Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase-9 (MMP-9) plays a crucial role in both angiogenesis and tumor invasion. Vascular endothelial growth factor (VEGF) has been shown to up-regulate the expression of MMP-9 in vascular smooth muscle cells. We recently reported that hemoglobin (Hb) enhances the expression of tissue factor (TF) and VEGF on TF-positive human malignant cells. Therefore, to explore the relationship between tumor cell angiogenic protein VEGF and MMP-9, we studied the effect of Hb on MMP-9 production in human A375 malignant melanoma and J82 bladder carcinoma (TF+) cells and in KG1 myeloid leukemia (TF-) cells. Malignant cells were incubated with varying concentrations (0-1.0 mg/ml) of Hb and analyzed for released MMP-9 by gelatin zymography, dot immunoblotting, enzyme-linked immunosorbent assay, and Western blotting. Hb (0.50 mg/ml) induced an almost two-fold increase of MMP-9 in both A375 malignant melanoma (398 +/- 62 versus 233 +/- 61.0 ng/ml, P = 0.027) and J82 bladder carcinoma cells (1.55 +/- 0.12 versus 0.80 +/- 0.004 ng/ml, P = 0.004), compared with cells incubated without Hb. This release of MMP-9 was significantly inhibited by cycloheximide (95%) and by the specific inhibitors of protein tyrosine kinase, genistein (70 +/- 3.0%, P = 0.00027 and 67 +/- 1.0%, P = 0.00005) and mitogen-activated protein (MAP)-kinase, PD98059 (56 +/- 2.0%, P = 0.0001 and 62 +/- 1.0%, P = 0.00003) in A375 and J82 cells, respectively. In contrast, Hb (2.0 mg/ml) did not increase MMP-9 in KG1 cells. We conclude that Hb-induced synthesis of active MMP-9 in TF-bearing malignant cells is due to de novo synthesis of newly formed protein and is mediated by protein tyrosine kinase and by mitogen-activated protein kinase pathways.
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PMID:Hemoglobin induces the production and release of matrix metalloproteinase-9 from human malignant cells. 1285 30

Vascular endothelial growth factor (VEGF) is a potent, multifunctional, endothelial-cell-specific growth factor. It stimulates proliferation and migration of endothelial cells. Characterization of intracellular signal transduction after VEGF and VEGF receptor (VEGFR) interaction has demonstrated the involvement of the mitogen-activated protein kinase pathway. However, several studies indicated that signal transducers and activators of transcription (STAT) is another important pathway downstream of VEGF/VEGFR interaction. Therefore, we studied the role of STAT3 in the migration and tube formation of the human dermal microvascular endothelial cells (HDMEC). HDMEC expressed phosphorylated forms of STAT1, STAT3, and STAT5, and a marked increase of phosphorylated STAT3 in the nuclear fraction after addition of VEGF was observed by Western blot and immunohistochemical staining. To verify the functional implication of STAT3 phosphorylation in HDMEC migration, we introduced a dominant-negative STAT3 using adenovirus vector system. Dominant-negative STAT3 abolished the VEGF-induced nuclear translocation of phosphorylated STAT3 and inhibited HDMEC migration completely. Dominant-negative STAT3 also suppressed VEGF-induced HDMEC tube formation on Matrigel and on collagen gel. These data demonstrate that STAT3 and its phosphorylation are involved in the downstream pathway of VEGF/VEGFR interaction and regulate VEGF-induced HDMEC migration and tube formation.
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PMID:Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. 1287 94

Vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/Flk-1) is a high-affinity receptor for vascular endothelial growth factor-A (VEGF-A), and mediates most of the endothelial growth and survival signals from VEGF-A. VEGFR-2 has a typical tyrosine kinase receptor structure with seven immunoglobulin (Ig)-like domains in the extracellular region, as well as a long kinase insert in the tyrosine kinase domain. It utilizes a unique signaling system for DNA synthesis in vascular endothelial cells, i.e. a phospholipase C gamma-protein kinase C-Raf-MAP kinase pathway. Although VEGF-A binds two receptors, VEGFR-1 and -2, a newly isolated ligand VEGF-E (Orf-virus-derived VEGF) binds and activates only VEGFR-2. Transgenic mice expressing VEGF-E(NZ-7) showed a dramatic increase in angiogenesis with very few side effects (such as edema and hemorrhagic spots), suggesting strong angiogenic signaling and a potential clinical utility of VEGF-E. VEGF family members bear three loops produced via three intramolecular disulfide bonds, and cooperation between loop-1 and loop-3 is necessary for the specific binding and activation of VEGFR-2 for angiogenesis. As it directly upregulates tumor angiogenesis, VEGFR-2 is an appropriate target for suppression of solid tumor growth using exogenous antibodies, small inhibitory molecules and in vivo stimulation of the immune system.
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PMID:Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E. 1296 71

Vascular endothelial growth factor (VEGF) is a major agent in choroidal and retinal neovascularization, events associated with age-related macular degeneration (AMD) and diabetic retinopathy. Retinal pigment epithelium (RPE), strategically located between retina and choroid, plays a critical role in retinal disorders. We have examined the effects of various growth factors on the expression and secretion of VEGF by human retinal pigment epithelial cell cultures (HRPE). RT-PCR analyses revealed the presence of three isoforms of mRNA corresponding to VEGF 121, 165, and 189 that were up regulated by TGF-beta1. TGF-beta1, beta2, and beta3 were the potent inducers of VEGF secretion by HRPE cells whereas bFGF, PDGF, TGF-alpha, and GM-CSF had no effects. TGF-beta receptor type II antibody significantly reversed induction of VEGF secretion by TGF-beta. In contrast activin, inhibin and BMP, members of TGF-beta super family, had no effects on VEGF expression in HRPE. VEGF mRNA levels and protein secretion induced by TGF-beta were significantly inhibited by SB203580 and U0126, inhibitors of MAP kinases, but not by staurosporine and PDTC, protein kinase C and NF-kappaB pathway inhibitors, respectively. TGF-beta also induced VEGF expression by fibroblasts derived from human choroid of eye. TGF-beta induction of VEGF secretion by RPE and choroid cells may play a significant role in choroidal neovascularization (CNV) in AMD. Since the secretion of VEGF by HRPE is regulated by MAP kinase pathways, MAP kinase inhibitors may have potential use as therapeutic agents for CNV in AMD.
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PMID:Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. 1456 75

Keloids are characterized as an "overexuberant" healing response in which disequilibrium between production and catabolism of extracellular matrix (ECM) occurs. Previous studies from our laboratory and others demonstrate an intrinsically higher level of plasminogen activator inhibitor-1 (PAI-1) expression in keloid tissues and cultured fibroblasts compared with normal bordering skin. These findings support the concept that an altered balance of activator and inhibitor activities in the plasminogen system, in particular, an overexpression of PAI-1, may partly contribute to keloid formation and tissue fibrosis. Vascular endothelial growth factor (VEGF) has been implicated as a critical factor in regulating angiogenesis and inflammation under both physiological and pathological conditions. This study was designed to assess whether VEGF plays a role in keloid fibrosis. We report that VEGF was expressed at higher levels in keloid tissues and their derived fibroblasts compared with their associated normal skin. We have further demonstrated that VEGF stimulated the expression of PAI-1, but not urokinase plasminogen activator (uPA), in keloid fibroblasts at both mRNA and protein levels, in a dose- and time-dependent manner. However, treatment of normal skin fibroblasts with VEGF exerted little effects on PAI-1 gene expression. Additionally, we have characterized for the first time that the extracellular signal-regulated kinase (ERK)1/2 signaling pathway is mainly involved in VEGF-induced PAI-1 expression and have demonstrated its potential as a target molecule for modulation of scar fibrosis. These findings suggest that VEGF may play an important role in keloid formation by altering ECM homeostasis toward a state of impaired degradation and excessive accumulation.
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PMID:Increased vascular endothelial growth factor may account for elevated level of plasminogen activator inhibitor-1 via activating ERK1/2 in keloid fibroblasts. 1464 71

Vascular endothelial growth factor (VEGF) and semaphorin-3A (Sema-3A) play important roles in the transduction of promitotic and antimitotic signals, respectively. Here, we report that these conflicting signals are integrated via negative feedback between VEGF and Sema-3A pathways in several primary normal, but not malignant, mesothelial cells. Unlike malignant mesothelial (MM) cells, in which VEGF induces cell proliferation, normal mesothelial (NM) cell growth was repressed by VEGF. Although both cell-types expressed an overlapping set of VEGF tyrosine-kinase receptors, only in NM cells VEGF exposure entails a p38 mitogen-activated protein kinase (MAPK)-dependent increased of Sema-3A production. Inhibition of p38 MAPK (by SB202190 and SB203580) or a dominant-negative mutant of Sema-3A receptor plexin-A1 reversed the inhibitory effects of VEGF in NM cells, increasing cyclin D1 synthesis and cell growth. Conversely, sustained activation of p38 MAPK by the p38 MAPK-activating kinases MKK3 and MKK6 or transfection with Sema-3A inhibited VEGF-induced cyclin D1 up-regulation and MM cell proliferation. Therefore, these results delineate a new role of Sema-3A in VEGF function mediated by p38 MAPK and suggest that the abrogation of regulated Sema-3A expression is responsible for VEGF-driven growth of tumor cells.
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PMID:Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation. 1465 93

Vascular endothelial growth factor (VEGF) induces activation of p38 mitogen-activated protein kinase (MAPK) in primary endothelial cells and may be critical for VEGF-induced angiogenesis. We investigated the molecular basis for p38 activation in response to VEGF. The expression of a C-terminal splice variant of FAK, FRNK, had no affect on VEGF-induced activation of p38; however, expression of a dominant-negative RAFTK/Pyk2 mutant led to a decrease in the activation of p38, but had no affect on extracellular signal-regulated kinase (ERK). Since calcium regulates RAFTK/Pyk2, we investigated its role in p38 activity. Preincubation with EGTA suppressed p38 activation, while calcium ionophore induced p38 activity. Inhibition of phospholipase C (PLC) resulted in complete inhibition of ERK, while having no affect on p38 activity. These data suggested a bifurcation in the regulation of MAPKs that occurs at the level of PLC and RAFTK/Pyk2 activation. Src family kinases interact with RAFTK/Pyk2. Inhibition of Src by either pharmacological or genetic means decreased p38 activity. Finally, we found that both Src and RAFTK/Pyk2 were essential for endothelial cell migration. These data identified a novel regulatory network involving extracellular calcium, RAFTK/Pyk2, Src and p38. This signaling network appears to be critical for VEGF-induced endothelial cell migration.
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PMID:Vascular endothelial growth factor-mediated activation of p38 is dependent upon Src and RAFTK/Pyk2. 1467 43

Vascular endothelial growth factor (VEGF) is essential for the induction of angiogenesis and drives both endothelial cell (EC) proliferation and migration. It has been suggested that VEGF also regulates vessel diameter, although this has not been tested explicitly. The two most abundant isoforms, VEGF(121) and VEGF(165), both signal through VEGF receptor 2 (VEGFR-2). We recently optimized a three-dimensional in vitro angiogenesis assay using HUVECs growing on Cytodex beads and embedded in fibrin gels. Fibroblasts provide critical factors that promote sprouting, lumen formation, and vessel stability. Using this assay, we have examined the role of VEGF in setting vessel diameter. Low concentrations of both VEGF(121) and VEGF(165) promote growth of long, thin vessels, whereas higher concentrations of VEGF remarkably enhance vessel diameter. Placental growth factor, which binds to VEGFR-1 but not VEGFR-2, does not promote capillary sprouting. Moreover, specific inhibition of VEGFR-2 signaling results in a dramatic reduction of EC sprouting in response to VEGF, indicating the critical importance of this receptor. The increase in vessel diameter is the result of cell proliferation and migration, rather than cellular hypertrophy, and likely depends on MEK1-ERK1/2 signaling. Both phosphatidylinositol 3-kinase and p38 activity are required for cell survival. We conclude that the diameter of new capillary sprouts can be determined by the local concentration of VEGF and that the action of VEGF on angiogenic EC in this assay is critically dependent on signaling through VEGFR-2.
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PMID:VEGF(121) and VEGF(165) regulate blood vessel diameter through vascular endothelial growth factor receptor 2 in an in vitro angiogenesis model. 1469 6

Insulin-like growth factor-1 (IGF-1) has been described as an important factor in proliferation, cell survival and migration of multiple myeloma (MM) cells. Angiogenesis correlates with development and prognosis of the MM disease. Vascular endothelial growth factor (VEGF) is one of the prominent factors involved in this process. The different functions of IGF-1 were investigated in the 5TMM mouse model with emphasis on proliferation, migration and VEGF secretion, and the signalling pathways involved. Western Blot analysis revealed that ERK1/2 and Akt (PKB) were activated after IGF-1 stimulation. The activation of ERK1/2 was reduced by the PI3K inhibitor Wortmannin, implying that the PI3K pathway is involved in its activation. Insulin-like growth factor-1 induced an increase in DNA synthesis in MM cells, which was mediated by a PI3K/Akt-MEK/ERK pathway. Insulin-like growth factor-1 enhanced F-actin assembly and this process was only PI3K mediated. Stimulation by IGF-1 of VEGF production was reduced by PD98059, indicating that only the MEK-ERK pathway is involved in IGF-1-stimulated VEGF production. In conclusion, IGF-1 mediates its multiple effects on MM cells through different signal transduction pathways. In the future, we can study the potential in vivo effects of IGF-1 inhibition on tumour growth and angiogenesis in MM.
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PMID:Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model. 1499 10

Heparan sulfates, the carbohydrate chains of heparan sulfate proteoglycans, play an important role in basement membrane organization and endothelial barrier function. We explored whether endothelial cells secrete a heparan sulfate degrading heparanase under inflammatory conditions and what pathways were responsible for heparanase expression. Heparanase mRNA and protein by Western blot were induced when cultured endothelial cells were treated with cytokines, oxidized low-density lipoprotein (LDL) or fatty acids. Heparanase protein in the cell media was induced 2-10-fold when cells were treated with tumor necrosis factor alpha (TNFalpha) or interleukin 1beta (IL-1beta). Vascular endothelial growth factor (VEGF), in contrast, decreased heparanase secretion. Inhibitors to nuclear factor-kappaB (NFkappaB), PI3-kinase, MAP kinase, or c-jun kinase (JNK) did not affect TNFalpha-induced heparanase secretion. Interestingly, inhibition of caspase-8 completely abolished heparanase secretion induced by TNFalpha. Fatty acids also induced heparanase, and this required an Sp1 site in the heparanase promoter. Immunohistochemical analyses of cross sections of aorta showed intense staining for heparanase in the endothelium of apoE-null mice but not wild-type mice. Thus, heparanase is an inducible inflammatory gene product that may play an important role in vascular biology.
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PMID:Inflammatory cytokines and fatty acids regulate endothelial cell heparanase expression. 1510 55


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