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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was reported over a decade ago that tissue inhibitor of metalloproteinases-1 (TIMP-1) suppresses angiogenesis in experimental models but the mechanism is still incompletely understood. This in vitro study focused on the molecular basis of TIMP-1-mediated inhibition of endothelial cell (EC) migration, a key step in the angiogenic process. Both recombinant human TIMP-1 and the synthetic MMP inhibitors, GM6001 and MMP-2-MMP-9 Inhibitor III, suppressed migration of human dermal microvascular endothelial cells (HDMVEC) in a dose-dependent fashion. The MMP-dependent inhibition of migration was associated with increased expression of the junctional adhesion proteins, VE-cadherin and PECAM-1, and VE-cadherin accumulation at cell-cell junctions. TIMP-1 also caused MMP-independent dephosphorylation of focal adhesion kinase (FAK) (pY397) and paxillin, which was associated with reduced number of F-actin stress fibers and focal adhesions. Moreover, TIMP-1 stimulated expression of PTEN that has been shown to reduce phosphorylation of FAK and inhibit cell migration. Our data suggest that TIMP-1 inhibits HDMVEC migration through MMP-dependent stimulation of VE-cadherin and MMP-independent stimulation of PTEN with subsequent dephosphorylation of FAK and cytoskeletal remodeling.
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PMID:TIMP-1 inhibits microvascular endothelial cell migration by MMP-dependent and MMP-independent mechanisms. 1553 Aug 52

Pulmonary fibrosis is characterized by a loss of lung epithelial cells, replaced by interstitial myofibroblasts to deposit extracellular matrix (ECM) proteins. Previous studies demonstrated that hepatocyte growth factor (HGF) improved lung fibrosis in murine models, whereas molecular mechanisms whereby HGF improved lung fibrosis have yet to be fully understood. When MRC-5 human lung fibroblasts were treated with transforming growth factor-beta1, the cells underwent phenotypic change similar to myofibroblasts and this was associated with up-regulation of c-Met/HGF receptor expression. For the myofibroblast-like cells, HGF increased activities of MMP-2/-9, predominant enzymes for breakdown of fibronectin (FN). Under such conditions, HGF induced caspase-dependent apoptosis, linked with a decrease in a FN central cell binding (CCB) domain involved in FAK phosphorylation. When MMI270 (a broad-spectrum MMP inhibitor) was added together with HGF, decreases in FN-CCB domain expression and FAK phosphorylation by HGF were restored, and these events were associated with an inhibition of HGF-induced apoptosis, suggesting that increased activities of MMPs underlie the major mechanism of HGF-mediated apoptosis in myofibroblasts. In bleomycin-treated mice, c-Met expression was found on interstitial myofibroblasts and HGF increased apoptosis in culture of myofibroblasts isolated from bleomycin-treated murine lungs. Furthermore, administration of recombinant HGF to bleomycin-treated mice increased lung MMP activities and enhanced myofibroblast apoptosis, while in vivo MMI270 injections together with HGF inhibited such MMP activation, leading to suppressed myofibroblast apoptosis. In conclusion, we identified HGF as a key ligand to elicit myofibroblast apoptosis and ECM degradation, whereas activation of the HGF/c-Met system in fibrotic lungs may be considered a target to attenuate progression of chronic lung disorders.
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PMID:HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. 1566 32

Epidemiological studies indicate that dietary fiber-derived fermentation products such as butyrate can prevent colon cancer development. To further dissect the role of butyrate in anticarcinogenesis, its effect on cellular growth and invasion as well as the expression of c-Src and FAK, two mutually interactive nonreceptor tyrosine kinases, in three different human colon cancer cell lines (Caco-2, SW480, and SW620) were investigated. In addition to growth inhibition, butyrate treatment results in a significant downregulation of c-Src and FAK in human colon cancer cells, which can be attributable to their reduced transcripts and implicates the participation of a butyrate-sensitive pathway in modulating their expression. Concurrent to butyrate-reduced c-Src and FAK expression is the decrease of FAK Tyr-decrease 397 phosphorylation. Besides, butyrate also abolished the secretion of MMP-2 and MMP-9. And these butyrate-mediated effects severely impaired invasion of SW620 cells through Matrigel in vitro. Interestingly, in situ parallel enhancement of c-Src and FAK was also observed in human colorectal tumor specimens. These results imply that by virtue of suppression of c-Src and FAK along with other butyrate targets in colonocytes, butyrate could effectively inhibit tumor growth and invasion.
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PMID:Butyrate regulates the expression of c-Src and focal adhesion kinase and inhibits cell invasion of human colon cancer cells. 1600 24

The homeopathic compound of resonance FMS*Calciumfluor (FMS*) reportedly promotes osteogenic differentiation of rat pre-osteoblasts in vitro. Here, we show that the continuous exposure of differentiating rat osteogenic cells (ROB) to FMS* modulates the level of expression of mRNAs for 7 of the 8 osteogenic markers tested. Alkaline phosphatase (AP), osteocalcin (OC), metalloproteinases (MMP-2 and -14), procollagenase C (BMP-1), biglycan (BG) and integrin 1 are expressed at higher levels in FMS*-treated osteoblasts than in control cultures. MMP-2 and -14 mRNA are not down-modulated at mineralization. Also, the pattern of expression induced by FMS* for some of these genes (BMP-1, BG and integrin 1) is changed, but collagen type I (Coll I) mRNA levels are not affected by treatment with FMS*. This suggests that FMS* modulates mRNA levels and that this is not generalized, but gene(s) specific. We also report that exposure to FMS* rapidly and transiently induces activation of mitogen-activated protein kinases (MAPKs) 42,44 in populations of early osteoblasts, but not in pre-osteoblasts, with a cell differentiation stage-dependent and pertussis toxin (PTX)-sensitive response. Subsequent to FMS* MAPK signaling activation, an increase in AP and MMP-14 mRNA is detected, which is also inhibited by PTX, suggesting that FMS* activation of MAPK signaling could be an early event required for the induction of these genes. Exposure to FMS* does not cause changes in the activity of p125 (FAK)-mediated signaling.
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PMID:FMS*Calciumfluor specifically increases mRNA levels and induces signaling via MAPK 42,44 and not FAK in differentiating rat osteoblasts. 1602 62

Craniofacial sutures create a soft tissue interface between various calvarial and facial bones. Facial and cranial sutures show differences in their surrounding anatomical structures and local mechanical strain environments. Despite previous attempts to identify the expression of matrix metalloproteinase genes (MMPs) in cranial sutures, little is known regarding whether facial and cranial sutures differ in MMP expression. We have investigated the expression of MMP-1 and MMP-2 in the pre-maxillomaxillary suture (PMS; facial suture) and the frontoparietal suture (FPS; cranial suture) in 32-day-old rats with or without the application of cyclic loading. Expression of MMP-1 and MMP-2 was detected by the reverse transcription/polymerase chain reaction technique. At 32 days of postnatal development (n=6), both MMP-1 and MMP-2 were reproducibly expressed in the facial PMS, in comparison with negligible MMP-1 and MMP-2 expression in the cranial FPS. In six age- and sex-matched control rats, cyclic loading at 4 Hz and 1000 mN was applied to the maxilla for two 20-min episodes within a 12-h interval. In some (but not all) cases, cyclic loading induced marked expression of MMP-1 and MMP-2 in the PMS and FPS in comparison with corresponding non-loaded controls. These data confirm our previous finding that short doses of cyclic loading upregulate MMP-2 expression in craniofacial sutures and suggest the possibility that facial and cranial sutures differ in matrix degradation rates during postnatal development.
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PMID:Expression and mechanical modulation of matrix metalloproteinase-1 and -2 genes in facial and cranial sutures. 1604 57

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic-MMP-2 and -9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP-2 and -9 in ailing to failing myocardium. Activation of MMP-2 and -9 leads to induction of proteinase activated receptor-1 (PAR-1). We hypothesize that the early induction of MMP-9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase-1 (ERK-1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP-2 and -9 gelatinolytic activities was made by real-time quantitative zymography. Gel phosphorylation staining for PAR-1 showed a significant increase in ICM hearts. Western blot and RT-PCR analysis and in-situ labeling, showed significant increased expression of PAR-1, ERK-1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP-9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end-stage human heart failure.
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PMID:Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. 1620 18

In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFbeta1-Smad (transforming growth factor-beta1-Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (proximal-tubule epithelial cells) and EMT (epithelial-mesenchymal transdifferentiation) of PTECs to myofibroblasts in response to TGFbeta are critical Smad-dependent events in the development of tubulo-interstitial fibrosis. In the present study we have investigated the distinct contributions of Smad2 and Smad3 to expression of CTGF, E-cadherin, alpha-SMA (alpha-smooth-muscle actin) and MMP-2 (matrix-metalloproteinase-2) in response to TGFbeta1 treatment in an in vitro culture model of HKC-8 (transformed human PTECs). RNA interference was used to achieve selective and specific knockdown of Smad2 and Smad3. Cellular E-cadherin, alpha-SMA as well as secreted CTGF and MMP-2 were assessed by Western immunoblotting. TGFbeta1 treatment induced a fibrotic phenotype with increased expression of CTGF, MMP-2 and alpha-SMA, and decreased expression of E-cadherin. TGFbeta1-induced increases in CTGF and decreases in E-cadherin expression were Smad3-dependent, whereas increases in MMP-2 expression were Smad2-dependent. Increases in alpha-SMA expression were dependent on both Smad2 and Smad3 and were abolished by combined knockdown of both Smad2 and Smad3. In conclusion, we have demonstrated distinct roles for Smad2 and Smad3 in TGFbeta1-induced CTGF expression and markers of EMT in human PTECs. This can be of therapeutic value in designing targeted anti-fibrotic therapies for tubulo-interstitial fibrosis.
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PMID:The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1 responses in human proximal-tubule epithelial cells. 1625 18

Biventricular dilation and severe cardiac dysfunction are observed during septic shock. However, when endotoxemia and vasoconstrictor-masked hypovolemia work in concert in the pathogenesis of shock, the clinical scenario is more adverse compared to one of the insults acting alone. Matrix metalloproteinases (MMPs) are involved in chronic and acute heart failure by degrading the mechanical scaffold of the heart and several intracellular proteins. Therefore, the roles of MMP-2, MMP-9, MT1-MMP, focal adhesion kinase (FAK), and Paxillin in hearts of early multiple organ failure induced by norfenefrine-masked hypovolemia and endotoxemia were investigated in an ovine model. Experimental groups included (1) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) (n=6), (2) norfenefrine-masked hypovolemia without endotoxemia (NMH) (n=6), (3) recurrent endotoxemia during normovolemia (ENDO) (n=6), and (4) healthy untreated controls (CON) (n=3). Apoptosis was determined by TUNEL-staining. Gel zymography revealed significantly increased MMP-2 activity in NMH+ENDO compared to ENDO and controls. MMP-9 activity was significantly elevated in all experimental groups. MMP-2 was significantly increased at the protein level, while MMP-9 was unaltered. MT1-MMP was not significantly changed in any group. Increased MMP activities were associated with cardiac deterioration. MMP-2/-9 activity and phosphorylated Paxillin (p-Paxillin) expression correlated positively with cardiomyocyte apoptosis. This study underscores the pivotal roles of MMP in acute cardiac dysfunction during early multiple organ failure in combined vasoconstrictor-masked hypovolemic and endotoxemia shock.
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PMID:Roles of MMP-2/-9 in cardiac dysfunction during early multiple organ failure in an ovine animal model. 1630 6

Calcitonin (CT) is synthesized and secreted in prostate epithelium, and its secretion from malignant prostates is several folds higher than that in benign prostates. CT receptor (CTR) is expressed in malignant prostate epithelium, and its activation increases invasiveness of prostate cancer (PC) cells via activation of protein kinase A. Since the role of urokinase-type plasminogen activator (uPA) in invasion of PC has been established, we tested the hypothesis that CT increases invasion of PC cells by stimulating uPA secretion from PC cells. Exogenously added CT stimulated the secretion of uPA from PC-3M cells in a dose-dependent manner, which was blocked by Rp.cAMP, a competitive inhibitor of protein kinase A. CT stimulated the secretion of MMP-2 and MMP-9 from PC-3M cells, and also increased their invasiveness. Both these actions of CT were blocked by uPA-neutralizing antibodies. Immunofluorescence studies with PC-3M cells suggest that CT stimulated redistribution of cellular uPA to focal adhesion sites, which was further confirmed by co-immunoprecipitation of uPA with focal adhesion kinase (FAK) in response to CT. These results suggest that CT increases invasiveness of PC cells by stimulating PKA-mediated uPA secretion and by redirecting the secreted uPA to focal adhesion sites. The results also suggest that uPA may, at least in part, mediate proinvasive actions of CT on PC cells by stimulating the secretion of gelatinases and degradation of focal adhesion sites.
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PMID:Calcitonin stimulates the secretion of urokinase-type plasminogen activator from prostate cancer cells: its possible implications on tumor cell invasion. 1638 Oct 4

The ovarian surface epithelium (OSE) is the precursor of common epithelial ovarian carcinomas. In the present study, we examined the molecular mechanisms and possible physiological basis for the propensity of OSE cells to undergo epithelio-mesenchymal transition (EMT) in response to environmental influences. We hypothesized that EMT may be a homeostatic mechanism that permits displaced OSE to assume a stromal phenotype within the ovarian cortex. We report that EGF in conjunction with hydrocortisone is the EMT-inducing factor of OSE as shown by changes to a fibroblast-like morphology and growth pattern. EGF increased cell motility, enhanced the activities of secreted pro-matrix metalloproteinase (MMP)-2 and -9, and enhanced expression and activation of Erk and integrin-linked kinase (ILK). Increased ILK expression correlated with the activation of PKB/Akt, the phosphorylation of GSK-3beta, and the increased expression of cyclin E and cdk2 kinase. EGF withdrawal resulted in a more epithelial morphology and reversal of the EGF-induced activation of signaling pathways and pro-MMP activity. In contrast, treatment of EGF-treated cells with specific inhibitors of phosphatidylinositol 3-kinase, Mek, or ILK inhibited the inhibitor-specific pathways. The inhibitors caused suppression of EGF-induced migration and pro-MMP-2/-9 activities but did not lead to any change in EGF-induced mesenchymal morphology. ILK small interfering RNA inhibited Akt phosphorylation and reduced pro-MMP-2/-9 activities but had no effect on Erk activation or cell morphology. These results indicate that the EGF-induced morphological and functional changes in OSE cells are controlled by distinct signaling mechanisms working in concert. EMT of OSE cells displaced by ovulation likely permits their survival and integration with a fibroblast-like identity within the stroma. Failure to do so may lead to the formation of epithelium-derived inclusion cysts, which are known preferential sites of malignant transformation.
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PMID:Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. 1639 28


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