Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenicity of Plasmodium falciparum is due to the unique ability of infected erythrocytes (IRBCs) to adhere to vascular endothelium. We investigated whether adhesion of IRBCs to CD36, the major cytoadherence receptor on human dermal microvascular endothelial cells (HDMECs), induces intracellular signaling and regulates adhesion. A recombinant peptide corresponding to the minimal CD36-binding domain from P falciparum erythrocyte membrane protein 1 (PfEMP1), as well as an anti-CD36 monoclonal antibody (mAb) that inhibits IRBC binding, activated the mitogen-activated protein (MAP) kinase pathway that was dependent on Src-family kinase activity. Treatment of HDMECs with a Src-family kinase-selective inhibitor (PP1) inhibited adhesion of IRBCs in a flow-chamber assay by 72% (P <.001). More importantly, Src-family kinase activity was also required for cytoadherence to intact human microvessels in a human/severe combined immunodeficient (SCID) mouse model in vivo. The effect of PP1 could be mimicked by levamisole, a specific alkaline-phosphatase inhibitor. Firm adhesion to PP1-treated endothelium was restored by exogenous alkaline phosphatase. In contrast, inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 MAP kinase pathways had no immediate effect on IRBC adhesion. These results suggest a novel mechanism for the modulation of cytoadherence under flow conditions through a signaling pathway involving CD36, Src-family kinases, and an ectoalkaline phosphatase. Targeting endothelial ectoalkaline phosphatases and/or signaling molecules may constitute a novel therapeutic strategy against severe falciparum malaria.
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PMID:Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow. 1251 11

The c-fes protooncogene encodes a non-receptor protein-tyrosine kinase (Fes) that has been implicated in the differentiation of myeloid haematopoietic cells. Fes is also expressed in several neuronal cell types and the vascular endothelium, suggestive of a more general function in development. To examine the role of Fes in neuronal differentiation, we investigated the effect of Fes expression on process outgrowth in PC12 cells following stimulation with nerve growth factor (NGF). PC12 cells expressing wild-type and activated mutants of Fes extended processes faster and of greater length than control cells. In contrast, expression of kinase-inactive Fes was without effect, indicating that cooperation with NGF requires Fes kinase activity. Short-term treatment of PC12-Fes cells with NGF enhanced tyrosine phosphorylation of Fes, suggesting upstream regulation by the NGF receptor. Fes-mediated acceleration of neurite outgrowth was blocked by wortmannin and LY294002, implicating phosphatidylinositol 3-kinase (PI3K) activation in the Fes-induced response. In contrast, the MEK inhibitor PD98059 was without effect, suggesting that the Ras-Erk pathway is not involved. These data provide the first evidence that Fes may contribute to morphological differentiation of neuronal cells by enhancing NGF signalling through the PI3K pathway.
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PMID:The c-Fes protein-tyrosine kinase accelerates NGF-induced differentiation of PC12 cells through a PI3K-dependent mechanism. 1253 26

The angiopoietins are an important family of growth factors specific for vascular endothelium. Most of them bind to the TIE2 receptor and are related to regulation of angiogenesis. During large-scale DNA sequencing of the human fetal brain cDNA library, we cloned a novel human angiopoietin-like cDNA and termed it human angiopoietin-like 5 ( ANGPTL5). Like other members of the angiopoietin family, ANGPTL5-deduced protein also has an N-terminal cleavable signal peptide, a predicted coiled-coil domain, and a fibrinogen-like domain. The search against the human genome database indicated that ANGPTL5 maps to 11q22. Expression analysis of ANGPTL5 shows that it is mainly expressed in adult human heart.
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PMID:Identification of a novel human angiopoietin-like gene expressed mainly in heart. 1262 29

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) functions by activating two receptor-tyrosine kinases, Flt-1 (VEGF receptor (VEGFR)-1) and KDR (VEGFR-2), both of which are selectively expressed on primary vascular endothelium. KDR is responsible for VPF/VEGF-stimulated endothelial cell proliferation and migration, whereas Flt-1 down-modulates KDR-mediated endothelial cell proliferation. Our most recent works show that pertussis toxin-sensitive G proteins and Gbetagamma subunits are required for Flt-1-mediated down-regulation of human umbilical vein endothelial cell (HUVEC) proliferation and that Gq/11 proteins are required for KDR-mediated RhoA activation and HUVEC migration. In this study, we demonstrate that Gq/11 proteins are also required for VPF/VEGF-stimulated HUVEC proliferation. Our results further indicate that Gq/11 proteins specifically mediate KDR signaling such as intracellular Ca2+ mobilization rather than Flt-1-induced CDC42 activation and that a Gq/11 antisense oligonucleotide completely inhibits MAPK phosphorylation induced by KDR but has no effect on Flt-1-induced MAPK activation. More importantly, we demonstrate that Gq/11 proteins interact with KDR in vivo, and the interaction of Gq/11 proteins with KDR does not require KDR tyrosine phosphorylation. Surprisingly, the Gq/11 antisense oligonucleotide completely inhibits VPF/VEGF-stimulated KDR phosphorylation. Expression of a constitutively active mutant of G11 but not Gq can cause phosphorylation of KDR and MAPK. In addition, a Gbetagamma minigene, hbetaARK1(495), inhibits VPF/VEGF-stimulated HUVEC proliferation, MAPK phosphorylation, and intracellular Ca2+ mobilization but has no effect on KDR phosphorylation. Taken together, this study demonstrates that Gq/11 proteins mediate KDR tyrosine phosphorylation and KDR-mediated HUVEC proliferation through interaction with KDR.
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PMID:Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. 1267 Sep 61

Vascular endothelial cells respond to nitric oxide by activating MAPK pathways and upregulating stress-activated proteins such as gamma-glutamylcysteine synthetase (gamma-GCS) and heme oxygenase-1 (HO-1). Since consensus sequences for the antioxidant response element (ARE) are found in the promoters of the gamma-GCS and HO-1 genes, we examined nuclear translocation of Nrf2, a CNC-bZIP protein which binds to and activates the ARE. We found a dramatic increase in Nrf2 nuclear translocation 1-8h following the nitric oxide donor spermine NONOate. Translocation was inhibited by pretreatment of cells with N-acetylcysteine suggesting involvement of an oxidative mechanism in this response. Translocation was also blocked by PD 98059 and SB 203580, inhibitors of ERK and p38 pathways, respectively. In addition to effects on Nrf2 subcellular localization, spermine NONOate increased Nrf2 protein levels by a mechanism which was inhibited by PD 98059. Pretreatment with N-acetylcysteine, PD 98059, and SB 203580 decreased HO-1 upregulation in spermine NONOate-treated cells. These results suggest that ERK and p38 pathways may regulate nitric oxide-mediated adaptive responses in vascular endothelium via translocation of Nrf2 and activation of the ARE.
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PMID:Nitric oxide stimulates Nrf2 nuclear translocation in vascular endothelium. 1287 7

We generated a panel of eight rat IgG(2a) monoclonal antibodies with high affinity for mouse VEGFR2 (KDR/Flk-1), the main receptor that mediates the angiogenic effect of VEGF-A. The antibodies (termed RAFL, R at Anti Flk) bound to dividing endothelial cells more strongly than they did to nondividing cells. Most of the RAFL antibodies blocked [(125)I]VEGF(165) binding to VEGFR2. Three of eight antibodies localized to VEGFR2-positive tumor endothelium after intravenous injection into mice bearing orthotopic MDA-MB-231 breast carcinomas, as judged by indirect immunohistochemistry. An average of 60% of vessels in the tumors was stained. The majority (50-80%) of vessels were also stained in a variety of other human and murine tumors growing in mice. The antibodies did not bind detectably to the vascular endothelium in normal heart, lung, liver, and brain cortex, whereas the vascular endothelium in kidney glomerulus and pancreatic islets was stained. Treatment of mice bearing orthotopic MDA-MB-231 tumors with RAFL-1 antibody inhibited tumor growth by an average of 48% and reduced vascular density by 65%, compared to tumors in mice treated with control IgG. Vascular damage was not observed in normal organs, including kidneys and pancreas. These studies demonstrate that anti-VEGFR2 antibodies have potential for vascular targeting and imaging of tumors in vivo.
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PMID:Evaluation of novel antimouse VEGFR2 antibodies as potential antiangiogenic or vascular targeting agents for tumor therapy. 1451 1

Vascular endothelial growth factor (VEGF) is an endothelium-specific growth factor with potent angiogenic activity and a stimulator of microvascular permeability. Because endometrial cyclic development is associated with vascular growth, we examined the expression of VEGF protein throughout the menstrual cycle and studied the regulation of VEGF mRNA by ovarian steroids in isolated human endometrial stromal cells. VEGF was localized immunohistochemically in glandular epithelial cells and in the surrounding stroma, as well as in capillaries and spiral arterioles, a localization which has not been described before. The strongest immunoreactivity for VEGF on endothelial cells was detected in the late proliferative and secretory phases. The localization of VEGF bound to the endothelium correlates with the presence of flt-1 and flk/KDR receptors on vascular structures, including capillary strands which have not yet formed a lumen, present during the mid-secretory period, which corresponds to a high estroprogestin influence and to implantation. Heparinase treatment of the sections decreases the staining intensity of VEGF bound to endothelial cells, suggesting that VEGF also binds to heparin-like molecules on the cell surface. These new results demonstrate a major role of VEGF on capillary formation and on hyperpermeability and edema during the menstrual cycle. Consistent with these in vivo observations, the treatment of isolated endometrial stromal cells with estradiol (E2) or E2 plus progesterone, significantly increased VEGF mRNA over the control value in a dose-dependent manner; the VEGF mRNA response to E2 was rapid (3h) and persisted with continuous estradiol treatment up to 12 days. Three species, VEGF_121, VEGF165 and VEGF189, were observed upon hormonal stimulation. The estradiol up-regulation of VEGF response did not require de novo protein synthesis as it was not blocked by cycloheximide. Also, the ability of the pure anti-estrogen ICI 182,780 to significantly block induction of VEGF mRNA by E2 suggests estrogen receptor-mediated transcriptional regulation. These results demonstrate that VEGF is an estrogen-responsive angiogenic factor that acts on vascular endothelium in a paracrine fashion, as previously suggested. This growth factor controls angiogenesis and hyperpermeability required for adequate receptivity to implantation of the cycling human endometrium. These findings also raise the possibility that estrogen effects on uterine edema, proliferation and tumoral transformation may involve local increases in tissue VEGF production.
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PMID:Paracrine action of vascular endothelial growth factor in the human endometrium: production and target sites, and hormonal regulation. 1451 72

Tissue engineering may offer patients new options when replacement or repair of an organ is needed. However, most tissues will require a microvascular network to supply oxygen and nutrients. One strategy for creating a microvascular network would be promotion of vasculogenesis in situ by seeding vascular progenitor cells within the biopolymeric construct. To pursue this strategy, we isolated CD34(+)/CD133(+) endothelial progenitor cells (EPC) from human umbilical cord blood and expanded the cells ex vivo as EPC-derived endothelial cells (EC). The EPC lost expression of the stem cell marker CD133 but continued to express the endothelial markers KDR/VEGF-R2, VE-cadherin, CD31, von Willebrand factor, and E-selectin. The cells were also shown to mediate calcium-dependent adhesion of HL-60 cells, a human promyelocytic leukemia cell line, providing evidence for a proinflammatory endothelial phenotype. The EPC-derived EC maintained this endothelial phenotype when expanded in roller bottles and subsequently seeded on polyglycolic acid-poly-l-lactic acid (PGA-PLLA) scaffolds, but microvessel formation was not observed. In contrast, EPC-derived EC seeded with human smooth muscle cells formed capillary-like structures throughout the scaffold (76.5 +/- 35 microvessels/mm(2)). These results indicate that 1) EPC-derived EC can be expanded in vitro and seeded on biodegradable scaffolds with preservation of endothelial phenotype and 2) EPC-derived EC seeded with human smooth muscle cells form microvessels on porous PGA-PLLA scaffolds. These properties indicate that EPC may be well suited for creating microvascular networks within tissue-engineered constructs.
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PMID:Tissue-engineered microvessels on three-dimensional biodegradable scaffolds using human endothelial progenitor cells. 1527 91

A natural fragment of an enzyme that catalyzes the first step of protein synthesis-human tryptophanyl-tRNA synthetase (T2-TrpRS) has potent anti-angiogenic activity. A cellular receptor through which T2-TrpRS exerts its anti-angiogenic activity has not previously been identified. Here T2-TrpRS was shown to bind at intercellular junctions of endothelial cells (ECs). Using genetic knock-outs, binding was established to depend on VE-cadherin, a calcium-dependent adhesion molecule, which is selectively expressed in ECs, concentrated at adherens junctions, and is essential for normal vascular development. In contrast, T2-TrpRS binding to EC junctions was not dependent on platelet endothelial cell adhesion molecule type-1, another adhesion molecule found at EC junctions. Pull-down assays confirmed direct complex formation between T2-TrpRS and VE-cadherin. Binding of T2-TrpRS inhibited VEGF-induced ERK activation and EC migration. Thus, a VE-cadherin-dependent pathway is proposed to link T2-TrpRS to inhibition of new blood vessel formation.
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PMID:VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. 1557 7

C-reactive protein (CRP) is significantly associated with the risk of ischemic cardiovascular disease in epidemiological studies. To explore if CRP has a functional role, we investigated its effect on the gene expression profile of vascular endothelial cells. Human vascular endothelial cells (human umbilical vein endothelial cells and human aortic endothelial cells) were incubated with CRP at various concentrations (0-10 mug/ml). Microarray analysis showed that a total of 11 genes increased (IL-8, core promoter element binding protein, activin A, monocyte chemoattractant protein 1, Exostoses 1, Cbp/p300-interacting transactivator with Glu/Asp-rich COOH-terminal domain 2, plasminogen activator inhibitor 1, fibronectin-1, gravin, connexin43, and sortilin-related receptor-1) and 6 genes decreased (methionine adenosyltransferase 2A, tryptophan-rich basic protein, reticulocalbin 1, membrane-associated RING-CH protein VI, cytoplasmic dynein1, and annexin A(1)) by more than twofold for their mRNA levels. IL-8 was the most significantly upregulated gene (13.6-fold), which demonstrated a clear dose- and time-dependent pattern revealed by quantitative real-time PCR. Cell adhesion assay showed that CRP enhanced the monocyte adhesion to endothelial cell monolayer by 2-fold (P < 0.01), which was partially blocked by an anti-IL-8 antibody (34.2% inhibition, P < 0.01). Inhibition of ERK MAPK pathway using U0126 prevented CRP-induced IL-8 upregulation, and Western blot analysis revealed a rapid activation of ERK1/2 after CRP stimulation. These data showed that CRP can significantly influence gene expressions in vascular endothelium. The CRP-responsive genes suggested that CRP may have a broad functional role in cell growth and differentiation, vascular remodeling and solid tumor development.
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PMID:Effect of C-reactive protein on gene expression in vascular endothelial cells. 1559 Oct 95


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