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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)

Vascular endothelial growth factor (VEGF) mediates endothelial cell proliferation, angiogenesis, and vascular permeability via the endothelial cell receptors, KDR/Flk-1 and Flt-1. Recently, a gene encoding a polypeptide with about 25% amino acid identity to mammalian VEGF was identified in the genome of Orf virus (OV), a parapoxvirus that affects sheep and goats and occasionally, humans, to generate lesions with angiogenesis. In this study, we examined the biological activities and receptor of OV-derived NZ-7 VEGF (VEGF-E). VEGF-E was found to be a dimer of about 20 kDa with no basic domain nor affinity for heparin column, similar to VEGF121 subtype. VEGF121 has 10-100-fold less endothelial cell mitotic activity than VEGF165 due to lack of a heparin-binding basic region. Interestingly, however, VEGF-E showed almost equal levels of mitotic activity on primary endothelial cells and vascular permeability activity as VEGF165. Furthermore, VEGF-E bound KDR/Flk-1 (VEGFR-2) and induced its autophosphorylation to almost the same extent as VEGF165, but did not bind Flt-1 (VEGFR-1) nor induce autophosphorylation of Flt-1. These results indicate that VEGF-E is a novel type of endothelial growth factor, utilizing only one of the VEGF receptors, and carrying a potent mitogenic activity without affinity to heparin.
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PMID:A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. 981 35

The different members of the vascular endothelial growth factor (VEGF) family act as key regulators of endothelial cell function controlling vasculogenesis, angiogenesis, vascular permeability and endothelial cell survival. In this study, we have functionally characterized a novel member of the VEGF family, designated VEGF-E. VEGF-E sequences are encoded by the parapoxvirus Orf virus (OV). They carry the characteristic cysteine knot motif present in all mammalian VEGFs, while forming a microheterogenic group distinct from previously described members of this family. VEGF-E was expressed as the native protein in mammalian cells or as a recombinant protein in Escherichia coli and was shown to act as a heat-stable, secreted dimer. VEGF-E and VEGF-A were found to possess similar bioactivities, i.e. both factors stimulate the release of tissue factor (TF), the proliferation, chemotaxis and sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF-A, VEGF-E was found to bind with high affinity to VEGF receptor-2 (KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2+ concentration, whilst in contrast to VEGF-A, VEGF-E did not bind to VEGF receptor-1 (Flt-1). VEGF-E is thus a potent angiogenic factor selectively binding to VEGF receptor-2. These data strongly indicate that activation of VEGF receptor-2 alone can efficiently stimulate angiogenesis.
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PMID:A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. 988 93

VEGF-A induces angiogenesis and regulates endothelial function via production and release of nitric oxide (NO), which is produced by endothelial nitric oxide synthase (eNOS). While the upregulation of eNOS expression has been shown to be mediated via VEGF receptor KDR, there is controversy about which of the VEGF receptors triggers the release of nitric oxide in endothelial cells. In order to determine the levels of NO produced in response to VEGF-A stimulation in different endothelial cells, a reporter assay measuring the formation of cGMP as the direct product of NO-induced activation of guanylate cyclase was performed. Using two independent experimental strategies, we were able to prove that VEGF receptor KDR, but not VEGF receptor Flt-1, can induce NO release in endothelial cells. First, we made use of porcine aortic endothelial cells (PAE) expressing either KDR or Flt-1. While KDR-expressing PAE/KDR cells responded to VEGF-A stimulation with a significant elevation of intracellular cGMP already after 2 min, Flt-1-expressing PAE/Flt-1 cells did not show any signal in this RIA-based cGMP assay. In a second experimental strategy freshly isolated human umbilical vein endothelial cells (HUVEC) were stimulated either with the KDR-specific ligand VEGF-E or with the Flt-1-specific ligand PIGF-2. VEGF-E induces cGMP elevation in this setting, while PIGF-2 was unable to do so, clearly demonstrating that KDR is responsible for NO release in endothelial cells. In our assays cGMP formation is fully dependent on NO generation since the NOS inhibitor L-NAME can block this VEGF-A-induced action. These data show that the VEGF receptor KDR is responsible for NO release in endothelial cells, highlighting a new function of KDR and further supporting the importance of KDR in the regulation of the vasculature.
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PMID:A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. 1060 Apr 73

The signaling activity of Platelet-derived growth factors A and B (PDGF-A and PDGF-B) that is mediated through the two receptor kinases, PDGFR-alpha and PDGFR-beta has been shown to be critical for the development of the cardiovascular organs, the kidney, the lung and the central nervous system. During the cloning of genes for VEGF related proteins, we isolated a mouse cDNA that can encode for a protein of 345 amino acids. A comparison of the amino acid sequence reveals that this predicted gene product displays 95% identity to human PDGF-C. The mouse Pdgfc gene maps to a region of chromosome 17 that is syntenic to human chromosome 6p21.3 In E9. 5-E15.5 mouse embryo, Pdgfc is widely expressed in the surface ectoderm and later in the germinal layer of the skin, the olfactory and otic placode and their derivatives and the lining of the oral cavity. In the gut and visceral organs, such as the lung and the kidney, Pdgfc mRNA is first expressed in the endodermal epithelium and later in mesenchymal tissues associated with the endodermal structures. Similar to other PDGFs, Pdgfc is widely expressed in mesenchymal precursors and the myoblast of the smooth and skeletal muscles. Contrary to PDGF-A, Pdgfc is not expressed in the central nervous system, except in the cerebellum, and neurogenic derivatives of the neural crest cells. Pdgfc is also absent from the heart and the vascular endothelium
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PMID:The mouse Pdgfc gene: dynamic expression in embryonic tissues during organogenesis. 1096 Jul 85

The term 'platelet-derived growth factor' (PDGF) refers to a family of disulphide-bonded dimeric isoforms that are important for growth, survival and function in several types of connective tissue cell. So far, three different PDGF chains have been identified - the classical PDGF-A and PDGF-B and the recently identified PDGF-C. PDGF isoforms (PDGF-AA, AB, BB and CC) exert their cellular effects by differential binding to two receptor tyrosine kinases. The PDGF alpha-receptor (PDGFR-alpha) binds to all three PDGF chains, whereas the beta-receptor (PDGFR-beta) binds only to PDGF-B. Gene-targeting studies using mice have shown that the genes for PDGF-A and PDGF-B, as well as the two PDGFR genes, are essential for normal development. Furthermore, overexpression of PDGFs is linked to different pathological conditions, including malignancies, atherosclerosis and fibroproliferative diseases. Here we have identify and characterize a fourth member of the PDGF family, PDGF-D. PDGF-D has a two-domain structure similar to PDGF-C and is secreted as a disulphide-linked homodimer, PDGF-DD. Upon limited proteolysis, PDGF-DD is activated and becomes a specific agonistic ligand for PDGFR-beta. PDGF-DD is the first known PDGFR-beta-specific ligand, and its unique receptor specificity indicates that it may be important for development and pathophysiology in several organs.
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PMID:PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. 1133 81

There are four members of the platelet-derived growth factor (PDGF) family; PDGF-A, PDGF-B, PDGF-C and PDGF-D. Their biological effects are mediated via two tyrosine kinase receptors, PDGFR-alpha and PDGFR-beta, and PDGF-mediated signaling is critical for development of many organ systems. Analysis in adult tissues showed that PDGF-C was mainly expressed in kidney, testis, liver, heart and brain. During development, PDGF-C expression was widespread and dynamic, and found in somites and their derivatives, in kidney, lung, brain, and in several other tissues, particularly at sites of developing epidermal openings. PDGF-C may therefore have unique functions during tissue development and maintenance.
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PMID:Expression analysis of PDGF-C in adult and developing mouse tissues. 1174 81

Vascular endothelial growth factor (VEGF) is a major growth factor for developing endothelial cells (ECs). Embryonic lethality due to haploinsufficiency of VEGF in the mouse highlighted the strict dose dependency of VEGF on embryonic vascular development. Here we investigated the dose-dependent effects of VEGF on the differentiation of ES cell-derived fetal liver kinase 1 (Flk-1)/VEGF receptor 2(+) (VEGFR2(+)) mesodermal cells into ECs on type IV collagen under a chemically defined serum-free condition. These cells could grow even in the absence of VEGF, but differentiated mostly into mural cells positive for alpha-smooth muscle actin. VEGF supported in a dose-dependent manner the differentiation into ECs defined by the expression of VE-cadherin, platelet-endothelial cell adhesion molecule 1 (PECAM-1)/ CD31, CD34, and TIE2/TEK. VEGF requirement was greater at late than at early phase of culture during EC development, whereas response of VEGFR2(+) cells to VEGF-E, which is a virus-derived ligand for VEGFR2 but not for Flt-1/VEGFR1, was not dose sensitive even at late phase of culture. Delayed expression of VEGFR1 correlated with increased dose dependency of VEGF. These results suggested that greater requirement of VEGF in the maintenance than induction of ECs was due to the activity of VEGFR1 sequestering VEGF from VEGFR2 signal. The chemically defined serum-free culture system described here provides a new tool for assessing different factors for the proliferation and differentiation of VEGFR2(+) mesodermal cells.
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PMID:A chemically defined culture of VEGFR2+ cells derived from embryonic stem cells reveals the role of VEGFR1 in tuning the threshold for VEGF in developing endothelial cells. 1240 93

The vascular endothelial growth factor (VEGF) family plays important roles in angiogenesis and vascular permeability. Novel members of the VEGF family encoded in the Orf virus genome, VEGF-E, function as potent angiogenic factors by specifically binding and activating VEGFR-2 (KDR). VEGF-E is about 45% homologous to VEGF-A at amino acid levels, however, the amino acid residues in VEGF-A crucial for the VEGFR-2-binding are not conserved in VEGF-E. To understand the molecular basis of the biological activity of VEGF-E, we have functionally mapped residues important for interaction of VEGF-E with VEGFR-2 by exchanging the domains between VEGF-E(NZ-7) and PlGF, which binds only to VEGFR-1 (Flt-1). Exchange on the amino- and carboxyl-terminal regions had no suppressive effect on biological activity. However, exchange on either the loop-1 or -3 region of VEGF-E(NZ-7) significantly reduced activities. On the other hand, introduction of the loop-1 and -3 of VEGF-E(NZ-7) to placenta growth factor rescued the biological activities. The chimera between VEGF-A and VEGF-E(NZ-7) gave essentially the same results. These findings strongly suggest that a common rule exists for VEGFR-2 ligands (VEGF-E(NZ-7) and VEGF-A) that they build up the binding structure for VEGFR-2 through the appropriate interaction between loop-1 and -3 regions.
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PMID:A set of loop-1 and -3 structures in the novel vascular endothelial growth factor (VEGF) family member, VEGF-ENZ-7, is essential for the activation of VEGFR-2 signaling. 1255 14

VEGF family members play important roles in angiogenesis and vascular permeability. VEGF-A-transgenic mice showed an increased vascularization with edema due to hyper-vascular permeability and subcutaneous hemorrhage as side effects. VEGF-A binds and activates two receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). To dissect the signals of these two receptors, we generated transgenic mice overexpressing either the VEGFR-2-specific ligand VEGF-E(NZ-7) or VEGFR-1-specific ligand PlGF-II under the control of the Keratin-14 promoter. VEGF-E-mice showed a significant increase in vascularization (about 10-fold compared to control mice) in subcutaneous tissues, whereas PlGF-mice showed only a 2-3-fold increase. Interestingly, VEGF-E-mice did not show any clear edematous lesions or hemorrhagic spots on the skin. Microscopically, VEGF-E-induced capillary networks have a well organized structure with the recruitment of pericytes. These results indicate that VEGF-E is a new angiogenic agent with less side effects for clinical usage.
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PMID:VEGFR-2-specific ligand VEGF-E induces non-edematous hyper-vascularization in mice. 1256 70

The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell lines were found to express significant levels of beta-PDGFR. Interestingly, none of the tested cell lines expressed alpha-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for beta-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of beta-PDGFR and tyrosine phosphorylation of PLC-gamma, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express beta-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked beta-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express beta-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, beta-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.
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PMID:Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing's sarcoma cells. 1270 Jun 68


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