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)

Tissue factor (TF) has been shown to be up-regulated in endothelial cells by the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) as well as by the main angiogenic factor VEGF. Since both stimuli induce the transcription factor EGR-1, which is critically involved in TF gene regulation, we used EGR-1-dependent TF induction as a model to identify potential cross-talks between the various signal transduction cascades initiated by VEGF and TNF-alpha. The data show that at the MAP kinase level, VEGF mainly activates ERK1/2 and p38 MAP kinases in human endothelial cells. TNF-alpha is able to activate all three MAP kinase cascades as well as the classical inflammatory IkappaB/NFkappaB pathway. Furthermore, the MEK/ERK module of MAP kinases appears to act as the convergence point of VEGF- and TNF-alpha-initiated signaling cascades, which lead to the activation of EGR-1 and subsequent TF expression, whereas the upstream signals are distinct. We found that induction of TF by VEGF via EGR-1 is strongly PKC dependent. The TNF-alpha-initiated MEK/ERK cascade connected to EGR-1 and TF expression is clearly less sensitive to PKC inhibition. TNF-alpha-mediated activation of MEK/ERK and EGR-1 can be blocked by adenoviral expression of a dominant negative mutant of IKK2, whereas the VEGF signaling pathway is unaffected. Thus, our data demonstrate a new link between the classical inflammatory IKK/IkappaB and the MEK/ERK cascades triggered by TNF-alpha. The additional finding that EGF induces ERK and EGR-1 in a PKC-independent manner and that this signal is not sufficient to up-regulate TF emphasizes the importance of a VEGF-specific signaling pattern for the induction of TF.
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PMID:Specificity, diversity, and convergence in VEGF and TNF-alpha signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells. 1114 11

Flt-1, also known as vascular endothelial growth factor receptor 1 (VEGFR-1), is a high-affinity tyrosine kinase receptor for VEGF and is expressed almost exclusively on vascular endothelial cells. As an exception, Flt-1 transcript was recently found to be expressed in human peripheral blood monocytes. However, the protein of the Flt-1 receptor on the cell surface of monocytes is yet to be identified, and whether the Flt-1 protein is expressed during the differentiation of monocyte-macrophage lineage cells has not been examined. Using monoclonal antibodies against 2 different antigenic epitopes on the Flt-1 extracellular domain, this study found that the major population of the monocyte-marker CD97+ cells in human peripheral blood express Flt-1 as a cell surface molecule. VEGFR-2 (KDR/Flk-1) was not expressed at detectable levels in these cells. An Flt-1 neutralizing monoclonal antibody significantly suppressed VEGF-induced migration of the monocytes, suggesting an important role for Flt-1 in the biologic function of monocytes. Furthermore, CD34+ cells in human cord blood, originally negative for the Flt-1 expression, differentiated into Flt-1+ cells in association with the appearance of monocyte-macrophage markers after a 2-week culture in the presence of hematopoietic cytokines. In addition, the Flt-1+ CD11b+ cell fraction from CD34+ cells was found to efficiently differentiate into multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and osteoclast differentiation factor. These results strongly suggest that Flt-1 is a novel cell surface marker as well as a biologically functional molecule for monocyte-macrophage lineages in humans.
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PMID:Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. 1115 98

Five specific single-chain antibodies recognizing the human vascular endothelial growth factor receptor-2 (VEGFR-2/KDR) were selected from a V-gene phage display library constructed from mice immunized with the extracellular domain of VEGFR-2 (Ig-like domain 1-7). All five scFv antibodies (A2, A7, B11, G3, and H1) bound to the purified native antigen in enzyme-linked immunosorbent assay and Dot Blot, and showed no crossreactivity to the human VEGF-receptor 1 (VEGFR-1). The selected antibodies recognize a conformation-dependent epitope of the native receptor and do not recognize denatured antigen in Western blots, as well as linear overlapping peptides comprising the sequence of the human VEGFR-2. The five scFv antibodies bind to the surface of endothelial cells overexpressing human VEGFR-2 c-DNA (PAE/VEGFR-2 cells) as detected by surface immunofluorescence using confocal microscopy. In addition scFv A7 specifically detected VEGFR-2 expressing endothelial cells in the glomerulus of frozen human kidney tissue sections. Therefore, A7 has potential clinical application as a marker for angiogenesis in cryosections of different human tissues. Additionally, two recombinant scFvs (A2 and A7) very efficiently recognize VEGFR-2 on PAE/VEGFR-2 cells and freshly prepared human umbilical vein endothelial cells by fluorescence-activated cell sorter (FACS) analysis. The scFv fragment A7, which was the most sensitive antibody in FACS analysis, recognizes human CD34+VEGFR-2+ hematopoietic immature cells within the population of enriched CD34+ cells isolated from human cord blood. The dissociation constant of A7 was determined to be K(d) = 3.8 x 10(-9) M by BIAcore analysis. In conclusion, scFv fragment A7 seems to be an important tool for FACS analysis and cell sorting of vascular endothelial cells, progenitor cells and hematopoitic stem cells, which are positive for VEGFR-2 gene expression.
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PMID:Anti-VEGFR-2 scFvs for cell isolation. Single-chain antibodies recognizing the human vascular endothelial growth factor receptor-2 (VEGFR-2/flk-1) on the surface of primary endothelial cells and preselected CD34+ cells from cord blood. 1120 88

CD14-positive monocytes obtained from human peripheral blood were cultured with GM-CSF and IL-4. During the early culture phase immature dendritic cells (DCs) developed which not only expressed CD1a, HLA-DR and CD86, but also expressed the endothelial cell markers von Willebrand factor (vWF), VE-cadherin and VEGF receptors Flt-1 and Flt-4. Further maturation of DCs was achieved by prolonged cultivation with TNFalpha. These cells showed typical DC morphology and like professional antigen-presenting cells (APCs) expressed CD83 and high levels of HLA-DR and CD86. However, if immature DCs were grown with VEGF, bFGF and IGF-1 on fibronectin/vitronectin-coated culture dishes, a marked change in morphology into caudated or oval cells occurred. In the presence of these angiogenic growth factors the cultured cells developed into endothelial-like cells (ELCs), characterized by increased expression of vWF, KDR and Flt-4 and a disappearance of CD1a and CD83. Addition of IL-4 and Oncostatin M also increased VE-cadherin expression, and the loosely adherent cells formed clusters, cobblestones and network-like structures. vWF- expressing ELCs mainly originated from CD1a-positive cells, and VEGF was responsible for the decrease in the expression of the DC markers CD1a and CD83. In mixed leukocyte cultures, mature DCs were more potent APCs than ELCs. Moreover, Ac-LDL uptake, and the formation of tubular structures on a plasma matrix was restricted to ELCs. These results suggest that in the presence of specific cytokines immature DCs have the potential to differentiate along different lineages, i.e. into a cell type resembling ELCs.
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PMID:Dendritic cells derived from peripheral monocytes express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. 1121 40

Vascular endothelial growth factor, VEGF, stimulates angiogenesis by directly acting on endothelial cells. The effects of VEGF are mediated by two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR) that are highly related to receptors of the platelet derived growth factor (PDGF) receptor family. We are interested in early signalling events downstream from VEGF receptors that affect blood vessel homeostasis. Endothelial cells form multiple types of cell-cell junctions that are required for cellular organization into complex networks. These junctions also regulate communication among adjacent cells. Stimulation by various growth factors such as epidermal growth factor (EGF) or PDGF has been shown to disrupt cell-cell junctions, consequently affecting cell-to-cell communication. We investigated gap junctional communication (GJC) by monitoring the transfer of a low molecular mass fluorescent tracer molecule between adjacent cells using immunofluorescence microscopy. VEGF maximally blocked GJC 15 minutes after growth factor administration. The cells resumed communication via gap junctions within 1-2 hours after treatment. This early effect of VEGF on communication correlated with changes in the phosphorylation state of one of the proteins involved in gap junction formation, connexin 43 (Cx43). The signalling mechanisms involved in this phenomenon depend on activation of VEGFR-2, impinge on a tyrosine kinase of the Src family and activate the Erk family of MAP kinases. The function of VEGF-mediated disruption of GJC might be to restrict an increase in endothelium permeability to the environment affected by local injury to blood vessels.
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PMID:VEGF transiently disrupts gap junctional communication in endothelial cells. 1122 66

Thyroid nodule genesis may be considered as an amplification of thyroid heterogeneity due to genetic and/or epigenetic mechanisms. We classified the thyroid nodules in five types with distinct histological features: hyperplastic, neoplastic, colloid, cystic and thyroiditic nodules. Hyperplastic: Thyrocyte proliferation is under the control of TSH but several other paracrine and autocrine factors are secreted by follicular cells, the stromal apparatus and the lymphocytes, which are implicated in initiation and perpetuation of thyroid hyperplasia. Growth occurs mainly through TSHR, cAMP and PKA. Constitutive cAMP overproduction has been shown to be due to point mutation of the TSHR or Gs protein, producing overgrowth and hyperfunction. Neoplastic: Several activated oncogenes have been identified in thyroid malignancies. Oncogenes relevant to the thyroid carcinogenesis are: mutated TSHR and gsp (constitutive activation of cAMP); TRK (receptor for NGF); RET/PTC (phosphorylation of tyrosine kinase receptor)--an isoform of this oncogene is induced by radiation: ras (it encodes Gs proteins transducing mitogenic signals); and c-MET (receptor for hepatocyte growth factor). The evolution of a differentiated thyroid cancer towards an undifferentiated cancer is due to a mutation of a family of proteins (i.e., p53), which acts as a brake, preventing the genomic instability of cancer. It is suggested that a tumor initiates by RET or ras and possibly progresses--as a result of additional mutations and by p53 mutation--to anaplastic carcinoma. Colloid: Flattening of the epithelium and dilatation of follicles containing viscous material--made up by a concentrated solution of thyroglobulin (hTg)--is the characteristic of the colloid nodule. A defect of intraluminal reabsorption of hTg has been suggested but not proven. Experimentally, a load of iodine is able to change thyroid hyperplasia to a colloid feature; however, a load of iodine is rarely found in the clinical history of patients. A new clue to the pathogenesis comes from the finding that a relevant part of the colloid (10-20%) is made up of insoluble globules, where hTg is compacted in a polymeric form. It is suggested that stocking hTg into globules is defective in colloid nodules, leading to enormous enlargement of the follicle. Cystic: It is estimated that between 15 and 40% of thyroid nodules are partly or entirely cystic. The 'true cyst' is rare; most of the so-called cystic nodules are 'pseudocysts', which follow necrosis and colliquation. Necrosis issues as an imbalance between growth and the precisely regulated process of angiogenesis. More recently, the VEGF/VPF has been found to be at the origin of recent and recurrent cysts. Immunotoxic and apoptotic mechanisms have also been suggested. Chemical analysis of cystic fluid showed a 'denatured' and 'serum-like' pattern suggesting different mechanisms in the pathogenesis of the pseudocystic thyroid nodules. Thyroiditic: Nodular lymphocytic thyroiditis (NLT) includes two different entities: 1) lymphocyte thyroiditis growing as a nodule in a hyperplastic or normal gland, and 2) lymphocyte thyroiditis associated in the same nodule with other nodular diseases of the thyroid: papillary thyroid carcinoma and lymphoma have been found to be associated to chronic lymphocytic thyroiditis.
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PMID:Pathogenesis of thyroid nodules: histological classification? 1123 84

The function of VEGF in laryngeal carcinoma was studied by observing either the expressions of VEGF and its receptor flk-1 in laryngeal carcinoma, or the effect of anti-VEGF antibody and anti-VEGF receptor antibody on the growth of human laryngeal cancer cell line HEP-2 in vitro. The expression of VEGF and flt in the specimen of laryngeal carcinoma were determined by standardized immunohistochemistry (Elite ABC method). Anti-VEGF antibody and anti-VEGF receptor antibody were also added at various concentrations to the culture medium, respectively, and the growth of HEP-2 was measured by MTT assay. The immunohistochemical staining showed that the expressions of VEGF and flt were detected both in carcinoma cells and endothelial cells. The growth of HEP-2 cell line in vitro was suppressed when adding various concentration of anti-VEGF antibody and anti-VEGF receptor antibody to the culture medium. The laryngeal cancer cells can secret VEGF and there exists VEGF-binding site on laryngeal cancer cell. Both blockading VEGF with anti-VEGF antibody and blockading VEGF-binding site with anti-VEGF receptor antibody could inhibit HEP-2 growth.
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PMID:[The influence of vascular endothelial growth factor and its receptor on the growth of laryngeal cancer cell]. 1126 58

The vascular endothelial growth factor-A (VEGF-A), also known as the vascular permeability factor (VPF), has been shown to play an important role in malignant ascites formation. The effects of VEGF-A are mediated through flt-1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk-1) receptors. It has been shown that KDR/Flk-1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this receptor in hepatic ascites formation has not yet been elucidated. In this study, we examined the role of KDR/Flk-1 in the murine MH134 hepatic malignant ascites formation by means of VEGF-A- and KDR/Flk-1-specific neutralizing antibodies (VEGF-A nAb and KDR/Flk-1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb treatment. These inhibitory effects of KDR/Flk-1 nAb were more potent than those of VEGF-A nAb. The autophosphorylation of KDR/ Flk-1 in the peritoneal wall was almost completely abolished by KDR/ Flk-1 nAb, whereas a certain level of activation was still shown by VEGF-A nAb treatment. Another VEGF-family, VEGF-C, which also binds KDR/Flk-1, was detected in the ascites. Furthermore, in the therapeutic experiment, although both VEGF-A nAb and KDR/Flk-1 nAb prolonged the survival rate of ascites-bearing mice, the latter showed a more significant impact on the survival of animals. These results suggest that KDR/Flk-1 is a major regulator of malignant hepatic ascites formation, and that in addition to VEGF-A, VEGF-C may also be involved in the malignant ascites formation via KDR/ Flk-1 activation.
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PMID:The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model. 1128 48

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase [(VGP), metastatic phenotype] are not very well defined. We previously demonstrated that expression of the cell-surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. In this review, I will summarize our recent studies demonstrating that the expression of both genes is regulated by the AP-2 transcription factor. Moreover, we have observed a loss of AP-2 expression in metastatic melanoma cells. Re-expression of AP-2 in the highly metastatic A375SM cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice. MCAM/MUC18 mRNA and protein expression was significantly down-regulated while c-KIT expression was up-regulated in the AP-2-transfected cells. To further investigate the role of AP-2 in the progression of human melanoma, we attempted to inactivate AP-2 in primary cutaneous melanoma by using a dominant-negative AP-2, or the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice, and upregulated MMP-2 expression and activity. As AP-2 also regulates other genes that are involved in the progression of human melanoma such as E-cadherin, p21/WAF-1, HER2/neu, Bcl-2, FAS/APO-1, IGF-R-1, VEGF and the thrombin receptor (PAR-1), we therefore propose that loss of AP-2 is a crucial event in the development of malignant melanoma. In addition, the transition of melanoma cells from RGP to VGP is also associated with over-expression of the transcription factors CREB and ATF-1. The notion that the balance between AP-2 and CREB/ATF-1 expression determines the progression of melanoma cells towards the metastatic phenotype will be discussed.
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PMID:Gene regulation in melanoma progression by the AP-2 transcription factor. 1131 Jul 95

Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is structurally a typical tyrosine kinase receptor of about 180 kDa, and carries seven Ig-like domains in the extracellular region and a tyrosine kinase domain with a long kinase insert. Recent studies have revealed that the VEGFR-1 gene and its gene product have several unique characteristics structurally and functionally. In addition to the full length receptor, VEGFR-1 gene encodes for a soluble form carrying only six Ig domains via an alternative splicing. Both the full length and soluble form of VEGFR-1 show strong binding affinity for VEGF, but the kinase activity of the full length receptor is one order of magnitude lower than that of VEGFR-2 (KDR/Flk-1). Early in embryogenesis, null mutation of VEGFR-1 gene results in lethality due to a disorganization of blood vessels and an overgrowth of endothelial-like cells, suggesting a regulatory role in vivo. Mice carrying the extracellular domain of VEGFR-1 gene without the tyrosine kinase domain develop an almost normal circular system and survive. Thus, the extracellular region of VEGFR-1 is necessary and sufficient for physiological angiogenesis at the early stage of embryogenesis, possibly acting to trap VEGF and suppress VEGF levels to an appropriate range. The tyrosine kinase domain of VEGFR-1, although much weaker than that of VEGFR-2, transduces signals for endothelial cells. Furthermore, VEGFR-1 is involved in the VEGF-dependent migration and gene expression of monocyte/macrophages. Therefore, VEGFR-1 functions both in a positive and negative manner in different cellular systems and biological conditions.
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PMID:Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). 1131 9


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