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)

Angiogenesis, the process of new blood vessel formation, is important in wound healing, inflammation, tumorigenesis and metastases. During this process, it is a critical step of the loosening of cellular interactions between endothelial cells, which are dependent on the architecture of adherens junction constructed by homophilic interactions of cell surface cadherins. Several studies suggested that the dynamic changes of cadherins are necessary during angiogenesis. However, the mechanism of cadherins regulation on endothelial cells requires further delineation. Here, we showed that basic fibroblast growth factor (bFGF), a pivotal pro-angiogenic factor, can downregulate typical cadherins (E-, N-, P- and VE-cadherin) expression on the surface of human umbilical vein endothelial cells (HUVECs) via FGF receptor 1 (FGFR1) signaling. The bFGF-mediated surface cadherin downregulation was significantly reversed only when the HUVECs were treated with JNK inhibitor (SP600125), but not ERK (PD98059) or p38 inhibitor (SB203580). Infecting HUVECs with a dominant negative H-Ras mutant (Ras(S17N)) interferes bFGF-mediated cadherin downregulation, and the result suggests that bFGF attenuates surface cadherin expression on HUVECs via FGFR1 and intracellular Ras-JNK signaling. However, after growth factors withdrawal, FGFR1 blockade or JNK inhibition for 16 h, cadherins were re-expressed on cell surface of HUVECs. But the mRNA or total protein of cadherins had no significant change, suggesting that the effect of bFGF on cadherin expression may work through a post-translational control. Our data first suggest that JNK participates in bFGF-mediated surface cadherin downregulation. Loss of surface cadherins may affect the cell-cell interaction between endothelial cells and facilitate angiogenesis.
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PMID:JNK signaling pathway is required for bFGF-mediated surface cadherin downregulation on HUVEC. 1816 4

Capsiate, a nonpungent capsaicin analogue, and its dihydroderivative dihydrocapsiate are the major capsaicinoids of the nonpungent red pepper cultivar CH-19 Sweet. In this study, we report the biological actions and underlying molecular mechanisms of capsiate on angiogenesis and vascular permeability. In vitro, capsiate and dihydrocapsiate inhibited vascular endothelial growth factor (VEGF)-induced proliferation, chemotactic motility, and capillary-like tube formation of primary cultured human endothelial cells. They also inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessels in the mouse Matrigel plug assay in response to VEGF. Moreover, both compounds blocked VEGF-induced endothelial permeability and loss of vascular endothelial (VE)-cadherin-facilitated endothelial cell-cell junctions. Importantly, capsiate suppressed VEGF-induced activation of Src kinase and phosphorylation of its downstream substrates, such as p125(FAK) and VE-cadherin, without affecting autophosphorylation of the VEGF receptor KDR/Flk-1. In vitro kinase assay and molecular modeling studies revealed that capsiate inhibits Src kinase activity via its preferential docking to the ATP-binding site of Src kinase. Taken together, these results suggest that capsiate could be useful for blocking pathologic angiogenesis and vascular permeability caused by VEGF.
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PMID:Capsiate, a nonpungent capsaicin-like compound, inhibits angiogenesis and vascular permeability via a direct inhibition of Src kinase activity. 1817 15

Embryonic stem (ES) cells are exposed to fluid-mechanical forces, such as cyclic strain and shear stress, during the process of embryonic development but much remains to be elucidated concerning the role of fluid-mechanical forces in ES cell differentiation. Here, we show that cyclic strain induces vascular smooth muscle cell (VSMC) differentiation in murine ES cells. Flk-1-positive (Flk-1+) ES cells seeded on flexible silicone membranes were subjected to controlled levels of cyclic strain and examined for changes in cell proliferation and expression of various cell lineage markers. When exposed to cyclic strain (4-12% strain, 1 Hz, 24 h), the Flk-1+ ES cells significantly increased in cell number and became oriented perpendicular to the direction of strain. There were dose-dependent increases in the VSMC markers smooth muscle alpha-actin and smooth muscle-myosin heavy chain at both the protein and gene expression level in response to cyclic strain, whereas expression of the vascular endothelial cell marker Flk-1 decreased, and there were no changes in the other endothelial cell markers (Flt-1, VE-cadherin, and platelet endothelial cell adhesion molecule 1), the blood cell marker CD3, or the epithelial marker keratin. The PDGF receptor beta (PDGFR beta) kinase inhibitor AG-1296 completely blocked the cyclic strain-induced increase in cell number and VSMC marker expression. Cyclic strain immediately caused phosphorylation of PDGFR beta in a dose-dependent manner, but neutralizing antibody against PDGF-BB did not block the PDGFR beta phosphorylation. These results suggest that cyclic strain activates PDGFR beta in a ligand-independent manner and that the activation plays a critical role in VSMC differentiation from Flk-1+ ES cells.
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PMID:Cyclic strain induces mouse embryonic stem cell differentiation into vascular smooth muscle cells by activating PDGF receptor beta. 1818 12

Cell to cell junctions are important regulators of endothelial responses both in quiescent and angiogenic vessels. Endothelial cells express tight and adherens junctional structures. Although different in their specific molecular composition, these junctional complexes present a relatively similar general arrangement. Both types of junctions are formed by transmembrane adhesive proteins that bind homophilically to identical proteins on an adjacent cell and start a sequence of signalling events. Signal transmission is mediated by interaction with cytoplasmic and transmembrane partners. Adherens junctions are ubiquitous along the vascular tree. In these structures adhesion is mediated by VE-cadherin and its intracellular partners. In vitro and in vivo data show that VE-cadherin is required for endothelial integrity in quiescent vessels and for the correct organization of new vessels. VE-cadherin regulates endothelial functions through different mechanisms that include: (i) direct activation of signalling molecules such as PI3 kinase and Rac, to sustain survival and organization of the actin cytoskeleton; (ii) regulation of gene transcription, possibly modulating the nuclear level of transcription co-factors such as beta-catenin and p120; (iii) formation of complexes with growth factor receptors, such as the type 2 receptor of VEGF (VEGFR2) and modulation of their signalling properties.
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PMID:The control of endothelial cell functions by adherens junctions. 1830 Apr 10

Vascular endothelial growth factor A (VEGF-A) is an angiogenic growth factor that is a primary stimulant of the vascularization of solid tumors. In the tumor microenvironment, an upregulation of both VEGF and its receptors occurs, leading to a high concentration of occupied receptors on tumor vascular endothelium. Also, VEGF is involved in the development of the normal vascular network of the thymus. Little is known about VEGF expression in normal and malignant thymic tissue. Our purpose was to study the pattern and localization of VEGF expression in benign conditions of the thymus and thymoma to determine a possible correlation with VEGF receptors VEGFR1, VEGFR2 and microvascular density. All cases were positive for VEGF and VEGFR1, 2 in the epithelial cells, in a cytoplasmic, granular pattern. In the normal thymus, there were positive epithelial cells with subcapsular distribution and Hassall's corpuscle epithelial cells. In acute thymic involution, the positive fields were correlated with dilation and stasis of blood vessels and lymphocyte depletion. Rare positive cells were found in other types of involution; the myasthenic thymus showed an intense and diffuse reaction in lymphoid follicles of the medulla. A strong reaction for VEGF was observed in type B3 thymomas in neoplastic epithelial cells, normal endothelial cells, plasma within the blood vessels and focally in the stroma adjacent to the tumor. Receptors for VEGF were positive in neoplastic epithelial cells and endothelium. We hypothesized that VEGF acts as an immunoregulatory factor in the normal thymus and as proangiogenic and autocrine factor in thymomas.
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PMID:Immunohistochemical expression of vascular endothelial growth factor A (VEGF), and its receptors (VEGFR1, 2) in normal and pathologic conditions of the human thymus. 1835 31

The aim of this study was to establish the method of isolating and culturing endothelial progenitor cells (EPCs) from human umbilical cord blood. Mononuclear cells (MNCs) from human umbilical cord blood were cultured by using culture system supplemented with endothelial cell-conditioned medium. The obtained two types of cells were purified by picking up colonies, identified by uptake of acetylated low-density lipoprotein (Ac-LDL) and binding to lectin [Ulex European Agglatinin (UEA-1)], and were analyzed for the expression of markers by flow cytometry. The results showed that there were significant differences between two types of cells in proliferation, so they were referred as circulating angiogenic cells (CACs) and high proliferative potential endothelial progenitor cells (HPP-EPCs), respectively. They were in accordance with the standards of EPCs, could uptake DiI-Ac-LDL and bind to UEA-1, and expressed the markers of endothelial cells, such as CD31, CD144 and vWF detected by immunocytochemistry. The transcription of CD31, KDR, CD144 and ENOS in both of them could be detected by RT-PCR, but FACS analysis showed significant differences of surface marker expression between them. In conclusion, two types of EPCs are successfully obtained by culturing MNCs isolated from human umbilical cord blood using endothelial cell-conditioned medium.
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PMID:[Isolation, culture and identification of two types of endothelial progenitor cells from human umbilical cord blood]. 1842 71

Vascular endothelial growth factor (VEGF) binding induces phosphorylation of VEGF receptor (VEGFR)2 in tyrosine, which is followed by disruption of VE-cadherin-mediated cell-cell contacts of endothelial cells (ECs), thereby stimulating EC proliferation and migration to promote angiogenesis. Tyrosine phosphorylation events are controlled by the balance of activation of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Little is known about the role of endogenous PTPs in VEGF signaling in ECs. In this study, we found that PTP1B expression and activity are markedly increased in mice hindlimb ischemia model of angiogenesis. In ECs, overexpression of PTP1B, but not catalytically inactive mutant PTP1B-C/S, inhibits VEGF-induced phosphorylation of VEGFR2 and extracellular signal-regulated kinase 1/2, as well as EC proliferation, whereas knockdown of PTP1B by small interfering RNA enhances these responses, suggesting that PTP1B negatively regulates VEGFR2 signaling in ECs. VEGF-induced p38 mitogen-activated protein kinase phosphorylation and EC migration are not affected by PTP1B overexpression or knockdown. In vivo dephosphorylation and cotransfection assays reveal that PTP1B binds to VEGFR2 cytoplasmic domain in vivo and directly dephosphorylates activated VEGFR2 immunoprecipitates from human umbilical vein endothelial cells. Overexpression of PTP1B stabilizes VE-cadherin-mediated cell-cell adhesions by reducing VE-cadherin tyrosine phosphorylation, whereas PTP1B small interfering RNA causes opposite effects with increasing endothelial permeability, as measured by transendothelial electric resistance. In summary, PTP1B negatively regulates VEGFR2 receptor activation via binding to the VEGFR2, as well as stabilizes cell-cell adhesions through reducing tyrosine phosphorylation of VE-cadherin. Induction of PTP1B by hindlimb ischemia may represent an important counterregulatory mechanism that blunts overactivation of VEGFR2 during angiogenesis in vivo.
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PMID:Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. 1845 37

Following trauma to the brain significant changes occur in both the astroglial and vascular components of the neuropil. Angiogenesis is required to re-establish metabolic support and astrocyte activation encompasses several functions including scar formation and the production of growth factors. VEGF has seminal involvement in the process of brain repair and is upregulated during many pathological events. VEGF signaling is regulated mainly through its two primary receptors: flk-1 (KDR/VEGF-R2) is expressed on vascular endothelium and some neurons and flt-1 (VEGF-R1) in the CNS, is expressed predominantly by activated astrocytes. Using an injury model of chronic minipump infusion of neutralizing antibodies (NA) to block VEGF receptor signaling, this study takes advantage of these differences in VEGF receptor distribution in order to understand the role the cytokine plays after brain injury. Infusion of NA to flk-1 caused a significant decrease in vascular proliferation and increased endothelial cell degeneration compared to control IgG infusions but had no effect on astrogliosis. By contrast infusion of NA to flt-1 significantly decreased astroglial mitogenicity and scar formation and caused some increase in endothelial degeneration. Neutralization of the flt-1 receptor function, but not flk-1, caused significant reduction in the astroglial expression of the growth factors, CNTF and FGF by 7days. These data suggest that after CNS injury, endogenous VEGF upregulation (by astrocytes) induces angiogenesis and, by autocrine signaling, increases both astrocyte proliferation and facilitates expression of growth factors. It is likely that VEGF plays an important role in aspects of astroglial scar formation.
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PMID:Roles of the endogenous VEGF receptors flt-1 and flk-1 in astroglial and vascular remodeling after brain injury. 1848 23

The journey of the Chagas' disease parasite Trypanosoma cruzi in the human body usually starts in the skin after an insect bite, when trypomastigotes get through the extracellular matrix to bind specific surface receptors in the epidermis and dermis to enter cells, where they differentiate and replicate. As the infection spreads to the heart, nervous system, and other parts of the body via the circulatory system, the parasite must also cope with additional receptors in the immune system and vascular endothelium. The molecular underpinnings that govern host cell receptor recognition by T. cruzi counterreceptors remain largely unknown. Here, we describe an immunoprecipitation strategy designed to concurrently identify host receptors and complementing parasite counterreceptors. Extracellular domains of growth factor receptors fused to human immunoglobulin G (IgG) Fc were incubated with parasite lysates, immunoprecipitated on protein G-Sepharose, and eluted with Laemmli sample buffer. Possible T. cruzi counterreceptors pulled down by the receptor-Fc bait were visualized on immunoblots probed with multispecific high-affinity IgG from chronic chagasic sera and on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels stained with silver or Coomassie blue. In screening receptors important for nervous system repair, this parasite counterreceptor immunoprecipitation (PcIP) assay identified 7 to 11 polypeptides (molecular masses, 14 kDa to 55 kDa) that bound to the coreceptors of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) GFRalpha-1, -2, and -3. Binding was specific because the T. cruzi mimic of host GFLs, named TGFL, did not react with GFL coreceptor tyrosine kinase RET and with other neurotrophic receptors. The polypeptides were located on the parasite outer membrane and bound noncovalently to each other. TGFL eluted from the GFL receptor/protein G affinity column with 0.5 M NaCl, pH 7.5, and potently promoted neurite outgrowth and cell survival in a GFL-sensitive mouse pheochromocytoma cell line. Given that GFLs are neuron survival factors crucial for development and maintenance of central and peripheral nervous systems, it may be that T. cruzi mimicry of host GFLs helps in mutually beneficial host repair of infected and damaged nervous tissue. As there are >30 growth factor receptor-Fc chimeras commercially available, this PcIP assay can be readily adapted to identify receptors/counterreceptors in other T. cruzi invasion sites and in other infections such as Lyme disease, amebiasis, and schistosomiasis.
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PMID:A novel immunoprecipitation strategy identifies a unique functional mimic of the glial cell line-derived neurotrophic factor family ligands in the pathogen Trypanosoma cruzi. 1854 56

Angiogenesis is induced by multiple growth factors including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). In vascular endothelium VEGF signals through two receptor-tyrosine kinases, VEGFR1 and VEGFR2. The VEGFR1 gene encodes both a receptor-tyrosine kinase and a secreted splice variant, soluble VEGFR1. Whereas VEGFR1 is essential for vascular development, mechanisms that regulate VEGFR1 expression in endothelial cells are poorly understood. We demonstrate here that in endothelial cells, FGF2 and epidermal growth factor (EGF) signaling induce VEGFR1 mRNA expression in a combinatorial fashion. EGF/FGF2-mediated VEGFR1 induction is mediated via functional interaction of transcription factors ETS1 and HIF-2alpha. Mechanistic analyses revealed that in endothelial cells EGF/FGF2 signaling induces ETS1 expression, increases HIF-2alpha protein level in absence of hypoxia, and recruits both ETS1 and HIF-2alpha to the VEGFR1 chromatin domain. Knockdown of ETS1 and HIF-2alpha by RNA interference inhibits EGF/FGF2-induced VEGFR1 expression, and loss of expression is associated with impaired RNA-polymerase II recruitment and histone modifications at the VEGFR1 promoter region. In addition, using a mouse embryonic stem cell in vitro differentiation system, we found that induction of VEGFR1 in embryoid bodies is also associated with ETS1 and HIF-2alpha recruitment to the VEGFR1 locus. These results establish an angiogenic signal-ETS1/HIF-2alpha axis that regulates the VEGFR1 chromatin domain to induce VEGFR1 transcription in endothelial cells and in differentiating embryonic stem cells.
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PMID:Activation of the VEGFR1 chromatin domain: an angiogenic signal-ETS1/HIF-2alpha regulatory axis. 1862 4


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