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

Vascular endothelial growth factor (VEGF) stimulated the tyrosine phosphorylation of multiple components in confluent human umbilical vein endothelial cells (HUVECs) including bands of Mr 205,000, corresponding to the VEGF receptors Flt-1 and KDR, and Mr 145,000, 120,000, 97,000, and 65,000-70,000. VEGF caused a striking and transient increase in mitogen-activated protein (MAP) kinase activity and stimulated phospholipase C-gamma tyrosine phosphorylation, but it had no effect on phosphatidylinositol 3'-kinase activity. VEGF caused a marked increase in tyrosine phosphorylation of p125 focal adhesion kinase (p125(FAK)), which was both rapid and concentration-dependent. VEGF produced similar effects on p125(FAK) in the endothelial cell line ECV.304. VEGF stimulated tyrosine phosphorylation of the 68-kDa focal adhesion-associated component, paxillin, with similar kinetics and concentration dependence to that for p125(FAK). Thrombin and the phorbol ester, phorbol 12-myristate 13-acetate, also increased p125(FAK) tyrosine phosphorylation in HUVECs. The effect of VEGF on p125(FAK) tyrosine phosphorylation was completely inhibited by the actin filament-disrupting agent cytochalasin D and was partially inhibited by the protein kinase C inhibitor GF109203X. Inhibition of the MAP kinase pathway using a specific inhibitor of MAP kinase kinase had no effect on p125(FAK) tyrosine phosphorylation. VEGF stimulated migration and actin stress fiber formation in confluent HUVEC, and VEGF-induced p125(FAK)/paxillin tyrosine phosphorylation was accompanied by increased immunofluorescent staining of p125(FAK), paxillin, and phosphotyrosine in focal adhesions in confluent cultures of HUVECs. These findings identify p125(FAK) and paxillin as components in a VEGF-stimulated signaling pathway and suggest a novel mechanism for VEGF regulation of endothelial cell functions.
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PMID:Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. 918 76

Vascular endothelial growth factor (VEGF) is a potent chemotactic agent for endothelial cells. Yet the signalling pathways that modulate the motogenic effects of VEGF in vascular endothelial cells are still ill defined. In the present study, we found in primary cultures of human umbilical vein endothelial cells (HUVEC) that VEGF increased cell migration and induced a marked reorganization of the microfilament network that was characterized by the formation of stress fibers and the recruitment of vinculin to focal adhesions. VEGF also stimulated the mitogen activated protein (MAP) kinases ERK (extracellular signal-regulated kinase) and p38 (stress activated protein kinase-2), but not SAPK1/JNK (stress activated protein kinase-1/c-Jun NH2-terminal kinase). Activation of p38 resulted in activation of MAP kinase activated protein kinase-2/3 and phosphorylation of the F-actin polymerization modulator, heat shock protein 27 (HSP27). Inhibiting the VEGF-induced activation of ERK with PD098059 did not influence actin organization or cell migration but totally inhibited the VEGF-induced incorporation of thymidine into DNA. Inhibition of p38 activity by the specific inhibitor SB203580 led to an inhibition of HSP27 phosphorylation, actin reorganization and cell migration. The results indicate that the p38 pathway conveys the VEGF signal to microfilaments inducing rearrangements of the actin cytoskeleton that regulate cell migration. By modulating cell migration, p38 may thus be an important regulator of angiogenesis.
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PMID:p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. 939 75

Vascular endothelial growth factor (VEGF) stimulated a time- and concentration-dependent increase in PGI2 synthesis in human umbilical vein endothelial cells with a mean maximum increase of 2-fold above basal levels at 25 ng/ml after 60 min. VEGF also rapidly stimulated the release of arachidonic acid and phosphorylation and activation of cytosolic phospholipase A2 (cPLA2). The VEGF-related factor, placenta growth factor (PIGF), had little effect on PGI2 synthesis, arachidonic acid release or cPLA2 activation. PD98059, a selective inhibitor of MAP kinase kinase, caused complete inhibition of VEGF-stimulated MAP kinase activity, PGI2 synthesis and cPLA2 gel retardation, but had no effect on VEGF-induced vWF secretion. These findings provide the first evidence that VEGF can stimulate PGI2 synthesis via cPLA2-mediated arachidonic acid release and indicate that VEGF stimulation of this biosynthetic pathway may occur, at least in part, via activation of p42/p44 MAP kinases.
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PMID:Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase. 945 May 44

Vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) are structurally related growth factors for endothelial cells. VEGF binds to the related receptor tyrosine kinases Flt 1 and KDR/Flk 1 with high affinity, whereas PlGF binds only to Flt 1. Ligand-stimulated KDR is known to transduce signals for cellular activity such as proliferation and migration, whereas weak or no responses have been recorded for Flt 1. We examined VEGF and PlGF for their capacity to stimulate signal transduction in porcine aortic endothelial cells expressing Flt 1 or KDR. VEGF had essentially no effect on Flt 1 expressing cells, but induced DNA synthesis and migration of KDR expressing cells. PIGF on the other hand induced DNA synthesis but not migration of the Flt 1 cells. In agreement, MAP kinase, examined as a marker for DNA synthesis, was activated both by VEGF-stimulation of the KDR cells and by PlGF-stimulation of the Flt 1 cells. In contrast, phospholipase C-gamma (PLC-gamma), was tyrosine phosphorylated only in VEGF stimulated KDR cells, and not in the PlGF-stimulated Flt 1 cells, which is in agreement with a role for PLC-gamma in cellular migration. We furthermore examined induction of protein levels of plasminogen activator (PA), which was evident in the PlGF-stimulated Flt 1 cells, but not in the VEGF-stimulated KDR cells. These data show that Flt 1 is able to mediate an array of biological signals when appropriately stimulated and that the pattern of responses of PlGF-stimulation of Flt 1 is distinct from the pattern of responses to VEGF-stimulation of KDR.
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PMID:Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. 946 61

Rapid activation of intracellular signaling cascades is induced in cardiac myocytes in response to various external stresses. Vascular endothelial growth factor (VEGF) is a potent angiogenic mitogen secreted from tumor cells and cells exposed to hypoxia such as ischemic myocardial cells. To clarify the mechanisms of how cardiac myocytes respond and adapt to ischemic stresses, we investigated the intracellular signaling cascades in cultured rat cardiac myocytes in response to VEGF. We show that rapid activation of mitogen-activated protein kinase kinase kinase (MAPKKK) of Raf-1, MAP kinases, and S6 kinase (p90rsk) was induced in cardiac myocytes in response to VEGF. This activation of MAP kinases was also induced in fibroblasts. VEGF also caused phosphorylation of the activating transcription factor 2. Furthermore, VEGF strongly induced a transcription factor jun-B mRNA in cardiac myocytes. These results indicated that MAP kinase pathway is rapidly activated in cardiac myocytes and fibroblasts in response to VEGF. It is strongly suggested that cardiac myocytes are one of the targets of VEGF and that cardiac response to ischemic stresses may be at least partly mediated by VEGF.
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PMID:Vascular endothelial growth factor (VEGF) activates Raf-1, mitogen-activated protein (MAP) kinases, and S6 kinase (p90rsk) in cultured rat cardiac myocytes. 957 68

Eicosapentaenoic acid (EPA; 20:5, n-3) can restrain tumor growth and metastasis in vivo; however, the mechanism of its antitumor effect is still not fully understood. Angiogenesis is a crucial process for tumor growth and metastasis and inhibition of tumor angiogenesis can suppress tumor growth and metastasis in vivo. Vascular endothelial growth factor (VEGF) is an important angiogenic factor. In this study, we investigated the mechanisms of the inhibitory effect of EPA on VEGF-induced proliferation of bovine carotid artery endothelial (BAE) cells. BAE cells, treated with 0-5 microg/ml EPA for 48 h, displayed a dose-dependent suppression to VEGF (0.2 nM)-induced proliferation. Similar inhibitory effect was not found in BAE cells treated with arachidonic acid (AA; 20:4, n-6), or docasahexaenoic acid (DHA; 22:5, n-3). In contrast to its effect on VEGF-induced proliferation, EPA had no inhibition to basic fibroblast growth factor (bFGF, 0.2 nM)-induced proliferation in BAE cells. Both VEGF and bFGF activated mitogen-activated protein (MAP) kinase in BAE cells; however, EPA selectively inhibited VEGF-induced, but not bFGF-induced activation of MAP kinase. Flk-1 expression was inhibited dose-dependently in EPA-treated cells, whereas Flt-1 expression was increased in EPA treated cells. This in vitro inhibitory effect by EPA on Flk-1 receptor expression provides indirect evidence that one of the mechanisms of EPA for antitumor action in vivo maybe related to its antiangiogenic action.
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PMID:Eicosapentaenoic acid attenuates vascular endothelial growth factor-induced proliferation via inhibiting Flk-1 receptor expression in bovine carotid artery endothelial cells. 964 21

Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, promotes endothelial cell survival and angiogenesis. We recently showed that VEGF can support the growth of human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells in serum-free medium. Reasoning that VEGF might be modulating apoptotic signal transduction pathways, we examined mechanisms involved in the anti-apoptotic effect of VEGF on starvation- and ceramide-induced apoptosis in HDMEC. We observed that VEGF ameliorated the time-dependent increase in apoptosis, as demonstrated by morphologic observations, TUNEL assay, and DNA fragmentation. On the other hand, basic fibroblast growth factor only partially prevented apoptosis in serum-starved HDMEC; platelet-derived growth factor-BB was completely ineffective. VEGF activated the phosphorylation of extracellular signal regulated kinase (ERK)1 (p44 mitogen-activated protein kinase; MAPK) and ERK2 (p42 MAPK) in a time- and concentration-dependent manner. Both the VEGF-induced activation and its anti-apoptotic effect were prevented by the specific MAPK/ERK inhibitor PD98059. The presence of VEGF also inhibited the sustained activation of stress-activated protein kinase/c-jun-NH2-kinase (SAPK/JNK) caused by serum starvation and ceramide treatment. Activation of the MAPK pathway together with inhibition of SAPK/JNK activity by VEGF appears to be a key event in determining whether an endothelial cell survives or undergoes programmed cell death.
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PMID:VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. 1006 77

Vascular endothelial growth factor (VEGF) receptor Flk-1/KDR in endothelial cells is activated during vasculogenesis and angiogenesis upon ligand-receptor interaction. Activated Flk-1/KDR has been shown to recruit Src homology 2 domain-containing signaling molecules that are known to serve as links to the activation of the mitogen-activated protein (MAP) kinase signaling pathway. To define the functional significance of phosphatidylinositol (PI) 3-kinase in VEGF signaling, we have examined its role in human umbilical vein endothelial cell (HUVEC) cycle progression. We show herein that p85, the regulatory subunit of PI 3-kinase, is constitutively associated with Flk-1/KDR. The treatment of HUVECs with VEGF promoted tyrosine autophosphorylation of Flk-1/KDR and also induced phosphorylation of p85. This was followed by an increase in the PI 3-kinase activity, which was sensitive to wortmannin, a potent PI 3-kinase inhibitor. VEGF also induced a striking activation of MAP kinase in a time-dependent manner. Inhibition studies with both a dominant-negative p85 mutant and the PI 3-kinase inhibitor, wortmannin, were employed to show for the first time that VEGF-stimulated PI 3-kinase modulates MAP kinase activation and nuclear events such as transcription from c-fos promoter and entry into the synthesis (S)-phase. Our data demonstrate the importance of PI 3-kinase as a necessary signaling component of VEGF-mediated cell cycle progression.
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PMID:The role of phosphatidylinositol 3-kinase in vascular endothelial growth factor signaling. 1018 76

Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathogenesis of diabetic vascular complications. In the present study, we investigated whether expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine that has been proposed to recruit leukocytes to sites of inflammation, neovascularization, and vascular injury, can be modulated by VEGF in bovine retinal microvascular endothelial cells (BRECs). VEGF induced expression of MCP-1 mRNA in BRECs in a concentration- and time-dependent manner. Secretion of MCP-1 into the culture medium of BRECs treated with VEGF for 24 h was increased by 2.2-fold compared with the control. Inhibitors of transcription factor NF-kappaB, N-alpha-tosyl-L-lysine chloromethylketone (TLCK) and N-acetylcysteine (NAC), as well as an inhibitor of the extracellular signal-regulated kinase (ERK) pathway, PD 98059, attenuated VEGF-induced expression of MCP-1 mRNA. Using electrophoretic gel mobility shift assay, we observed that VEGF stimulated binding activity of NF-kappaB. VEGF-induced NF-kappaB activation was inhibited by TLCK and NAC, but not by PD 98059. Binding activity of transcription factor AP-1, which is suggested to regulate induction of the MCP-1 gene together with NF-kappaB, was also stimulated by VEGF. PD 98059 inhibited the VEGF-induced activation of AP-1. These results indicate that VEGF induces MCP-1 expression in BRECs most likely by activating NF-kappaB and AP-1 via ERK-independent and -dependent pathways. Activation of NF-kappaB and induction of MCP-1 by VEGF in microvascular endothelial cells may contribute to the development of diabetic vascular complications.
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PMID:Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. 1033 20

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are angiogenic molecules whose combined mitogenic activity is potently synergistic. However, the molecular mechanism underlying this synergy is incompletely understood. We examined whether VEGF and bFGF affect expression of each other or alter expression of the VEGF receptor KDR in retinal capillary endothelial cells. In addition, we investigated the intracellular signaling mechanisms involved in this response. VEGF-induced [3H]thymidine uptake was tightly correlated with KDR mRNA and protein concentrations, suggesting that increased KDR expression might account for VEGF's synergistic activity in the presence of bFGF. bFGF (10 ng/ml) induced KDR mRNA expression within 4 h and attained a 4.0-fold increase after 24 h. KDR protein expression was increased 7.5-fold after 48 h. VEGF (= 50 ng/ml) did not alter bFGF, VEGF, or KDR mRNA expression under serum-deprived conditions. In contrast, VEGF increased KDR mRNA expression 87% under growth conditions and 2.9-fold under serum-deprived conditions in the presence of bFGF. The protein kinase C (PKC) agonist phorbol myristate acetate (PMA) induced KDR mRNA expression 5.1-fold at 100 nmol/l. bFGF increased p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation within 5 min, reaching a maximum within 15 min and remaining significantly elevated for >6 h. bFGF-induced MAPK phosphorylation and KDR mRNA expression were almost completely inhibited by 5 micromol/l GFX, a non-isoform-selective PKC inhibitor. MAPK inhibitor PD98059 reduced KDR mRNA expression 72% at concentrations that inhibited bFGF-induced MAPK phosphorylation 100%, suggesting that pathways in addition to MAPK might also be involved. Inhibitors of the beta isoform of PKC (LY333531), protein kinase A (PKA) (H89), and phosphotidylinositol (PI) 3 kinase (wortmannin) had no significant effect. These data suggest that bFGF stimulates KDR expression through a PKC and p44/p42 MAPK-dependent pathway not primarily involving the beta isoform of PKC, PKA, or PI-3 kinase. Since bFGF induces VEGF expression and since increased KDR expression potentiates VEGF action, resulting in additional KDR expression and marked mitogenic activity, these data provide a novel mechanistic explanation for the angiogenic synergy between VEGF and bFGF.
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PMID:Basic fibroblast growth factor induces expression of VEGF receptor KDR through a protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway. 1033 22


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