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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cross-talk between G protein-coupled receptor (GPCR) and epidermal growth factor receptor (EGFR) signaling systems is widely established in a variety of normal and transformed cell types. Here, we demonstrate that the EGFR transactivation signal requires metalloproteinase cleavage of epidermal growth factor-like growth factor precursors in fibroblasts, ACHN kidney, and TccSup bladder carcinoma cells. Furthermore, we present evidence that blockade of the metalloproteinase-disintegrin tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17) by a dominant negative ADAM17 mutant prevents angiotensin II-stimulated pro-HB-EGF cleavage, EGFR activation, and cell proliferation in ACHN tumor cells. Moreover, we found that in TccSup cancer cells, the lysophosphatidic acid-induced transactivation signal is mediated by ADAM15, demonstrating that distinct combinations of growth factor precursors and ADAMs (a disintegrin and metalloproteinases) regulate GPCR-EGFR cross-talk pathways in cell lines derived from urogenital cancer. Our data show further that activation of ADAMs results in discrete cellular responses; whereas GPCR agonists promote activation of the Ras/MAPK pathway and cell proliferation via the EGFR in fibroblasts and ACHN cells, EGFR transactivation pathways regulate activation of the survival mediator Akt/protein kinase B and the susceptibility of fibroblasts and TccSup bladder carcinoma cells to proapoptotic signals such as serum deprivation, death receptor stimulation, and the chemotherapeutic drug doxorubicin. Thus, ADAM15 and -17 function as effectors of GPCR-mediated signaling and define critical characteristics of cancer cells.
...
PMID:Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival. 1533 56

Chronic obstructive pulmonary disease is marked by alveolar enlargement and excess production of airway mucus. Acrolein, a component of cigarette smoke, increases mucin 5AC (MUC5AC), a prevalent airway mucin in NCI-H292 cells by transcriptional activation, but the signal transduction pathways involved in acrolein-induced MUC5AC expression are unknown. Acrolein depleted cellular glutathione at doses of 10 muM or greater, higher than those sufficient (0.03 muM) to increase MUC5AC mRNA, suggesting that MUC5AC expression was independent of oxidative stress. In contrast, acrolein increased MUC5AC mRNA levels by phosphorylating epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase 3/2, or MAPK 3/2(ERK1/2). Pretreating the cells with an EGFR-neutralizing antibody, or a metalloproteinase inhibitor, decreased the acrolein-induced MUC5AC mRNA increase. Small, interfering RNA directed against ADAM17 or MMP9 inhibited the acrolein-induced MUC5AC mRNA increase. Acrolein increased the release and subsequent activation of pro-MMP9. Acrolein increased MMP9 and decreased tissue inhibitor of metalloproteinase 3 (TIMP3), an endogenous inhibitor of ADAM17, transcripts. Together, these data suggest that acrolein induces MUC5AC expression via an initial ligand-dependent activation of EGFR mediated by ADAM17 and MMP9. In addition, a prolonged effect of acrolein may be mediated by altering MMP9 and TIMP3 transcription.
...
PMID:Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. 1553 49

The amyloid precursor protein (APP) is proteolytically processed by beta- and gamma-secretases to release amyloid beta, the main component in senile plaques found in the brains of patients with Alzheimer disease. Alternatively, APP can be cleaved within the amyloid beta domain by alpha-secretase releasing the non-amyloidogenic product sAPP alpha, which has been shown to have neuroprotective properties. Several G protein-coupled receptors are known to activate alpha-secretase-dependent processing of APP; however, the role of G protein-coupled nucleotide receptors in APP processing has not been investigated. Here it is demonstrated that activation of the G protein-coupled P2Y2 receptor (P2Y2R) subtype expressed in human 1321N1 astrocytoma cells enhanced the release of sAPP alpha in a time- and dose-dependent manner. P2Y2 R-mediated sAPP alpha release was dependent on extracellular calcium but was not affected by 1,2-bis(2-aminophenoxy)ethane-N,N,N,-trimethylammonium salt, an intracellular calcium chelator, indicating that P2Y2R-stimulated intracellular calcium mobilization was not involved. Inhibition of protein kinase C (PKC) with GF109203 or by PKC down-regulation with phorbol ester pre-treatment had no effect on UTP-stimulated sAPP alpha release, indicating a PKC-independent mechanism. U0126, an inhibitor of the mitogen-activated protein kinase pathway, partially inhibited sAPPalpha release by UTP, whereas inhibitors of Src-dependent epidermal growth factor receptor transactivation by P2Y2Rs had no effect. The metalloprotease inhibitors phenanthroline and TAPI-2 and the furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone also diminished UTP-induced sAPP alpha release. Furthermore, small interfering RNA silencing of an endogenous adamalysin, ADAM10 or ADAM17/TACE, partially suppressed P2Y2R-activated sAPP alpha release, whereas treatment of cells with both ADAM10 and ADAM17/TACE small interfering RNAs completely abolished UTP-activated sAPP alpha release. These results may contribute to an understanding of the non-amyloidogenic processing of APP.
...
PMID:P2Y2 nucleotide receptors enhance alpha-secretase-dependent amyloid precursor protein processing. 1577 2

Tumor necrosis factor alpha-converting enzyme (TACE/ADAM17) has been implicated in the inducible shedding of numerous cell surface proteins. In light of this, the regulation of TACE catalytic activation and protein maturation has recently received considerable interest in the context of extracellular signal-regulated kinase activation and the subsequent phosphorylation of TACE at residue Thr735. In this study, we analysed the subcellular localisation of TACE derivatives using laser-scanning confocal microscopy and cell surface biotinylation. Whereas WT.TACE- and T735A.TACE-enhanced green fluorescent protein (-eGFP) fusion derivatives of TACE were both found to localise with the endoplasmic reticulum, a phosphomimicking form of TACE (T735E.TACE-eGFP) was found to colocalise predominantly with components of the protein secretory pathway (COPII vesicles and trans-Golgi network). Additionally, upon analysis of biotinylated ectopic TACE, we observed that inducible trafficking of TACE to the cell surface was dependent upon extracellular signal-regulated kinase activation and phosphorylation of Thr735. We conclude from our observations that phosphorylation of TACE at Thr735 highlights a key step in inducible TACE protein trafficking and maturation.
...
PMID:ERK-mediated phosphorylation of Thr735 in TNFalpha-converting enzyme and its potential role in TACE protein trafficking. 1592 50

Transactivation of EGF receptors by G protein-coupled receptors is a well-known phenomenon. This process involves the ectodomain shedding of growth factors in the EGF family by matrix metalloproteinases. However, many of these studies employ transformed and/or cultured cells that overexpress labeled growth factors. In addition, few studies have shown that EGF itself is the growth factor that is shed and is responsible for transactivation of the EGF receptor. In this study, we show that freshly isolated, nontransformed lacrimal gland acini express two of the three known alpha(1)-adrenergic receptors (ARs), namely, alpha(1B)- and alpha(1D)-ARs. Alpha(1D)-ARs mediate phenylephrine (an alpha(1)-adrenergic agonist)-induced protein secretion and activation of p42/p44 MAPK, because the alpha(1D)-AR inhibitor BMY-7378, but not the alpha(1A)-AR inhibitor 5-methylurapidil, inhibits these processes. Activation of p42/p44 MAPK occurs through transactivation of the EGF receptor, which is inhibited by the matrix metalloproteinase ADAM17 inhibitor TAPI-1. In addition, phenylephrine caused the shedding of EGF from freshly isolated acini into the buffer. Incubation of freshly isolated cells with conditioned buffer from cells treated with phenylephrine resulted in activation of the EGF receptor and p42/p44 MAPK. The EGF receptor inhibitor AG1478 and an EGF-neutralizing antibody blocked this activation of p42/p44 MAPK. We conclude that in freshly isolated lacrimal gland acini, alpha(1)-adrenergic agonists activate the alpha(1D)-AR to stimulate protein secretion and the ectodomain shedding of EGF to transactivate the EGF receptor, potentially via ADAM17, which activates p42/p44 MAPK to negatively modulate protein secretion.
...
PMID:Effects of alpha1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells. 1687 Aug 26

Bile acids, which have been implicated in gastrointestinal-tract cell carcinogenesis, share properties with tumor promoters in that both affect signal transduction pathways responsible for cell proliferation and apoptosis. In the present study, we demonstrate that EGFR-ERK1/2 is activated following treatment of AGS human gastric carcinoma cells with bile acids. EGFR phosphoactivation is ligand-dependent, since treatment of cells with HB-EGF antisera or CM197 (a selective inhibitor of HB-EGF) markedly inhibits deoxycholate (DC)-promoted activation. Membrane-type bile acid receptor (M-BAR)/TGR5 is a recently identified G-protein-coupled receptor (GPCR). In AGS cells, siRNAs that target M-BAR suppress DC-induced phosphorylation of EGFR. Furthermore, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results suggest that in AGS cells, DC transactivates EGFR through M-BAR- and ADAM/HB-EGF-dependent mechanisms.
...
PMID:Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. 1721 62

Alpha-secretase (alpha-secretase), cleaves the amyloid precursor protein (APP) within the amyloid-beta (Abeta) sequence, resulting in the release of a secreted fragment of APP (alphaAPPs) and precluding Abeta generation. We investigated the effects of the acetylcholinesterase inhibitor, huperzine A (Hup A), on APP processing and Abeta generation in human neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. Hup A dose-dependently (0-10 microM) increased alphaAPPs release. Therefore, we evaluated two alpha-secretase candidates, a disintegrin and metalloprotease (ADAM) 10 and ADAM17 in Hup A-induced non-amyloidogenic APP metabolism. Hup A enhanced the level of ADAM10, and the inhibitor of tumor necrosis factor-alpha converting enzyme (TACE)/ADAM17 inhibited the Hup A-induced rise in alphaAPPs levels, further suggesting Hup A directed APP metabolism toward the non-amyloidogenic alpha-secretase pathway. Hup A had no effect on Abeta generation in this cell line. The steady-state levels of full-length APP and cell viability were unaffected by Hup A. Alpha-APPs release induced by Hup A treatment was significantly reduced by muscarinic acetylcholine receptor antagonists (particularly by an M1 antagonist), protein kinase C (PKC) inhibitors, GF109203X and calphostin C, and the mitogen-activated kinase kinase (MEK) inhibitors, U0126 and PD98059. Furthermore, Hup A markedly increased the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, which was blocked by treatment with U0126 and PD98059. In addition, Hup A inhibited acetylcholinesterase activity by 20% in neuroblastoma cells. Our results indicate that the activation of muscarinic acetylcholine receptors, PKC and MAP kinase may be involved in Hup A-induced alphaAPPs secretion in neuroblastoma cells and suggest multiple pharmacological mechanisms of Hup A regarding the treatment of Alzheimer's disease (AD).
...
PMID:Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695. 1794 34

The aim of this study was to investigate whether atorvastatin inhibits epidermal growth factor receptor (EGFR) activation in cardiomyocytes in vitro and slows the progression of cardiac remodeling induced by pressure overload in mice. Either atorvastatin (5 mg/kg/day) or vehicle was orally administered to male C57BL/6J mice with transverse aortic constriction (TAC). Physiological parameters were obtained by echocardiography or left ventricular (LV) catheterization, and morphological and molecular parameters of the heart were also examined. Furthermore, cultured neonatal rat cardiomyocytes were studied to clarify the underlying mechanisms. Four weeks after TAC, atorvastatin reduced the heart/body weight and lung/body weight ratios (8.69+/-0.38 to 6.45+/-0.31 mg/g (p<0.001) and 10.89+/-0.68 to 6.61+/-0.39 mg/g (p<0.01) in TAC mice with and without atorvastatin, respectively). Decrease of LV end-diastolic pressure and the time constant of relaxation, increased fractional shortening, downregulation of a disintegrin and metalloproteinase (ADAM)12, ADAM17 and heparin-binding epidermal growth factor genes, and reduction of the activity of EGFR and extracellular signal-regulated kinase (ERK) were observed in the atorvastatin group. Phenylephrine-induced protein synthesis, phosphorylation of EGFR, and activation of ERK in neonatal rat cardiomyocytes were all inhibited by atorvastatin. These findings indicated that atorvastatin ameliorates cardiac remodeling in mice with pressure overload, and its actions are associated with inhibition of the EGFR signaling pathway.
...
PMID:Atorvastatin slows the progression of cardiac remodeling in mice with pressure overload and inhibits epidermal growth factor receptor activation. 1836 54

UVA (315-400 nm), which constitutes approximately 95% of the UV irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with phosphatidylinositol-3-OH kinase/AKT inhibitor or infected with dominant-negative AKT, cyclin D1 up-regulation, cell cycle progression, and proliferation were inhibited, suggesting that AKT activation is required for UVA-induced cell cycle progression. In contrast, extracellular signal-regulated kinase (ERK) was not activated by UVA exposure; incubation with ERK/mitogen-activated protein kinase inhibitor had no effect on UVA-induced cyclin D1 up-regulation and cell cycle progression. Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of a disintegrin and metalloprotease (ADAM)17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer.
...
PMID:UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes. 1848 58

Vascular endothelial growth factor (VEGF)-A and the VEGF receptors are critical for regulating angiogenesis during development and homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its coreceptor, neuropilin (NRP)-1. Here, we show that VEGFR2 is shed from cells by the metalloprotease disintegrin ADAM17, whereas NRP-1 is released by ADAM10. VEGF-A enhances VEGFR2 shedding by ADAM17 but not shedding of NRP-1 by ADAM10. VEGF-A activates ADAM17 via the extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase pathways, thereby also triggering shedding of other ADAM17 substrates, including tumor necrosis factor alpha, transforming growth factor alpha, heparin-binding epidermal growth factor-like growth factor, and Tie-2. Interestingly, an ADAM17-selective inhibitor shortens the duration of VEGF-A-stimulated ERK phosphorylation in human umbilical vein endothelial cells, providing evidence for an ADAM17-dependent crosstalk between the VEGFR2 and ERK signaling. Targeting the sheddases of VEGFR2 or NRP-1 might offer new opportunities to modulate VEGF-A signaling, an already-established target for treatment of pathological neovascularization.
...
PMID:VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling. 1881 6


1 2 3 4 5 6 7 8 9 Next >>

---