UNIPROT:P00750 - FACTA Search

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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor (EGF) stimulates the migration and proliferation of, and tissue-type plasminogen activator (tPA) synthesis in, human omental microvascular endothelial (HOME) cells in culture, as well as inducing the formation by these cells. In the present study, we examined the effects of various growth factors, i.e., transforming growth factor-alpha (TGF-alpha), insulin-like growth factor 1 (IGF-1), and hepatocyte growth factor (HGF) on HOME cells, and compared their effects with that of EGF. IGF-1 stimulated the proliferation and migration of these cells at a level comparable to EGF. EGF and TGF-alpha induced expression of tPA in HOME cells, while IGF-1 and HGF did not. EGF and TGF-alpha induced tube formation by HOME cells in type I collagen gel, while IGF-1 and HGF did not. The stimulatory effect of EGF on tube formation in the gel was blocked by anti-tPA antibody and by a serine protease inhibitor, aprotinin. When exogenous tPA and IGF-1 or HGF were added simultaneously to the culture, a marked induction of tube formation in the gel was observed. Exogenously added tPA alone, however, had no such inducible effect on tube formation. These results indicated an indispensable role of tPA in growth factor-dependent tube formation by HOME cells. Two subsets of growth factors appeared to modulate angiogenesis: One with fully active angiogenic activity which could induce PA (this included EGF and TGF-alpha), and the other, which could not induce PA and was not angiogenic, but could promote angiogenesis in the presence of PA. This subset included IGF-1 and HGF.
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PMID:Indispensable role of tissue-type plasminogen activator in growth factor-dependent tube formation of human microvascular endothelial cells in vitro. 767 96

Human omental microvascular endothelial (HOME) cells seeded on Matrigel begin to migrate within 1 h, forming honeycomb-like structures and capillary-like networks within 18 h. Cross-sections of the capillary networks show them to be tube-like structures. Northern blot analysis showed that tissue-type plasminogen activator (t-PA) mRNA synthesis increased from the initial state at 0 h after seeding on Matrigel, reaching a steady state after 4 h. This elevated cellular t-PA mRNA level decreased markedly at 24 h. In contrast, the cellular plasminogen activator inhibitor-1 (PAI-1) mRNA level demonstrated biphasic curves during the 24 h after seeding on Matrigel: the PAI-1 mRNA level was increased eightfold initially at 4 h over that at 0 h, then declined, and again secondarily increased to greater than tenfold at 18 h. Cellular levels of both 72 kD type IV collagenase and tissue inhibitor of metalloproteinase (TIMP-2) mRNA were increased only a slightly within 2-4 h. These elevated mRNA levels were maintained for 18 h, while the TIMP-1 mRNA level increased up to 18 h, reaching around three times the level at 0 h. However, on collagen-coated dishes, cellular levels of t-PA, PAI-1, 72 kD type IV collagenase, TIMP-1, and TIMP-2 mRNA were not greatly changed during incubation for 24 h. On Matrigel, the cellular t-PA mRNA level at 18 h after seeding was greatly increased when treated with specific anti-transforming growth factor-beta (TGF-beta) antibody. In contrast, both PAI-1 and TIMP-1 mRNA levels at 18 h were reduced in the presence of anti-TGF-beta antibody. Development of the capillary network on Matrigel was inhibited in the presence of anti-t-PA antibody. Epidermal growth factor (EGF) enhanced t-PA gene expression and TGF-beta inhibited its expression in HOME cells cultured on collagen-coated dishes. On the other hand, TGF-beta enhanced cellular expression of the PAI-1 gene. The formation of a capillary network by HOME cells on Matrigel appears to be balanced by angiogenic EGF and anti-angiogenic TGF-beta through modulation of PA activity.
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PMID:Expression of tissue-type plasminogen activator and its inhibitor couples with development of capillary network by human microvascular endothelial cells on Matrigel. 782 31

Glomerular plasminogen activator inhibitor-1 (PAI-1) steady-state mRNA and bioactivity were increased after the induction of an augmented form of antiglomerular basement membrane (GBM) antibody glomerulonephritis. PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and although falling thereafter, remained higher than that of the control group through Day 17. PAI-1 mRNA expression correlated with glomerular PAI-1 bioactivity as determined by a functional tissue type plasminogen activator (t-PA) binding assay. Glomerular PAI-1 bioactivity, not detected in controls, increased to 1.4 +/- 0.3 ng/mg of glomerular lysate at 6 h and then decreased to 0.7 +/- 0.1 ng/mg of glomerular lysate by Day 6. The mRNA of the plasminogen activators (urokinase plasminogen activator), t-PA) either remained unchanged or declined through Day 1, with a slight increase in t-PA mRNA at Day 6. Interleukin-1 beta mRNA expression was maximal at 6 h, declining by Day 3. Transforming growth factor beta 1 (TGF-beta 1) mRNA began to increase at Day 1, was maximal at Day 6, and fell only slightly by Day 17. Epidermal growth factor mRNA decreased. The increase in PAI-1 mRNA and bioactivity, possibly induced early by the interleukin-1 beta response and perhaps later by the TGF-beta 1 response, was associated with striking glomerular capillary lumen fibrin accumulations on Day 1, which decreased and appeared to recanalize as the PAI-1 mRNA and bioactivity fell. The glomerular lesion continued to have some fibrin deposits even on Day 17 and, in addition, had changes of thickened GBM, suggestive of the early stages of diffuse glomerulosclerosis. The latter had a temporal relationship with the persisting increase in TGF-beta 1 and PAI-1 mRNA levels. These observations suggest the possibility that inhibition of enzymes capable of remodeling excessive extracellular matrix production may have contributed to the thickened GBM.
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PMID:Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis. 832 70

Plasminogen activators and their inhibitors have been implicated in the process of fibrinolysis, tissue remodeling, and ovulation. Epidermal growth factor (EGF), a paracrine hormone found in the human ovary, increases plasminogen activator (PA) activity and the gene expression of PA and plasminogen activator inhibitor (PAI) in human endothelial cells and human cell lines. Gonadotropins also increase PA activity and gene expression in rat preovulatory granulosa cells. We have now analyzed the gene expression of PAI-1 and PAI-2 in uncultured human cumulus cells (CC), uncultured granulosa-luteal cells (GLC), and cultured GLC obtained from preovulatory follicles of patients undergoing assisted reproductive technologies. We also studied the effects of hCG and EGF on PAI-1 and PAI-2 mRNA levels in cultured GLC; GLC were cultured in serum-free medium for various times within 24 h with or without hCG and for 6 h with or without hCG, EGF, or EGF plus hCG. Total RNAs from CC and GLC were extracted, and blot hybridizations with 32P-labeled PAI-1, PAI-2, or 28S ribosomal RNA cDNA probes were performed. Both CC and GLC expressed PAI-1 and PAI-2 genes. In GLC, steady state levels of PAI-1 mRNA levels steadily increased within 24 h of culture, whereas PAI-2 levels peaked at 6 h of culture. PAI-1 mRNA levels were not affected by hCG or EGF at 6 h of culture, but PAI-2 mRNA levels were significantly increased by EGF at 6 h of culture. These studies demonstrate that human GLC PAI-1 and PAI-2 mRNA levels are differentially regulated and suggest that EGF may be involved in modulation of the human ovarian PA system during the periovulatory period.
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PMID:Regulation of plasminogen activator inhibitor-1 and -2 messenger ribonucleic acid levels in human cumulus and granulosa-luteal cells. 843 98

Epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) stimulates cell migration, proliferation and the formation of tube-like structures of human microvascular endothelial cells in culture. Heparin-binding EGF-like growth factor(HB-EGF), which shows 35% homology with EGF/TGF-alpha, is a member of the EGF family, and it is ubiquitous in many tissues and organs. We examined whether or not HB-EGF induced angiogenic responses in human microvascular endothelial cells. HB-EGF inhibited the binding of (125) I-EGF to the EGF receptor and induced autophosphorylation of the receptor on endothelial cells. Exogenous HB-EGF induced the loss of more than 70% of the EGF receptor from the cell surface within 30 min, with similar kinetics to that of EGF. The level of c-fos mRNA markedly increased at 30 min in response to HB-EGF as well as EGF. A gel shift assay demonstrated the activation of the transcription factor p91 by HB-EGF and EGF. This factor directly interacts with EGF receptor and mediates the activation of c-fos gene promoter. HB-EGF enhanced the mRNA expression of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) mRNA. However, the enhancement of t-PA and PAI-1 by HB-EGF was less than that by EGF. Heparitinase/chlorate, which digests the heparan sulfate proteoglycan of the endothelial cell surface, restored both t-PA and PAI-1 mRNA levels in response to HB-EGF in a manner similar to that by EGF. HB-EGF at 10 ng/ml developed tube-like structures in type I collagen gel at similar levels to that of EGF at 10 ng/ml, suggesting that HB-EGF is also a potent angiogenic factor in the model system for angiogenesis. The tubulogenesis activity of HB-EGF is discussed in relation to the expression of the t-PA and PAI-1 genes.
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PMID:Heparin-binding epidermal growth factor-like growth factor: p91 activation induction of plasminogen activator/inhibitor, and tubular morphogenesis in human microvascular endothelial cells. 860 52

Embryo implantation in the mouse is an invasive process and requires the action of proteinases, including plasminogen activator (PA) and metalloproteinases. After the implanting embryo establishes close contact with the endometrium, the invasion process begins, at least in part, through interactions of the embryo with the extracellular matrix in the endometrium. This study determined whether embryo interaction with extracellular matrix components would affect the secretion of PA in vitro. PA in vitro. Mouse embryos were collected from the uterus on Day 3.5 of development, just before implantation, and were cultured dishes precoated with bovine serum, plasma fibronectin, or BSA (control). Embryos cultured on serum- or fibronectin-coated dishes secretes significantly more PA than those cultured on BSA. The effect of fibronectin was inhibited by hexapeptides that contained the integrin-recognizing Arg-Gly-Asp sequence. This indicates that the action of fibronectin in enhancing PA secretion is mediated through its receptor (integrins) in the embryo. Fibronectin fragments reproduced the effect of the whole fibronectin molecule, suggesting that the clustering of integrins by specific ligands is responsible, at least in part, for the increase PA secretion. The increase in PA secretion was a specific response to fibronectin rather than a reflection of increased total protein secretion, and was at least partially a result of the increased steady-state level of PA mRNA in the cultured embryos. Laminin was as effective as fibronectin in promoting PA secretion. Epidermal growth factor increased PA secretion, probably by promoting the interaction of the embryos with the extracellular matrix. In summary, our findings indicate that the interactions of the implanting embryos with their extracellular matrix may regulate trophoblast invasion by controlling PA secretion.
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PMID:Regulation of urokinase plasminogen activator production in implanting mouse embryo: effect of embryo interaction with extracellular matrix. 872 26

The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases,mitogen-activated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [(14)C]PAH was abolished by the phospholipase A(2) inhibitor AACOCF3.[(14)C]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA(2). In addition, EGF stimulated the influx of extracellular Ca(2+). However, Ca(2+)-influx was not required for the stimulatory action of EGF on [(14)C]PAH uptake. Inhibitors of COX and lipoxygenases reduced [(14)C]PAH uptake dose-dependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [(14)C]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E(2) (PGE(2)) increased basolateral [(14)C]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [(14)C]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [(14)C]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA(2), leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.
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PMID:Short-term regulation of basolateral organic anion uptake in proximal tubular OK cells: EGF acts via MAPK, PLA(2), and COX1. 1213 28

Epidermal growth factor (EGF) is known to play an important role in modulating renal transport functions. Thus, we investigated the effect of EGF on Ca(2+) uptake and its related signals in the primary cultured rabbit renal proximal tubule cells. EGF (50 ng/ml, 1 h) stimulated Ca(2+) uptake. Its effect was blocked by AG 1478 (an EGF receptor antagonist), genistein or herbimycin A (tyrosine kinase inhibitors). EGF increased intracellular cAMP level and SQ 22536 (an adenylate cyclase inhibitor), Rp-cAMP (a cAMP analogue), or PKI (a protein kinase A inhibitor) blocked the EGF-induced stimulation of Ca(2+) uptake. EGF-induced stimulation of Ca(2+) uptake was also blocked by neomycin or U-73122 (phospholipase C inhibitors), staurosporine, H-7, or bisindolylmaleimide I (protein kinase C inhibitors), nifedipine or methoxyverapamil (L-type Ca(2+) channel blockers). It increased IPs formation by 167 +/- 5% compare to control within 90 s. On the other hand, EGF increased [(3)H]-arachidonic acid release, which was significantly blocked by PKC inhibitors. In addition, PGE(2), one of cyclooxygenase metabolites, and 5,6-EET, one of cytochrome P-450 metabolites, increased Ca(2+) uptake. These results suggest that cAMP, PLC/PKC, and PLA(2) are involved in EGF-induced stimulation of Ca(2+) uptake.
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PMID:Epidermal growth factor regulates Ca2+ uptake in primary cultured renal proximal tubule cells: involvement of cAMP, PKC and cPLA2. 1288 43

The effect of EGF on (14)C-alpha-methyl-D-glucopyranoside (alpha-MG) uptake and its related signaling pathways were examined in primary cultured rabbit renal proximal tubule cells (PTCs). Epidermal growth factor (EGF) (50 ng/ml) was found to inhibit alpha-MG uptake, a distinctive proximal tubule marker. The EGF effect was blocked by AG1478 (an EGF receptor antagonist) or genistein and herbimycin (tyrosine kinase inhibitors), respectively. In addition, the EGF-induced inhibition of alpha-MG uptake was blocked by neomycin and U73122 (phospholipase C inhibitors) as well as staurosporine, H-7, and bisindolylmaleimide I (protein kinase C inhibitors). EGF was also observed to increase inositol phosphate formation. Furthermore, both the EGF-induced inhibition of alpha-MG uptake and increase of arachidonic acid (AA) release were blocked by AACOCF(3) (a cytosolic phospholipase A(2) inhibitor), indomethacin (a cyclooxygenase inhibitor), and econazole (a cytochrome P-450 epoxygenase inhibitor). We examined the involvement of mitogen-activated protein kinases (MAPKs) in mediating the effect of EGF on alpha-MG uptake. Indeed, EGF increased phosphorylation of p44/p42 MAPK and the EGF-induced inhibition of alpha-MG uptake as well as the stimulatory effect of EGF on AA release was blocked by PD 98059 (a p44/42 MAPK inhibitor), suggesting a causal relationship. However, inhibitors of PKC also prevented the EGF-induced increase of AA release. In conclusion, EGF partially inhibited alpha-MG uptake via PLC/PKC, p44/42 MAPK, and PLA(2) signaling pathways.
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PMID:Epidermal growth factor inhibits 14C-alpha-methyl-D-glucopyranoside uptake in renal proximal tubule cells: involvement of PLC/PKC, p44/42 MAPK, and cPLA2. 1504 3

During ovarian follicle growth, there is expansion of the basal lamina and changes in the follicular extracellular matrix (ECM) that are mediated in part by proteolytic enzyme cascades regulated by tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA). One PA inhibitor, serine protease inhibitor-E2 (SERPINE2) is expressed in granulosa but not theca cells, and expression changes with follicle development. In this study, we hypothesized that PA and SERPINE2 expression/secretion by granulosa cells are regulated by FSH and growth factors. SERPINE2 mRNA and protein levels, tPA gene expression and uPA secretion were stimulated by FSH. Insulin-like growth factor-I stimulated SERPINE2 secretion and uPA activity, and decreased secreted tPA activity and gene expression. Bone morphogenetic protein-7 increased SERPINE2 secretion and expression and tPA secretion. In contrast, fibroblast growth factor-2 inhibited tPA secretion and SERPINE2 secretion and expression. Epidermal growth factor inhibited SERPINE2 secretion and expression, but increased secreted tPA activity. Estradiol and SERPINE2 secretion were highly positively correlated, but estradiol did not alter SERPINE2 expression. These data demonstrate that SERPINE2 expression and protein secretion are regulated by FSH and growth factors in non-luteinizing bovine granulosa cells. As estradiol is a known marker of follicle health, and SERPINE2 is an anti-apoptotic factor, we propose that SERPINE2 is involved in the regulation of atresia in bovine follicles.
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PMID:Regulation of serine protease inhibitor-E2 and plasminogen activator expression and secretion by follicle stimulating hormone and growth factors in non-luteinizing bovine granulosa cells in vitro. 1680 68

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