Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.
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PMID:Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. 1117 16

A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as 'ectodomain shedding', under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.
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PMID:Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase. 1122 64

This study examined the premise that the atherogenic lipoprotein, beta-migrating very low density lipoprotein (betaVLDL), might activate the mitogen-activated protein (MAP) kinases ERK1/ERK2, thereby contributing to the induction of smooth muscle cell proliferation in atherosclerosis. The data show that betaVLDL activates rabbit smooth muscle cell ERK1/ERK2. Interestingly, ERK1/ERK2 activation is mediated by G protein-coupled receptors that transactivate the epidermal growth factor (EGF) receptor. betaVLDL-induced MAP kinase activation depends on Ras and Src activity as well as protein kinase C. The inhibition of lysosomal degradation of betaVLDL has no effect on ERK1/ERK2 activation. The contribution of betaVLDL-induced activation of ERK1/ERK2 to smooth muscle cell proliferation was also explored. betaVLDL induces expression of egr-1 and c-fos mRNA. Despite its ability to stimulate early gene expression, betaVLDL alone is unable to inspire quiescent cells into S phase. When added in conjunction with EGF, however, stimulation of [(3)H]thymidine incorporation into DNA and an increase in histone gene expression are observed. Moreover, betaVLDL plus EGF synergistically induce cyclin D1 expression and down-regulate p27(KIP1) expression. The addition of either betaVLDL or EGF stimulates a robust activation of ERK1/ERK2, but the addition of both agents simultaneously sustains the activation for a longer time period. Inhibition of MAP kinase kinase, pertussis toxin-sensitive G proteins, the EGF receptor, or protein kinase C blocks betaVLDL plus EGF-induced proliferation, demonstrating that activation of the betaVLDL-induced signaling pathway results in smooth muscle cell proliferation.
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PMID:beta-Migrating very low density lipoprotein (beta VLDL) activates smooth muscle cell mitogen-activated protein (MAP) kinase via G protein-coupled receptor-mediated transactivation of the epidermal growth factor (EGF) receptor: effect of MAP kinase activation on beta VLDL plus EGF-induced cell proliferation. 1137 98

We investigated the effects of glycyrrhizin (GL-1) and some analogues on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. The hepatocytes underwent DNA synthesis and proliferation in response to GL-1 and some analogues. The effects of these agents occurred in a time- and dose-dependent manner. The proliferative potency as judged by half-maximal effective concentrations was in the following order: 18-beta-H-glycyrrhetinic acid (GL-3; 4.5 x 10(-9) M)<18-beta-H-glycyrrhizin (GL-1; 4.4 x 10(-8) M)<18-alpha-H-glycyrrhetinic acid (GL-6; 6.0 x 10(-8) M). The analogue 18-alpha-H-glycyrrhetinic acid 3-O-beta-D-monoglucuronide (GL-5; 1.0 x 10(-7) M) weakly stimulated hepatocyte DNA synthesis and proliferation, whereas 18-alpha-H-glycyrrhizin (GL-4) and 18-beta-H-glycyrrhetinic acid 3-O-beta-D-monoglucuronide (GL-2) did not. The growth-promoting effects of GL-1, GL-3 and GL-6 were significantly inhibited at higher initial plating densities (7.0 x 10(4) and 10 x 10(4) cells/cm(2)). A monoclonal antibody against epidermal growth factor (EGF) receptor (1-100 ng/ml), but not that against EGF (1-100 ng/ml), dose-dependently inhibited glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Specific inhibitors of growth-related signal transducers, such as genistein, PD98059 (2'-amino-3'-methoxyflavone) and rapamycin, completely blocked glycyrrhizin- and analogue-induced hepatocyte DNA synthesis and proliferation. Treatment of hepatocytes with GL-1, GL-3 and GL-6 rapidly stimulated tyrosine phosphorylation of the EGF receptor and p42 MAP kinase, which were inhibited by genistein and PD98059, respectively. These results suggest that glycyrrhizin and some analogues are primary hepatocyte mitogens that bind to EGF receptors and subsequently stimulate the receptor tyrosine kinase/mitogen-activated protein kinase pathway to induce hepatocyte DNA synthesis and proliferation.
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PMID:Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors. 1172 21

G-protein-coupled receptors (GPCRs) induce the phosphorylation of mitogen-activated protein (MAP) kinase by actions on any of a number of signal transduction systems. Previous studies have revealed that activation of the G(q)-coupled metabotropic glutamate receptor 5 (mGluR5) induces phosphorylation of the MAP kinase extracellular signal-regulated kinase 2 (ERK2) in cultured rat cortical astrocytes. We performed a series of studies to determine the mechanisms underlying mGluR5-induced phosphorylation of MAP kinase in these cells. Interestingly, our studies suggest that mGluR5-mediated ERK2 phosphorylation is dependent on the activation of G(alphaq) but is not mediated by the activation of phospholipase Cbeta1, activation of protein kinase C, or increases in intracellular calcium. Studies with peptide inhibitors suggest that this response is not dependent on G(betagamma) subunits. However, the activation of ERK2 was dependent on activation of the epidermal growth factor (EGF) receptor and activation of a Src family tyrosine kinase. Furthermore, activation of mGluR5 induced an association of this receptor and the EGF receptor, suggesting the formation of a signaling complex involved in the activation of ERK2. These data suggest that mGluR5 increases ERK2 phosphorylation in astrocytes by a novel mechanism involving the activation of G(alphaq) and both receptor and nonreceptor tyrosine kinases but that is independent of the activation of phospholipase Cbeta1.
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PMID:Metabotropic glutamate receptor 5-induced phosphorylation of extracellular signal-regulated kinase in astrocytes depends on transactivation of the epidermal growth factor receptor. 1173 72

Lysophosphatidic acid (LPA) is known to induce protein tyrosine phosphorylation and has growth factor-like effects. In the last several years, the epidermal growth factor (EGF) receptor has been recognized as a protein tyrosine kinase that plays a central role in mediating LPA-induced tyrosine phosphorylation and Erk MAP kinase activation. In this article, we review recent progress in the study of trans-regulation of EGF receptor by LPA and G protein-coupled receptors (GPCR) and discuss the gap in our knowledge of the mechanism by which LPA induces EGF receptor activation.
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PMID:Trans-regulation of epidermal growth factor receptor by lysophosphatidic acid and G protein-coupled receptors. 1206 16

Transmembrane receptor tyrosine kinases have been shown to play an important role in the modulation of growth factor signaling and regulation of key cellular processes. The erbB receptor family is part of the receptor tyrosine kinase superfamily and consists of four members, erbB-1, erbB-2, erbB-3, and erbB-4. A majority of solid tumors express one or more members of this receptor family, and coexpression of multiple erbB receptors leads to an enhanced transforming potential and worsened prognosis. The erbB receptor family has been shown to play an important role in both the development of the normal breast and in the pathogenesis and progression of breast cancer. Receptor overexpression has also been shown to be a negative prognostic indicator and to correlate with both tumor invasiveness and a lack of responsiveness to standard treatment. Clinically, blockade of the erbB-2 receptor has recently been shown to provide benefit in a subset of chemotherapy-resistant breast cancer patients. CI-1033 is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/MAP kinase, and PI-3 kinase/AKT pathways. CI-1033 is also unique in that it is an irreversible inhibitor, thereby providing prolonged suppression of erbB receptor-mediated signaling. Preclinical data have shown CI-1033 to be efficacious against a variety of human tumors in mouse xenograft models, including breast carcinomas. In a phase I study, CI-1033 has been shown to have an acceptable side effect profile at potentially therapeutic dose levels and demonstrates evidence of target biomarker modulation. Antitumor activity has also been observed in this study, including one partial clinical response and stable disease in over 30% of patients, including one patient with heavily pretreated breast cancer. By virtue of its pan-erbB receptor inhibition and potent interruption of downstream mitogenic signaling pathways, CI-1033 may have clinical activity for solid tumors that overexpress one erbB family member, coexpress multiple members of the erbB family, or express a constitutively activated, mutated form of these receptors. Given the important role of the erbB receptor family in the pathogenesis and progression of breast cancer, an irreversible pan-erbB inhibitor like CI-1033 could have an important role to play in the future treatment of breast cancer.
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PMID:Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. 1213 93

Responses to G protein-coupled receptor stimulation may be mediated by paracrine factors. We have developed a coculture system to study paracrine regulation of migration of gastric epithelial (AGS) cells after stimulation of gastrin-CCK(B) receptors. In cells expressing this receptor, G-17 stimulated migration by activation of protein kinase C. However, G-17 also stimulated the migration of cells expressing green fluorescent protein, but not the receptor, when they were cocultured with receptor-expressing cells consistent with activation of paracrine signals. The use of various pharmacological inhibitors indicated that gastrin stimulated migration via activation of the EGF receptor (EGR-R), the erbB-2 receptor tyrosine kinase, and the MAP kinase pathway. However, gastrin also released fibroblast growth factor (FGF)-1, and migration was inhibited by the FGF receptor tyrosine kinase inhibitor SU-5402. Flow cytometry indicated that in both cell types, gastrin increased MAP kinase via activation of EGF-R but not FGF-R1 or erbB-2. We conclude that gastrin-CCK(B) receptors stimulate epithelial cell migration partly via paracrine mechanisms; transactivation of EGF-R is only one component of the paracrine pathway.
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PMID:Stimulation of gastrin-CCKB receptor promotes migration of gastric AGS cells via multiple paracrine pathways. 1248 36

1 Alpha(2) adrenoceptors cause vasoconstriction in the porcine palmar lateral vein through a mechanism involving the ERK signal transduction cascade, calcium influx, and a Src tyrosine kinase. The aim of the present study was to determine if phosphatidylinositol 3-kinase (PI 3-kinase) and/or epidermal growth factor (EGF) receptor transactivation are also involved. 2 alpha(2) Adrenoceptor-mediated vasoconstriction and ERK2 activation in the porcine palmar lateral vein was inhibited in the presence of either the PI 3-kinase inhibitor LY294002, or the EGF receptor tyrosine kinase inhibitor AG1478 suggesting the involvement of both PI 3-kinase and EGF receptor transactivation. 3 Akt phosphorylation was increased in segments of porcine palmar lateral vein contracted with UK14304 indicating an increase in Akt activation. This is a further indication that PI 3-kinase is involved in alpha(2) adrenoceptor-mediated vasoconstriction. Akt activation was inhibited by the Src tyrosine kinase inhibitor PP2, and removal of extracellular calcium. 4 UK14304 (10 microM) stimulated an increase in intracellular calcium in segments of palmar lateral vein. This was inhibited by removal of extracellular calcium, but not by nifedipine suggesting the rise in calcium is due to influx of calcium through non-L type calcium channels. The increase in calcium was also inhibited by LY294002 indicating that PI 3-kinase is upstream of calcium influx. 5 These data indicate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon stimulation of PI 3-kinase, leading to an influx of calcium. This results in activation of the EGF receptor tyrosine kinase, and finally activation of ERK-MAP kinase.
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PMID:Alpha 2 adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein: role of phosphatidylinositol 3-kinase and EGF receptor transactivation. 1252 79

Bombesin and its mammalian homologue gastrin-releasing peptide have been shown to be highly expressed and secreted by neuroendocrine cells in prostate cancer, and are thought to be related to the carcinogenesis and progression of this disease. We found, in this study, bombesin specifically induced mitogen-activated protein (MAP) kinase activation as shown by increased extracellular regulated kinase (ERK) phosphorylation and epidermal growth factor (EGF) receptor transactivation in prostate cancer cells, which express functional gastrin-releasing peptide receptor. The transactivation of EGF receptor was required for bombesin-induced ERK phosphorylation. Furthermore, non-receptor tyrosine kinase Src and cellular Ca2+ were shown to be involved in bombesin-induced EGF receptor transactivation and ERK phosphorylation. Inhibition of either EGF receptor transactivation or ERK activation blocked bombesin-induced DNA synthesis in these cells. Taken together, these data suggest bombesin may act as a mitogen in prostate cancer by activating MAP kinase pathway via EGFR transactivation.
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PMID:Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. 1287 8


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