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

Signalling through G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTK) is involved in the regulation of essential cellular processes and its deregulation is associated with tumorigenesis in vitro and in vivo. We investigated pathophysiological processes that are regulated by GPCR pathways in human kidney and bladder cancer cell lines. Our results show that GPCR ligands induce tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) as well as downstream signalling events such as recruitment of the adapter protein Shc and activation of the mitogen-activated protein kinases (MAPK) ERK1/2, JNK and p38. Moreover, we report that the EGFR transactivation signal involves the EGFR ligands amphiregulin, HB-EGF and TGFalpha as well as the metalloproteinases ADAM 10, 15 and 17, depending on the cellular system. Finally, we demonstrate that EGFR transactivation is part of a regulatory system that modulates the migratory and invasive behaviour of kidney and bladder cancer cells. In conclusion, our findings demonstrate that metalloproteinase-mediated transactivation of the EGFR is a key mechanism of the cellular signalling network that promotes MAPK activation as well as tumour cell migration and invasion in response to a variety of physiologically relevant GPCR ligands, and therefore represents a novel target for cancer intervention strategies.
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PMID:Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. 1464 23

Antimicrobial peptides produced by epithelial cells and neutrophils represent essential elements of innate immunity, and include the defensin and cathelicidin family of antimicrobial polypeptides. The human cathelicidin cationic antimicrobial protein-18 is an antimicrobial peptide precursor predominantly expressed in neutrophils, and its active peptide LL-37 is released from the precursor through the action of neutrophil serine proteinases. LL-37 has been shown to display antimicrobial activity against a broad spectrum of microorganisms, to neutralize LPS bioactivity, and to chemoattract neutrophils, monocytes, mast cells, and T cells. In this study we show that LL-37 activates airway epithelial cells as demonstrated by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and increased release of IL-8. Epithelial cell activation was inhibited by the MAPK/ERK kinase (MEK) inhibitors PD98059 and U0126, by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, by blocking anti-EGFR and anti-EGFR-ligand Abs, and by the metalloproteinase inhibitor GM6001. These data suggest that LL-37 transactivates the EGFR via metalloproteinase-mediated cleavage of membrane-anchored EGFR-ligands. LL-37 may thus constitute one of the mediators by which neutrophils regulate epithelial cell activity in the lung.
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PMID:The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor. 1466 72

The thienopyridine platelet antagonist ticlopidine is associated with development of thrombotic thrombocytopenic purpura (TTP) but the pathophysiology of this link is unclear. Severe deficiency of disintegrin and metalloproteinase with thrombospondin motif-13 (ADAMTS13), described in familial cases and a significant fraction of idiopathic TTP, has been reported in only a few ticlopidine-linked cases. As ticlopidine can disrupt production of extracellular matrix (ECM) components critical to microvascular endothelial cell (MVEC) integrity in vitro, we explored the hypotheses that ticlopidine and ticlopidine-linked TTP plasmas induce MVEC apoptosis in a manner similar to that of idiopathic TTP plasmas, and that ECM components and related mitogen-activated protein kinase (MAPK) signalling cascades may be involved in this process. Replicating the activity of plasmas from patients with idiopathic TTP, plasma from five ticlopidine-linked TTP patients induced apoptosis of primary human dermal, glomerular and hepatic MVEC, but had no effect on pulmonary MVEC or large vessel endothelial cells (EC). Pharmacological levels of ticlopidine initiated apoptosis with similar EC lineage restriction. In parallel, ticlopidine and plasmas from idiopathic and ticlopidine-TTP patients decreased transcripts for the ECM component thrombospondin-1 in MVEC, but not in large vessel EC. These changes were accompanied by prolonged induction of MAPKs extracellular signal-related kinase (ERK)-1/2 and p38 only in TTP susceptible MVEC. Induction of apoptosis by ticlopidine and TTP plasma was abrogated by inhibitors of ERK-1/2 and p38 phosphorylation. In conclusion, MVEC apoptosis related to altered ECM-MVEC interactions may be a key part of the pathology of ticlopidine-linked and idiopathic TTP.
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PMID:Thienopyridine-linked thrombotic microangiopathy: association with endothelial cell apoptosis and activation of MAP kinase signalling cascades. 1468 31

Interleukin (IL)-17 promotes cartilage breakdown by inducing matrix metalloproteinases (MMPs) and aggrecanases (a disintegrin and metalloproteinase with thrombospondin motif, ADAMTS) in arthritic joints. We investigated IL-17 signaling pathways inducing MMP-3, MMP-13 and ADAM-TS4 genes in bovine articular chondrocytes. IL-17 stimulated phosphorylation of extracellular signal-regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK). ERK pathway inhibitors, PD98059 and U0126, down-regulated IL-17-induced MMP and ADAM-TS4 gene expression. Protein 38 and JNK pathway inhibitors, SB203580 and SP600125, also reduced induction of these genes. Antioxidants and activating protein-1 transcription factor inhibitors, nordihydroguaiaretic acid and N-acetyl-L-cysteine (NAC) suppressed MMP and ADAM-TS4 genes. Similarly, nuclear factor kappa B (NF-kappaB) pathways inhibitors curcumin and Bay-11-7085 also blocked their induction. Thus MMP-3, MMP-13 and ADAM-TS4 genes are coordinately up-regulated by IL-17 via MAP kinases, activating protein-1 (AP-1) and NF-kappaB mediators, which could be targeted for reducing IL-17-triggered cartilage damage.
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PMID:Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes. 1470 35

TIMP-1, an approximately 30 kDa glycosylated protein found predominantly in extracellular compartments, is involved in the regulation of a variety of developmental, remodelling, and pathological processes. One function of TIMP-1 is to inhibit certain members of a group of extracellular and cell surface enzymes known collectively as metalloproteinases (MP). These include the matrix metalloproteinases and the adamalysin-like disintegrin and metalloproteinases (ADAMs). Additional activities of TIMP-1 include potentiating the activity of erythroid precursors and stimulating proliferation of certain cancer cell lines. Published evidence suggests that the apparent proliferative action of TIMP-1 is independent of its MP-inhibitory activity; however, reports of a cell surface receptor for TIMP-1 have not been confirmed. We have utilised a baculovirus-based system to produce TIMP-1. Data presented here show that TIMP-1 and synthetic hydroxamate (GM6001) MP inhibitors stimulate proliferation and metabolic activity of MDA-MB-435 cancer cells with similar kinetics. An inactive hydroxamate derivative was ineffective. The TIMP-1-induced increase in proliferation and metabolic activity was not the consequence of the inhibition of apoptosis by TIMP-1 in the serum-free medium. These data taken together imply that the mechanism by which TIMP-1 enhances cell growth depends on its ability to inhibit a metalloproteinase, rather than to stimulate a cell surface receptor by a process independent of its MP-inhibitory activity. Inhibitors of extracellular regulated kinase (U0126) and p38 (SB203580), and to a lesser extent the phosphatidylinositol-3-kinase inhibitor LY294002, suppressed the action of TIMP-1. Assays for ERK1/2 and p38 showed that both were activated by TIMP-1 and GM6001. Mechanisms by which TIMP-1 might act to stimulate cell proliferation are described.
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PMID:Tissue inhibitor of metalloproteinase-1 stimulates proliferation of human cancer cells by inhibiting a metalloproteinase. 1473 94

Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinase-dependent release of transforming growth factor (TGF)-alpha, as demonstrated with TGF-alpha-blocking antibodies and measurement of TGF-alpha in culture medium; (ii) TGF-alpha-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-alpha-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.
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PMID:Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation. 1501 Apr 75

We found that thrombospondin-1 (TSP-1) has opposite functions on angiogenesis depending on the nature of the proteolytic fragment released in vivo by the action of proteases. We studied the effect of the 25 and 140 kDa fragments of TSP-1 generated by its proteolytic cleavage on the cascade of mitogen activated protein kinase (MAPK) activation and matrix-metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) function and expression in microvascular endothelium. Post-capillary endothelial cells (CVEC) isolated from bovine heart were used. The 25 kDa fragment enhanced the upregulation of MMP-2 and -9 and reduced TIMP-2 expression leading to CVEC chemoinvasion. Conversely, the 140 kDa fragment blocked MMP-2 and -9 stimulation and doubled TIMP-2 expression, leading to inhibition of endothelial chemoinvasion induced by fibroblast growth factor-2 (FGF-2). MAPK activity (ERK1-2) was induced by TSP-1 and by the 25 kDa fragment, but not by the 140 kDa fragment which, however, promoted MAPK p38 activation. This evidence indicates that fragments originating from TSP-1 switch the pro- or anti-angiogenic phenotype in endothelium by targeting MAPK cascades with opposite functions on MMP/TIMP balance.
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PMID:ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium. 1505 21

Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways inhibited the growth of TPras transgenic melanomas in severe combined immunodeficient mice, blocked invasive behavior, and reduced angiogenesis. The inhibitor Ly294002, which is specific for phosphatidylinositol 3'-kinase, effectively reduced melanoma cell growth both in vitro and in vivo. Both Ly294002 and U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, reduced invasion, which correlated with reduction of the metalloproteinase matrix metalloproteinase 2. Tumor angiogenesis was disrupted through inhibition of vascular endothelial growth factor production from the tumor cells and antiangiogenic effects on endothelial cells. Observations with TPras melanoma cells that express dominant negative Deltap85 or kinase-inactive Raf(301) supported the specificity of the phenomena observed with the chemical inhibitors. These studies demonstrate that topical treatment targeting Ras effectors is efficacious, without systemic toxicities, and may prove to be useful in treating and preventing the progression of cutaneous melanoma.
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PMID:Topical treatment with inhibitors of the phosphatidylinositol 3'-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. 1505 11

Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.
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PMID:Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism. 1523 57

Expression of the neuropeptide neurotensin (NT) and its high affinity receptor (NTR1) is increased during the course of Clostridium difficile toxin A-induced acute colitis, and NTR1 antagonism attenuates the severity of toxin A-induced inflammation. We recently demonstrated in non-transformed human colonic epithelial NCM460 cells that NT treatment caused activation of a Ras-mediated MAP kinase pathway that significantly contributes to NT-induced interleukin-8 (IL-8) secretion. Here we used NCM460 cells, which normally express low levels of NTR1, and NCM460 cells stably transfected with NTR1 to identify the upstream signaling molecules involved in NT-NTR1-mediated MAP kinase activation. We found that inhibition of the epidermal growth factor receptor (EGFR) by either an EGFR neutralizing antibody or by its specific inhibitor AG1478 (0.2 microm) blocked NT-induced MAP kinase activation. Moreover, NT stimulated tyrosine phosphorylation of the EGFR, and pretreatment with a broad spectrum metalloproteinase inhibitor batimastat reduced NT-induced MAP kinase activation. Using neutralizing antibodies against the EGFR ligands EGF, heparin-binding-EGF, transforming growth factor-alpha (TGFalpha), or amphiregulin we have shown that only the anti-TGFalpha antibody significantly decreases NT-induced phosphorylation of EGFR and MAP kinases. Furthermore, inhibition of the EGF receptor by AG1478 significantly reduced NT-induced IL-8 promoter activity and IL-8 secretion. This is the first report demonstrating that NT binding to NTR1 transactivates the EGFR and that this response is linked to NT-mediated proinflammatory signaling. Our findings indicate that matrix metalloproteinase-mediated release of TGFalpha and subsequent EGFR transactivation triggers a NT-mediated MAP kinase pathway that leads to IL-8 gene expression in human colonic epithelial cells.
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PMID:Metalloproteinase-dependent transforming growth factor-alpha release mediates neurotensin-stimulated MAP kinase activation in human colonic epithelial cells. 1524 67


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