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1.
Members of the Eph family of receptor tyrosine kinases control many aspects of cellular interactions during development, including axon guidance. Here, we demonstrate that EphB2 also regulates postnatal synaptic function in the mammalian CNS. Mice lacking the EphB2 intracellular kinase domain showed wild-type levels of LTP, whereas mice lacking the entire EphB2 receptor had reduced LTP at hippocampal CA1 and dentate gyrus synapses. Synaptic NMDA-mediated current was reduced in dentate granule neurons in EphB2 null mice, as was synaptically localized NR1 as revealed by immunogold localization. Finally, we show that EphB2 is upregulated in hippocampal pyramidal neurons in vitro and in vivo by stimuli known to induce changes in synaptic structure. Together, these data demonstrate that EphB2 plays an important role in regulating synaptic function. 相似文献
2.
Sally-Anne Stephenson Stefan Slomka Evelyn L Douglas Peter J Hewett Jennifer E Hardingham 《BMC molecular biology》2001,2(1):15-9
Background
We have used commercially available cDNA arrays to identify EphB4 as a gene that is up-regulated in colon cancer tissue when compared with matched normal tissue from the same patient. 相似文献3.
Scott A. Mitchell Mihaela Diana Danca Peter A. Blomgren James W. Darrow Kevin S. Currie Jeffrey E. Kropf Seung H. Lee Steven L. Gallion Jin-Ming Xiong Douglas A. Pippin Robert W. DeSimone David R. Brittelli David C. Eustice Aaron Bourret Melissa Hill-Drzewi Patricia M. Maciejewski Lisa L. Elkin 《Bioorganic & medicinal chemistry letters》2009,19(24):6991-6995
Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent® and Nexavar®, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs. 相似文献
4.
The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis 总被引:10,自引:0,他引:10
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. 相似文献
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Catherine Bardelle Bernard Barlaam Nigel Brooks Tanya Coleman Darren Cross Richard Ducray Isabelle Green Christine Lambert-van der Brempt Annie Olivier Jon Read 《Bioorganic & medicinal chemistry letters》2010,20(21):6242-6245
Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo. 相似文献
7.
Ishibashi H Kojima N Obata K 《Biochemical and biophysical research communications》2000,276(2):707-709
We found that mice carrying constitutively active Fyn tyrosine kinase show low levels of spontaneous locomotor activity and that this activity increases when the mice are treated with the NMDA receptor antagonist MK-801. These findings indicate that the tyrosine phosphorylation of the NMDA receptors by Fyn participates in the control of locomotor activity. 相似文献
8.
Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction 下载免费PDF全文
Activation of the EphB2 receptor tyrosine kinase by clustered ephrin-B1 induces growth cone collapse and neurite retraction in differentiated NG108 neuronal cells. We have investigated the cytoplasmic signaling events associated with EphB2-induced cytoskeletal reorganization in these neuronal cells. We find that unlike other receptor tyrosine kinases, EphB2 induces a pronounced downregulation of GTP-bound Ras and consequently of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. A similar inhibition of the Ras-MAPK pathway was observed on stimulation of endogenous EphB2 in COS-1 cells. Inactivation of Ras, induced by ephrin B1 stimulation of NG108 neuronal cells, requires EphB2 tyrosine kinase activity and is blocked by a truncated form of p120-Ras GTPase-activating protein (p120-RasGAP), suggesting that EphB2 signals through the SH2 domain protein p120-RasGAP to inhibit the Ras-MAPK pathway. Suppression of Ras activity appears functionally important, since expression of a constitutively active variant of Ras impaired the ability of EphB2 to induce neurite retraction. In addition, EphB2 attenuated the elevation in ERK activation induced by attachment of NG108 cells to fibronectin, indicating that the EphB2 receptor can modulate integrin signaling to the Ras GTPase. These results suggest that a primary function of EphB2, a member of the most populous family of receptor tyrosine kinases, is to inactivate the Ras-MAPK pathway in a fashion that contributes to cytoskeletal reorganization and adhesion responses in neuronal growth cones. 相似文献
9.
RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6 总被引:2,自引:0,他引:2
RYK is an atypical orphan receptor tyrosine kinase that lacks detectable kinase activity. Nevertheless, using a chimeric receptor approach, we previously found that RYK can signal via the mitogen-activated protein kinase pathway. Recently, it has been shown that murine Ryk can bind to and be phosphorylated by the ephrin receptors EphB2 and EphB3. In this study, we show that human RYK associates with EphB2 and EphB3 but is not phosphorylated by them. This association requires both the extracellular and cytoplasmic domains of RYK and is not dependent on activation of the Eph receptors. It was also previously shown that AF-6 (afadin), a PDZ domain-containing protein, associates with murine Ryk. We show here that AF-6 does not bind to human RYK in vitro or in vivo. This suggests that there are significant functional differences between human and murine RYK. Further studies are required to determine whether RYK modulates the signaling of EphB2 and EphB3. 相似文献
10.
Barlaam B Ducray R Lambert-van der Brempt C Plé P Bardelle C Brooks N Coleman T Cross D Kettle JG Read J 《Bioorganic & medicinal chemistry letters》2011,21(8):2207-2211
Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors. 相似文献
11.
EphB receptor tyrosine kinases and ephrin-B ligands regulate several types of cell-cell interactions during brain development, generally by modulating the cytoskeleton. EphB/ephrinB genes are expressed in the developing neural tube of early mouse embryos with distinct overlapping expression in the ventral midbrain. To test EphB function in midbrain development, mouse embryos compound homozygous for mutations in the EphB2 and EphB3 receptor genes were examined for early brain phenotypes. These mutants displayed a morphological defect in the ventral midbrain, specifically an expanded ventral midline evident by embryonic day E9.5-10.5, which formed an abnormal protrusion into the cephalic flexure. The affected area was comprised of cells that normally express EphB2 and ephrin-B3. A truncated EphB2 receptor caused a more severe phenotype than a null mutation, implying a dominant negative effect through interference with EphB forward (intracellular) signaling. In mutant embryos, the overall number, size, and identity of the ventral midbrain cells were unaltered. Therefore, the defect in ventral midline morphology in the EphB2;EphB3 compound mutant embryos appears to be caused by cellular changes that thin the tissue, forcing a protrusion of the ventral midline into the cephalic space. Our data suggests a role for EphB signaling in morphological organization of specific regions of the developing neural tube. 相似文献
12.
Ross C. Overman Judit E. Debreczeni Caroline M. Truman Mark S. McAlister Teresa K. Attwood 《Protein science : a publication of the Protein Society》2014,23(5):627-638
The EphB receptors have key roles in cell morphology, adhesion, migration and invasion, and their aberrant action has been linked with the development and progression of many different tumor types. Their conflicting expression patterns in cancer tissues, combined with their high sequence and structural identity, present interesting challenges to those seeking to develop selective therapeutic molecules targeting this large receptor family. Here, we present the first structure of the EphB1 tyrosine kinase domain determined by X‐ray crystallography to 2.5Å. Our comparative crystalisation analysis of the human EphB family kinases has also yielded new crystal forms of the human EphB2 and EphB4 catalytic domains. Unable to crystallize the wild‐type EphB3 kinase domain, we used rational engineering (based on our new structures of EphB1, EphB2, and EphB4) to identify a single point mutation which facilitated its crystallization and structure determination to 2.2 Å. This mutation also improved the soluble recombinant yield of this kinase within Escherichia coli, and increased both its intrinsic stability and catalytic turnover, without affecting its ligand‐binding profile. The partial ordering of the activation loop in the EphB3 structure alludes to a potential cis‐phosphorylation mechanism for the EphB kinases. With the kinase domain structures of all four catalytically competent human EphB receptors now determined, a picture begins to emerge of possible opportunities to produce EphB isozyme‐selective kinase inhibitors for mechanistic studies and therapeutic applications. 相似文献
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Negre-Salvayre A Vieira O Escargueil-Blanc I Salvayre R 《Molecular aspects of medicine》2003,24(4-5):251-261
Among the diverse risk factors involved in atherosclerosis, LDL are thought to become atherogenic after undergoing oxidative modifications, characterized by oxidized lipid formation and structural alterations of apoB. Oxidized LDL alter various signaling pathways and exhibit a broad range of biological responses including inflammation, gene expression, cell proliferation or apoptosis. The biological effects of oxidized LDL are related to the presence of peroxidation products such as hydroperoxides, lysophosphatidylcholines, oxysterols and aldehydes.4-Hydroxynonenal (HNE) is one of the most abundant aldehydes formed during the oxidation of polyunsaturated fatty acids in LDL and in membranes. It is able to react with thiols and free amino group residues of proteins. HNE is involved in apoB modifications that alter LDL metabolism and cell protein-adduct formation which may mediate in part the biological effects of oxidized LDL. We report here that HNE delivered to cells by oxidized LDL reacts with cellular proteins, for instance with tyrosine kinase receptors (RTK) such as EGFR and PDGFR. HNE induces in vitro derivatization and tyrosine phosphorylation of RTK (the fine molecular mechanism and conformational changes remain to be elucidated). In intact living cells, oxidized LDL (and pure HNE) trigger HNE-adduct formation and activation of PDGFR and EGFR, through an antioxidant-insensitive and reactive oxygen species independent mechanism. The presence of HNE-PDGFR adducts in atherosclerotic areas lead one to hypothesize that oxidized lipids may also react in vivo with membrane RTK, thereby disturbing their cellular functions. 相似文献
15.
Radu DL Georgescu A Stavaru C Carale A Popov D 《Journal of cellular and molecular medicine》2004,8(3):349-358
The double transgenic mice (dTg) were obtained by mating: (i) transgenic mice expressing the hemagglutinin of influenza virus under the insulin promoter with (ii) transgenic mice expressing specific T lymphocytes with receptor for the immunodominant epitope of the same virus. In this study we show that dTg mice developed type 1 diabetes mellitus associated with hyperglycemia, low level of plasma insulin, glucosuria, weight loss and approximately 90% mortality (at 3 months biological age). The membrane of red blood cells was more sensitive to osmotic shock in diabetic mice, compared to non-diabetic mice, assessing systemic oxidative stress. Both vasoconstriction and vasorelaxation of the renal arteries decreased significantly in diabetic mice (compared to the control group of non-diabetic mice) related to the phenotypic change of endothelium and smooth muscle cells within the artery wall. This animal model, may be used in developing various strategies to study pancreatic beta-cell function, as well as for a better metabolic control conducting to a reduced risk of vascular complications. 相似文献
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Matsubara H Shibasaki Y Okigaki M Mori Y Masaki H Kosaki A Tsutsumi Y Uchiyama Y Fujiyama S Nose A Iba O Tateishi E Hasegawa T Horiuchi M Nahmias C Iwasaka T 《Biochemical and biophysical research communications》2001,282(5):1085-1091
Angiotensin II (Ang II) has two major receptor isoforms, AT1 and AT2. AT1 transphosphorylates Ca(2+)-sensitive tyrosine kinase Pyk2 to activate c-Jun NH2-terminal kinase (JNK). Although AT2 inactivates extracellular signal-regulated kinase (ERK) via tyrosine phosphatases (PTP), the action of AT2 on Pyk2 and JNK remains undefined. Using AT2-overexpressing vascular smooth muscle cells (AT2-VSMC) from AT2-transgenic mice, we studied these undefined actions of AT2. AT1-mediated JNK activity was increased 2.2-fold by AT2 inhibition, which was abolished by orthovanadate. AT2 did not affect AT1-mediated Pyk2 phosphorylation, but attenuated c-Jun mRNA accumulation by 32%. The activity of src-homology 2 domain-containing PTP (SHP-1) was significantly upregulated 1 min after AT2 stimulation. Stable overexpression of SHP-1 dominant negative mutant in AT2-VSMC completely abolished AT2-mediated inhibition of JNK activation and c-Jun expression. These findings suggest that AT2 inhibits JNK activity by affecting the downstream signal of Pyk2 in a SHP-1-dependent manner, leading to a decrease in c-Jun expression. 相似文献
18.
Vernersson E Khoo NK Henriksson ML Roos G Palmer RH Hallberg B 《Gene expression patterns : GEP》2006,6(5):448-461
Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, was first described as the fusion product causing a subtype of non-Hodgkin's lymphoma. To date Alk has been reported to be mainly expressed in CNS and other parts of the brain. Here we describe an extensive characterization of the mRNA and protein expression of ALK during mouse development. We show that mRNA and ALK protein show overlapping expressing patterns in specific regions of the central and the peripheral nervous systems. Furthermore, ALK is also expressed in the eye, nasal epithelium, olfactory nerve, tongue, skin, tissue surrounding the esophagus, stomach and midgut but not the hindgut. Expression of ALK is also found in testis and ovary. 相似文献
19.
Male homozygous transgenic c-ros knockout mice are sterile by natural mating, lack a part of their epididymis, and the epididymal sperm exhibit tail angulation in vivo and in vitro. To ascertain if this abnormal tail form caused the infertility, the number and nature of sperm in the tract of females mated to knockout and wild-type mice were determined. Percentage motility and numbers of sperm in the uterus 1 h after mating were similar between genotypes. The majority of the uterine sperm from the wild-type males had straight flagella, whereas 46-86% of knockout sperm were bent at the cytoplasmic droplet even when motile. Motile knockout sperm showed a 54 and 37% reduction in the straightline and curvilinear velocities compared with straight wild-type sperm. Sequential flushings of the oviduct 4 h after mating with the wild-type males contained sperm: 591 +/- 119 free, 371 +/- 70 loosely, and 122 +/- 47 tightly bound to the epithelium, but no knockout sperm were recovered from the oviduct or observed within the uterotubal junction in tissue sections. The infertility of c-ros knockout male mice can be explained by the sperm's inability to enter the oviduct, as a result of their bent tails forming the entangled sperm mass and their compromised flagellar vigor within the uterus. 相似文献
20.
Duffy SL Coulthard MG Spanevello MD Herath NI Yeadon TM McCarron JK Carter JC Tonks ID Kay GF Phillips GE Boyd AW 《Genesis (New York, N.Y. : 2000)》2008,46(10):553-561
Eph receptor tyrosine kinases (RTKs) are a highly conserved family of signaling proteins with functions in cellular migration, adhesion, apoptosis, and proliferation during both adult and embryonic life. Here, we describe a knock-in mouse in which EphA1 expression is disrupted via the insertion of an internal ribosome entry site (IRES)-human placental alkaline phosphatase (ALPP) reporter cassette into exon II of the EphA1 gene. This was shown to successfully knockout expression of endogenous EphA1 and enforce expression of the ALPP reporter by the EphA1 promoter. Staining for the ALPP reporter protein demonstrated an epithelially restricted expression pattern in mouse tissues. In EphA1 null mice, two separate phenotypes were identified: abnormal tail development manifesting as a kinky tail was found in approximately 80% of homozygous adults. A second, distinct abnormality present in approximately 18% of females was characterized by imperforate uterovaginal development with hydrometrocolpos and caused by a resistance of cells to apoptosis during reproductive tract canalization. These results indicate a possible role for EphA1 in tissue patterning and hormone-induced apoptotic processes. 相似文献