Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
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PMID:Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. 987 71

Elevated focal adhesion kinase (FAK) expression in human tumor cells has been correlated with an increased cell invasion potential. In cell culture, studies with FAK-null fibroblasts have shown that FAK function is required for cell migration. To determine the role of elevated FAK expression in facilitating epidermal growth factor (EGF)-stimulated human adenocarcinoma (A549) cell motility, antisense oligonucleotides were used to reduce FAK protein expression >75%. Treatment of A549 cells with FAK antisense (ISIS 15421) but not a mismatched control (ISIS 17636) oligonucleotide resulted in reduced EGF-stimulated p130(Cas)-Src complex formation, c-Jun NH(2)-terminal kinase (JNK) activation, directed cell motility, and serum-stimulated cell invasion through Matrigel. Because residual FAK protein in ISIS 15421-treated A549 cells was highly phosphorylated at the Tyr-397/Src homology (SH)2 binding site, expression of the FAK COOH-terminal domain (FRNK) was also used as an inhibitor of FAK function. Adenoviral-mediated infection and expression of FRNK promoted FAK dephosphorylation at Tyr-397, resulted in reduced EGF-stimulated JNK as well as extracellular-regulated kinase 2 (ERK2) kinase activation, inhibited matrix metalloproteinase-9 (MMP-9) secretion, and potently blocked both random and EGF-stimulated A549 cell motility. Equivalent expression of a FRNK (S-1034) point-mutant that did not promote FAK dephosphorylation also did not affect EGF-stimulated signaling or cell motility. Dose-dependent reduction in EGF-stimulated A549 motility was observed with the PD98059 MEK1 inhibitor and the batimastat (BB-94) inhibitor of MMP activity, but not with the SB203580 inhibitor of p38 kinase. Finally, comparisons between normal, FAK-null, and FAK-reconstituted fibroblasts revealed that FAK enhanced EGF-stimulated JNK and ERK2 kinase activation that was required for cell motility. These data indicate that FAK functions as an important signaling platform to coordinate EGF-stimulated cell migration in human tumor cells and support a role for inhibitors of FAK expression or activity in the control of neoplastic cell invasion.
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PMID:Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. 1158 39

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

The mechanisms by which c-erbB-dependent signaling contribute to the invasive potential of HNSCC remain to be fully elucidated. We have previously shown that c-erbB autocrine and/or paracrine stimulation upregulates MMP-9 but has no effect on the related gelatinase, MMP-2. BTC, a major c-erbB ligand, has the ability to efficiently activate all c-erbB receptors and to bind directly to EGFR and c-erbB-4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in terms of MMP induction relative to other c-erbB ligands so far tested. In the present study, we explored the contribution of major downstream events triggered by BTC/c-erbB receptor signaling to the regulation of MMP-9 and in vitro invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN-006 and Detroit-562, BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors whereas both endogenous MMP-9 and BTC-stimulated MMP-9 were predominantly mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase. The BTC-dependent activation of JNK and PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK-1/ERK pathway occurred via all 4 c-erbB receptors, although again predominantly via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by LY294002 or wortmannin) led to marked reduction of both basal and BTC-induced MMP-9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38 kinase with SB203580 produced no such effects. A specific inhibitor of NF-kappa B, BAY 11-7085, also blocked the stimulatory effect of BTC. No remarkable inhibition of MMP-9 and invasion was observed on targeting other cellular activities, such as PKA, PKC and PLC-gamma. Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells.
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PMID:Signaling pathways required for matrix metalloproteinase-9 induction by betacellulin in head-and-neck squamous carcinoma cells. 1519 68

Regulated shedding of cell surface proteins is a mechanism for rapid activation of autocrine and paracrine signaling. Here we report that chelerythrine, a protein kinase C (PKC) inhibitor that possesses a variety of biological functions, is a potent inducer of heparin-binding epidermal growth factor-like growth factor (HB-EGF) shedding from the cell surface. Chelerythrine induced a time- and dose-dependent shedding of an HB-EGF-alkaline phosphatase (HB-EGF-AP) fusion protein expressed in MC2 rat prostate epithelial cells. The soluble form of HB-EGF-AP bound to heparin and exhibited potent biological activity as measured by DNA synthesis assay. Chelerythrine-induced HB-EGF shedding was metalloproteinase-(MMP-) mediated because specific MMP antagonists inhibited shedding by > or =60%. Chelerythrine stimulated production of reactive oxygen species, and antioxidants prevented chelerythrine-induced HB-EGF shedding, suggesting that the production of intracellular peroxides is necessary for this event. Consistent with this possibility, antioxidant- and MMP-inhibitable shedding was also demonstrated when hydrogen peroxide was used as an inducer. Although JNK/SAPK and p38 MAPK pathways were activated by chelerythine, these signaling mechanisms were not required to mediate the shedding event. However, JNK signaling was involved in chelerythrine-stimulated apoptosis. Our results suggest that HB-EGF shedding induced by chelerythrine is mediated predominantly via the production of reactive oxygen species.
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PMID:An oxidative stress mechanism mediates chelerythrine-induced heparin-binding EGF-like growth factor ectodomain shedding. 1549 Apr 81

Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties. In our studies, carnosol inhibited the invasion of highly metastatic mouse melanoma B16/F10 cells in vitro. First, the antimetastatic potentials of carnosol were examined by soft agar colony formation assay. Second, carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFkappa-B and c-Jun. These results lead us to conclude that carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-kappaB and AP-1 binding activity. Taken together, these results indicate that carnosol targets MMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.
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PMID:Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun. 1562 74

Activation of cell surface components has been implicated in the activation of downstream signaling cascade in response to UV irradiation, and yet the identity and the interaction of those components have been scantly documented. Accumulating evidence indicates that caveolae encapsulating caveolins is the location for those interactions. We found in cultured human keratinocytes that UV irradiation induced both caveolin-1 and EGFR phosphorylation. Filipin, a caveolae disruptive agent, inhibited UV-induced caveolin-1 activation. Na+-K+-ATPase catalyzes active transport of Na+ and K+ across plasma membrane of mammalian cells, inactivation of which has recently been shown to be involved in the activation of signal transduction pathways including MAP kinase cascade. We found in this study that UV inactivated Na+-K+-ATPase in time-dependent manner, Na+-K+-ATPase activity started to decrease 5 min post UV irradiation and reduced to 60% of its original activity within 1 h. Pretreatment with Flipin and MMP inhibitor recovered Na+-K+-ATPase activity lost by UV irradiation. ECIS analysis indicated that both EGF treatment and UV irradiation increased membrane electric activity which was inhibited by MMP inhibitor and Filipin. Further study showed that pretreatment of human keratinocytes with MMP inhibitor or Filipin inhibited UV-induced phosphorylation of p38 and JNK, which was however not observed in LnCap cells, a prostate cancer cell line lacking caveolin-1. UV irradiation also induced ectodomain shedding of HB-EGF in a time-dependent manner in keratinocytes. Collectively, we conclude that UV-induced MAP kinase activation is mediated by cell surface receptor activation due to the matrix activity and membrane caveolae function and inactivation of Na+-K+-ATPase.
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PMID:Extracellular matrix activity and caveolae events contribute to cell surface receptor activation that leads to MAP kinase activation in response to UV irradiation in cultured human keratinocytes. 1575 25

WAVE3 is a member of the WASP/WAVE family of proteins, which play a critical role in the regulation of actin polymerization, cytoskeleton organization, and cell motility. We show here that knockdown of the WAVE3 protein, using RNA interference in MDA-MB-231 cells, decreases phospho-p38 MAPK levels, but not those of phospho-AKT, phospho-ERK, or phospho-JNK. Knockdown of WAVE3 expression also inhibited the expression levels of MMP-1, MMP-3, and MMP-9, but not MMP-2. MMP production could be restored by PMA treatment, without affecting siRNA-mediated WAVE3 knockdown. The WAVE3-mediated downregulation of p38 activity and MMP production is independent of the presence of both WAVE1 and WAVE2, whose expression levels were not affected by loss of WAVE3. We also show that the downstream effect of the WAVE3 knockdown is the inhibition of cell motility and invasion, coupled with increased actin stress fiber formation, as well as reorganization of focal adhesion complexes. These findings suggest that WAVE3 regulates actin cytoskeleton, cell motility, and invasion through the p38 MAPK pathway and MMP production.
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PMID:WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression. 1590 37

Aortic smooth muscle cell release of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) has been implicated in aortic aneurysm pathogenesis, but proximal modulation of release is poorly understood. Extracellular nucleotides regulate vascular smooth muscle cell metabolism in response to physiochemical stresses, but nucleotide modulation of MMP and/or TIMP release has not been reported. We hypothesized that nucleotides modulate MMP-2 and TIMP-2 release from human aortic smooth muscle cells (HASMCs) via distinct purinergic receptors and signaling pathways. We exposed HASMCs to exogenous ATP and other nucleotides with and without interleukin-1beta (IL-1beta). HASMCs were pretreated in some experiments with apyrase, which degrades ATP, and inhibitors of ERK1/2, JNK, and p38 MAPK. MMP-2 and TIMP-2 released into supernatant were assessed using ELISA and Western blotting. ATP, adenosine, and UTP significantly stimulated MMP-2 release in the presence of IL-1beta (300 nM ATP: 181 +/- 22%, P = 0.003; 30 microm adenosine: 244 +/- 150%, P = 0.001; and 200 microm UTP: 153 +/- 40%, P = 0.015; vs. 100% constitutive). ATP also stimulated MMP-2 release in the absence of IL-1beta (100 microm ATP: 148 +/- 38% vs. 100% constitutive). Apyrase significantly reduced ATP-stimulated MMP-2 release (apyrase + 500 nM ATP: 59 +/- 3% vs. 124 +/- 7% with 500 nM ATP). Rank-order agonist potency for MMP-2 release was consistent with ATP activation of PAY and PAY receptors. ATP induced phosphorylation of intracellular JNK, and inhibition of the JNK pathway blocked ATP-stimulated MMP-2 release, indicating signaling via this pathway. Nucleotides are thus novel stimulants of MMP-2 release from HASMCs and may provide a mechanistic link between physiochemical stress in the aorta and aneurysms, especially in the context of inflammation.
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PMID:ATP stimulates MMP-2 release from human aortic smooth muscle cells via JNK signaling pathway. 1636 61

Increased production and activation of matrix metalloproteinase-2 (MMP-2) are critical events in skeletal muscle angiogenesis and are known to occur in response to mechanical stresses. We hypothesized that reorganization of the actin cytoskeleton would increase endothelial cell production and activation of MMP-2 and that this increase would require a MAPK-dependent signaling pathway in endothelial cells. The pharmacological actin depolymerization agent cytochalasin D increased expression of MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP) mRNA, and this was reduced significantly in the presence of the JNK inhibitor SP600125. Activation of JNK by anisomycin was sufficient to induce expression of both MMP-2 and MT1-MMP mRNA in quiescent cells. Downregulation of c-Jun, a downstream target of JNK, with small interference (si)RNA inhibited MMP-2 expression in response to anisomycin. Inhibition of phosphoinositide 3-kinase (PI3K), but not JNK, significantly decreased the amount of active MMP-2 following cytochalasin D stimulation with a concurrent decrease in MT1-MMP protein. Physiological reorganization of actin occurs during VEGF stimulation. VEGF-induced MMP-2 protein production and activation, as well as MT1-MMP protein production, depended on PI3K activity. VEGF-induced MMP-2 mRNA expression was reduced by inhibition of JNK or by treatment with c-Jun siRNA. In summary, our results provide novel insight into the signaling cascades initiated in the early stages of angiogenesis through the reorganization of the actin cytoskeleton and demonstrate a critical role for JNK in regulating MMP-2 and MT1-MMP mRNA expression, whereas PI3K regulates protein levels of both MMP-2 and MT1-MMP.
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PMID:JNK and PI3K differentially regulate MMP-2 and MT1-MMP mRNA and protein in response to actin cytoskeleton reorganization in endothelial cells. 1667 91


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