4ephrinb2 protumorigenic signaling in mediating resistance to egfr inhibition and rt in head and neck cancers. Cardiovascular ephrinb2 function is essential for embryonic. The attachment of phosphate groups to tyrosine residues is one of such modifications.
The clinical success of targeted therapies such as cetuximab and radiotherapy rt is hampered by the low response rates and development of therapeutic resistance. Ephrin b2 sequesters pdgfrb into caveolin1positive membrane domains and thereby counteracts clathrinmediated endocytosis and excessive activation of the rtk. Ephrinb2 sequesters pdgfrb into caveolin1positive membrane domains and thereby counteracts clathrinmediated endocytosis and excessive activation of the rtk. Initial studies indicated that hev and niv use cell surface proteins as attachment targets based on the observation that virus infection is sensitive to protease treatment. Recombinant mouse ephrinb2 fc chimera protein, cf 496eb200. The endothelial cells in the artery are marked by ephrin b2, while ephb4 marks venous endothelial cells. Ephrin b2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth. The ephrin b2 icd binds src and promotes its dissociation from a negative src regulator called cterminal src kinase csk, thus allowing for the autophosphorylation and activation of src. Ephrinb2 is a 40 kda transmembrane protein that belongs to the ephrin ligand family and binds the receptors ephb2, b3, and b4. Jan, 2006 cultured ephrin b2 deficient smooth muscle cells are defective in spreading, focaladhesion formation, and polarized migration and show increased motility. Ephrins constitute a class of homologous ligands for the eph class of receptor tyrosine kinases and exhibit overlapping expression patterns. Ephrin b2 and its receptor ephb4 were first discovered to play a role in arterial vein specification and angiogenic remodeling during embryonic development gerety et al. Cell surface transmembrane ligand for eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Ephrinb2 was recently discovered as a functional receptor for nipah virus niv, a lethal emerging paramyxovirus.
To gain further insight into the functional role of ephrinb2 in vsmcs, we compared the gene expression profiles of previously generated control and efnb2 knockout vsmcs foo et al. View humanmouserat ephrinb2 antibody af496 validated in human, mouse and rat. The interaction of ephrin b2 in artery and eph receptor in veins is indicative of their roles in defining boundaries between veins and arteries. In the lamprey, the sequence to bind ephrin bs is not entirely conserved in epha4 supplementary fig. Measured by its binding ability in a functional elisa.
The ephrins and ephrelated receptors comprise the largest subfamily of receptor proteintyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Pdf ephrinb2 controls pdgfr internalization and signaling. Measured by its ability to compete with biotinylated recombinant mouse ephrin. These data suggest that activating the ephrin b2 ephb4 pathway of mononuclear cells may provide notable therapeutic benefits in stroke. In both chob2 and chob1 cells, ephrinb2fcmediated inhibition of cedvg was more potent than ephrinb1fc, further supporting our binding and entry data that suggest ephrinb2 is more efficiently used than ephrinb1. Research paper ephrinb2fc promotes proliferation and. Ephrin type b receptor 4 ephb4, eph receptor selectively binds ephrin b2 eph ligand. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Ephrinb2 is a protein that in humans is encoded by the efnb2 gene. Ephrin b2 and ephb4 have been regarded as the primary marker molecules for arteriovenous differentiation, with ephrin b2 expressed exclusively by arterial endothelial cells and ephb4 by venous endothelial cells.
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