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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

VEGF-KDR/Flk-1 signal utilizes the phospholipase C-gamma-protein kinase C (PKC)-Raf-MEK-ERK pathway as the major signaling pathway to induce gene expression and cPLA2 phosphorylation. However, the spatio-temporal activation of a specific PKC isoform induced by VEGF-KDR signal has not been clarified. We used HEK293T (human embryonic kidney) cells expressing transiently KDR to examine the activation mechanism of PKC. PKC specific inhibitors and human PKCdelta knock-down using siRNA method showed that PKCdelta played an important role in VEGF-KDR-induced ERK activation. Myristoylated alanine-rich C-kinase substrate (MARCKS) translocates from the plasma membrane to the cytoplasm depending upon phosphorylation by PKC. Translocation of MARCKS-GFP induced by VEGF-KDR stimulus was blocked by rottlerin, a PKCdelta specific inhibitor, or human PKCdelta siRNA. VEGF-KDR stimulation did not induce ERK phosphorylation in human PKCdelta-knockdown HEK293T cells, but co-expression of rat PKCdelta-GFP recovered the ERK phosphorylation. Y311/332F mutant of rat PKCdelta-GFP which cannot be activated by tyrosine-phosphorylation but activated by DAG recovered the ERK phosphorylation, while C1B-deletion mutant of rat PKCdelta-GFP, which can be activated by tyrosine-phosphorylation but not by DAG, failed to recover the ERK phosphorylation in human PKCdelta-knockdown HEK293T cell. These results indicate that PKCdelta is involved in VEGF-KDR-induced ERK activation via C1B domain.
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PMID:Activation and translocation of PKCdelta is necessary for VEGF-induced ERK activation through KDR in HEK293T cells. 1554 67

Tubulogenesis by epithelial cells regulates kidney, lung, and mammary development, whereas that by endothelial cells regulates vascular development. Although functionally dissimilar, the processes necessary for tubulation by epithelial and endothelial cells are very similar. We performed microarray analysis to further our understanding of tubulogenesis and observed a robust induction of regulator of G protein signaling 4 (RGS4) mRNA expression solely in tubulating cells, thereby implicating RGS4 as a potential regulator of tubulogenesis. Accordingly, RGS4 overexpression delayed and altered lung epithelial cell tubulation by selectively inhibiting G protein-mediated p38 MAPK activation, and, consequently, by reducing epithelial cell proliferation, migration, and expression of vascular endothelial growth factor (VEGF). The tubulogenic defects imparted by RGS4 in epithelial cells, including its reduction in VEGF expression, were rescued by overexpression of constitutively active MKK6, an activator of p38 MAPK. Similarly, RGS4 overexpression abrogated endothelial cell angiogenic sprouting by inhibiting their synthesis of DNA and invasion through synthetic basement membranes. We further show that RGS4 expression antagonized VEGF stimulation of DNA synthesis and extracellular signal-regulated kinase (ERK)1/ERK2 and p38 MAPK activation as well as ERK1/ERK2 activation stimulated by endothelin-1 and angiotensin II. RGS4 had no effect on the phosphorylation of Smad1 and Smad2 by bone morphogenic protein-7 and transforming growth factor-beta, respectively, indicating that RGS4 selectively inhibits G protein and VEGF signaling in endothelial cells. Finally, we found that RGS4 reduced endothelial cell response to VEGF by decreasing VEGF receptor-2 (KDR) expression. We therefore propose RGS4 as a novel antagonist of epithelial and endothelial cell tubulogenesis that selectively antagonizes intracellular signaling by G proteins and VEGF, thereby inhibiting cell proliferation, migration, and invasion, and VEGF and KDR expression.
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PMID:Identification and characterization of regulator of G protein signaling 4 (RGS4) as a novel inhibitor of tubulogenesis: RGS4 inhibits mitogen-activated protein kinases and vascular endothelial growth factor signaling. 1554

The Grb10 gene on chromosome 7p11.2-p12 belongs to a family of adapter proteins known to interact with a number of receptor tyrosine kinases, such as EGF, ErbB2/Her2, platelet-derived growth factor (PDGF), IGF-I receptors and vascular endothelial growth factor (VEGF) receptor, KDR (kinase insert domain containing receptor). In addition to receptor tyrosine kinases, Grb10 has also been found to interact with non-receptor tyrosine kinases such as Tec and Bcr-Abl, other cellular signaling molecules such as Raf-1, and the mitogen-activated protein (MAP) kinase, MEK. We demonstrated increased expression of Grb10 mRNA in more than one half of primary cervical squamous cell cancers (12 of 15 cases) when compared to corresponding non-cancerous uterine squamous cell tissues. In addition, immunohistochemical staining demonstrated that the Grb10 protein was prominent in the cytoplasm of cancer cells, whereas it was unreactive in the surrounding normal cervical squamous cells. In addition, its interruption by siRNA exhibited marked cell growth inhibition. These data indicate that amplification and increased expression of the Grb10 gene may play a role in the development of a portion of human cervical squamous cell cancer.
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PMID:Up-regulation of growth factor receptor-bound protein 10 in cervical squamous cell carcinoma. 1587 Sep 23

Unveiling of endothelial nuclear factor-kappaB (NF-kappaB) activation is pivotal for understanding the inflammatory reaction and the pathogenesis of inflammatory vascular diseases. We here report the novel function of extracellular signal-related kinase (ERK) in controlling endothelial NF-kappaB activation and inflammatory responses. In human endothelial cells, vascular endothelial growth factor (VEGF) induced NF-kappaB-dependent transcription of cell adhesion molecules (CAMs) and monocyte adhesion. These effects were prominently enhanced by either pretreatment with the MEK inhibitors, PD98059 and U0126 or overexpression of a dominant negative form of MEK, but blocked by a wild type ERK. Consistently, inhibition of ERK significantly increased IkappaB kinase (IKK) activity, IkappaBalpha phosphorylation, and nuclear translocation of NF-kappaB induced by VEGF, whereas overexpression of ERK resulted in the loss of these responses to VEGF. Using two PKC inhibitors has demonstrated that VEGF concomitantly stimulates IKK and its negative regulatory signal ERK through PKC that lies downstream of KDR/Flk-1. Strikingly, elevation of ERK in endothelial cells markedly inhibited CAM expression and NF-kappaB activation as well as monocyte adhesion induced by IL-1beta and TNF-alpha. The data collectively suggest that ERK serves as an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. Measuring the existence of ERK activity in vascular endothelial cells may be useful for predicting the feasibility and potency of inflammatory reactions in the vasculature.
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PMID:ERK is an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. 1624 16

A central challenge in chemical biology is profiling the activity of a large number of chemical structures against hundreds of biological targets, such as kinases. Conventional 32P-incorporation or immunoassay of phosphorylated residues produces high-quality signals for monitoring kinase reactions but is difficult to use in high-throughput screening (HTS) because of cost and the need for well-plate washing. The authors report a method for densely archiving compounds in nanodroplets on peptide or protein substrate-coated microarrays for subsequent profiling by aerosol deposition of kinases. Each microarray contains over 6000 reaction centers (1.0 nL each) whose phosphorylation progress can be detected by immunofluorescence. For p60c-src, the microarray produced a signal-to-background ratio of 36.3 and Z' factor of 0.63 for HTS and accurate enzyme kinetic parameters (KmATP = 3.3 microM) and IC50 values for staurosporine (210 nM) and PP2 (326 nM) at 10 microM adenosine triphosphate (ATP). Similarly, B-Raf phosphorylation of MEK-coated microarrays was inhibited in the nanoliter reactions by GW5074 at the expected IC50 of 9 nM. Common kinase inhibitors were printed on microarrays, and their inhibitory activities were systematically profiled against B-Raf (V599E), KDR, Met, Flt-3 (D835Y), Lyn, EGFR, PDGFRbeta, and Tie2. All results indicate that this platform is well suited for kinetic analysis, HTS, large-scale IC50 determinations, and selectivity profiling.
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PMID:Microarrays for the functional analysis of the chemical-kinase interactome. 1631 6

Vascular endothelial growth factor (VEGF, occurring in several isoforms: VEGF-A, -B, -C, -D) is a well-known endothelial cell mitogen and vascular growth and permeability factor. Recent work done over the last few years has elucidated the important role of VEGF, which participates in the regulation of normal (physiological or therapeutic) and pathological angiogenesis (VEGF-A, VEGF-B) and lymphangiogenesis (VEGF-C, VEGF-D). VEGF has also been implicated in practically every stage of angiogenesis, yet its role in the initiation of new blood vessel creation appears to be the most important. In addition to its role as a key angiogenic factor, VEGF also possesses neurotrophic and neuroprotective activity both in the peripheral and in the central nervous system, exerting a direct action on neurons, Schwann cells, astrocytes, neural stem cells, and microglia. VEGF interacts with three subtypes of VEGF receptors occurring on the cellular membrane known as VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4). All these receptor types possess an internal tyrosin kinase domain. Interaction of VEGF with particular subtypes of receptors activates a circuit of signaling pathways, e.g. PI3K/Akt, Ras/Raf-MEK/Erk, eNOS/NO, and IP3/Ca2+. These participate in the generation of specific biological responses connected with proliferation, migration, increasing vascular permeability, or promoting endothelial cell survival. Recent findings from experiments performed on animals with experimentally evoked focal cerebral ischemia suggest that the neuroprotective activity of VEGF runs in parallel with its ability to promote neurogenesis and angiogenesis and that these effects may operate independently through multiple mechanisms. The above-mentioned three major features characterizing the neurobiological activity of VEGF, i.e. neuroprotection, neurogenesis, and angiogenesis, together with their possible functional link(s), provide the rationale for considering VEGF-based therapy as a promising future avenue for a more effective treatment of at least some neurodegenerative disorders and stroke. Moreover, the possibility of using neutralizing factors of VEGF or VEGF receptor antagonists may reveal a way of preventing many dangerous pathologies, including post-ischemic disturbances in cardiac and neurological disorders, tumor growth, or hypervascularization in avascular structures of the eye.
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PMID:[VEGF as an angiogenic, neurotrophic, and neuroprotective factor]. 1640 96

Angiogenesis, the development of new blood vessels from preexisting capillary, is required for tumor growth and metastasis. The process is not fully understood yet, but involves endothelial cell proliferation, migration and differentiation. Recently, we have shown that overexpression of caveolin-1, a putative transformation suppressor gene, inhibits VEGFR-2 and MEK-1-mediated mitogenic signal to the nucleus. Conversely, angiogenic activators suppress caveolin-1 expression in endothelial cells. However, whether caveolin-1 expression affects endothelial cell proliferation is not clear. In the present study, we infect human endothelial cells with adenovirus expressing caveolin-1 and show that transient overexpression of caveolin-1 dramatically inhibits the proliferation of human endothelial cells. Consistent with caveolin-1 functioning as an inhibitor for protein kinases, overexpression of caveolin-1 inhibits the activity of VEGFR-2 (KDR) and down-stream p42/44 MAP kinase. Furthermore, overexpression of caveolin-1 prevents VEGF-induced down-regulation of the cyclin-dependent kinase inhibitor p27(kip1) and Rb phosphorylation, and subsequently arrests endothelial cells in the G(0)/G(1) phase. Thus, our results suggest that caveolin-1, as a negative regulator of endothelial cell proliferation, may be a potential target for the control of angiogenesis.
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PMID:Overexpression of caveolin-1 inhibits endothelial cell proliferation by arresting the cell cycle at G0/G1 phase. 1724 31

Different signaling routes seem to be simultaneously triggered in leukemia, with distinct and overlapping activities. To analyze if altered signals are coordinated and to evaluate their effect on this disease, we have investigated in acute myeloid leukemia samples (AML) the expression and activation status of procoagulant/proangiogenic tissue factor receptor (TF), angiogenic protein VEGF, its cell surface receptor, KDR, and two intracellular proteins involved in their regulation: extracellular regulated kinase (ERK1/2) and nuclear factor kappa-B (NFkappaB). Significantly higher mRNA and protein levels of VEGF, KDR, and TF were found in the AML samples versus controls. Enhanced ERK phosphorylation and NFkappaB activation in most AML samples were also found. In vitro MEK/ERK and NFkappaB-binding activity blockade suppressed the constitutive expression of TF, VEGF, and KDR. Anti-TF antibody treatment significantly suppressed VEGF and KDR expression as well as ERK activation, suggesting that TF expressed by AML cells may be both a regulatory target and a mediator of tumor-associated angiogenesis. Patients showing parallel activation of the studied proteins trended to exhibit higher incidence of fatal outcome. Our results show a coordinated deregulation of cellular receptors, proangiogenic factors, and intracellular pathways in leukemia cells, which may help to design mechanism-based combinations of single transduction-related therapies.
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PMID:Coordinated deregulation of cellular receptors, proangiogenic factors and intracellular pathways in acute myeloid leukaemia. 1757 83

Vascular angiogenesis has been shown to play a key role in many solid tumors. The vascular endothelial growth factor (VEGF) isoforms and their tyrosine kinase receptors (VEGFRs) have been under intense research for effective anticancer drug candidates. Epidermal growth factor (EGF) and its receptor (EGFR) provide another pathway critical in monitoring angiogenesis. VEGF exerts its effect through binding to tyrosine kinase receptors, mainly VEGFR-1 (Flt-1, the fms-like tyrosine kinase-1) and VEGFR-2 (Flk-1/KDR, fetal liver kinase-1). This paper reviews the progress, mechanism, and binding modes of recently approved kinase inhibitors, such as sunitinib (Sutent), sorafenib (Nexavar) and dasatinib (Sprycel), as well as other inhibitors that are still under clinical development. Recent clinical treatments suggest that most inhibitors of VEGFR (and/or EGFR) exert their therapeutic effect through not only targeting the VEGFR (and/or EGFR) pathway, but also inhibiting other pathways, such as RAF/MEK/ERK pathway. A new pharmacophore model for second generation of type II tyrosine kinase inhibitors and recent advances in the combination of VEGFR tyrosine kinase inhibitors and other chemotherapeutics are also covered.
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PMID:Molecular design and clinical development of VEGFR kinase inhibitors. 1769 27

VEGF dependent angiogenesis is required for normal bone development and has been implicated in cancer metastasis to bone. These processes, while dependent on osteoclastic bone resorption, are reportedly mediated by endothelial cells, stromal osteoblasts, chondrocytes, and/or tumor cells. We demonstrate here that VEGF treatment of purified murine bone marrow osteoclast precursors directly enhances their survival, differentiation into mature osteoclasts, and resorptive activity. The actions of VEGF on mature osteoclasts principally involve the receptor VEGFR2 (Flk1, KDR), and the receptor signaling utilizes both the PI3-kinase-->Akt and MEK-->ERK pathways. Increased osteoclast survival and resorptive activity is correlated with VEGF-dependent phosphorylation of multiple downstream targets of activated Akt [glycogen synthase kinase, GSK-3beta; forkhead transcription factor, FKHR; and the Bcl-2 antagonist of cell death, Bad (Ser136)] and activated ERK1/2 [ribosomal S6 kinase, p90RSK; and Bad (Ser112)]. Expression of the VEGFR2 gene increases 20-fold during the 6 day in vitro differentiation of mature osteoclasts from mononuclear precursors, while alternate receptors VEGFR1 and neuropilin-1, decrease 30- and 3-fold respectively. Additionally, VEGF enhancement of osteoclast survival is diminished in cells prepared from beta3 integrin-deficient mice, thus associating VEGF signaling in osteoclasts with their attachment to extracellular matrix. Our results indicate that VEGF directly targets osteoclasts, thereby playing a novel role in bone development, angiogenesis, and tumor metastasis.
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PMID:VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin. 1864 Feb 70


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