Gene/Protein Disease Symptom Drug Enzyme Compound
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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) domains are found in many proteins, particularly those of the coagulation/fibrinolytic system. We and others have demonstrated that tissue plasminogen activator (t-PA) and prourokinase are modified by the attachment of fucose to equivalent threonine residues within their EGF domains. Factor XII and protein C each contain two EGF domains; in both proteins, the EGF domain nearest the N terminus has a threonine residue in a position homologous to that which is fucosylated in t-PA. In protein C, this site is 3 residues from the position of another post-translational modification, beta-hydroxylation of Asp-71. We isolated peptides containing these sites to determine, primarily by mass spectrometric analysis, the presence of O-linked fucose and/or beta-hydroxyaspartate. We found that factor XII is fully fucosylated at Thr-90. Protein C is unmodified at the equivalent site (Thr-68) and is completely beta-hydroxylated at Asp-71. It has been recently reported that the first EGF domain of human factor VII has O-linked fucose at the equivalent position (Ser-60) (Bjoern, S., Foster, D. C., Thim, L., Wiberg, F. C., Christensen, M., Komiyama, Y., Pedersen, A. H., and Kisiel, W. (1991) J. Biol. Chem. 266, 11051-11057), while it is unmodified at Asp-63 despite having the consensus sequence for beta-hydroxylation at the latter site. These observations raise the possibility that O-linked fucosylation and beta-hydroxylation of EGF domains are mutually exclusive post-translational modifications.
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PMID:O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C. 154 94

Epidermal growth factor (EGF) induces tubular formation of cultured human omental microvascular endothelial (HOME) cells and EGF also stimulates cell migration as well as expression of tissue type plasminogen activator (t-PA). Here we studied the effects of hepatocyte growth factor (HGF) on cell proliferation, cell migration and expression of t-PA and other related genes. Migration of confluent HOME cells into the denuded space was stimulated by HGF after being wounded with razor blade, but at a reduced rate in comparison with EGF. HOME cells could be proliferated in response to exogenous 100 ng/ml of HGF at rates comparable to that of 20 ng/ml EGF. The chemotactic activity of HOME cells was significantly stimulated by HGF in a dose-dependent manner when assayed by Boyden chamber. HGF did not efficiently enhance expression of both the t-PA gene and a tissue inhibitor of metalloproteinase gene whereas it stimulated expression of plasminogen activator inhibitor-1. Our present study provides a new evidence that some of the biological effects of HGF on HOME cells in culture are similar to those of EGF.
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PMID:Hepatocyte growth factor modulates migration and proliferation of human microvascular endothelial cells in culture. 165 97

Epidermal growth factor (EGF) induces tissue-type plasminogen activator (t-PA) biosynthesis in HeLa cells. Based on nuclear run-on transcription assays, t-PA biosynthesis is modulated by EGF on the level of gene transcription. The effect of EGF is slow, requiring 4-8 h to induce t-PA gene transcription and up to 24 h to induce t-PA mRNA and antigen secretion. An additive response is observed when cells are treated with both phorbol 12-myristate 13-acetate and EGF, suggesting that the two pathways converge and act independently to implement their respective effects. cAMP has previously been shown to potentiate phorbol 12-myristate 13-acetate-mediated induction of t-PA biosynthesis in HeLa cells and in human endothelial cells. Akin to this observation, cAMP also potentiates the EGF-mediated increase in t-PA mRNA. Maximal levels of t-PA mRNA is seen in the presence of all three agonists. The regulation of t-PA by EGF alone and in the presence of either PMA or cAMP is consistent with a role of t-PA during growth and development, and further indicates a functional interplay between protein kinase C-, tyrosine kinase, - and cAMP-dependent signal transduction pathways during regulation of t-PA gene expression.
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PMID:Regulation of human tissue-type plasminogen activator gene transcription by epidermal growth factor and 3',5'-cyclic adenosine monophosphate. 166 1

Epidermal growth factor (EGF) induces tubular formation of cultured human microvascular endothelial (HME) cells in the gel matrix containing collagen, and tumor necrosis factor (TNF) disrupts the tubular formation (Mawatari et al. (1989) J. Immunol. 143, 1619-1627). Here we studied the effects of EGF and TNF on endothelial cell migration and on the production of proteases. Confluent HME cells, when wounded with a razor blade, moved into the denuded space. This migration was stimulated by EGF and inhibited by TNF in this assay and in the Boyden chamber assay. Antibody against tissue-type plasminogen activator (t-PA) inhibited the EGF-stimulated cell migration in both assays by approximately 70%, but antibody against urokinase-type plasminogen activator (u-PA) could not inhibit its migration. Quantitative immunoreactive assays showed an approximately three- to fourfold increase of t-PA at 6 to 12 h after EGF addition, and TNF inhibited the production of t-PA by 50%. Northern blot analysis showed increased expression of t-PA mRNA by EGF alone in a time- and dose-dependent manner, whereas TNF alone inhibited its expression in a time- and dose-dependent manner. Northern blot analysis showed a significant increase of plasminogen activator inhibitor-1 (PAI-1) mRNA when EGF or TNF was present. Stimulation by EGF of cell migration of HME cells and its inhibition by TNF appear to be closely correlated with the cellular modulation of t-PA and PAI-1 activities.
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PMID:Tumor necrosis factor and epidermal growth factor modulate migration of human microvascular endothelial cells and production of tissue-type plasminogen activator and its inhibitor. 189 74

1. Regulatory mechanism of cell growth of endometriosis in comparison with endometrium. Estradiol alone has no growth-promoting effect on both endometriotic and endometrial cells. Epidermal growth factor (EGF) stimulates cell growth of both cell types. Endometrial cells but not endometriotic cells produce and release EGF into culture media so that stimulatory effect of exogenous addition of EGF is blunted in endometrial cells. Estradiol exerts its mitogenic action by enhancing the mitogenic effect of EGF in endometrium. By contrast, the effect of estradiol is minimal in endometriotic cells, showing less dependency on estradiol for their proliferation. Progesterone inhibits cell growth of the both cell types in the same manner. 2. A biological role of EGF in endometriosis. Endometriotic cells possess EGF receptors. The affinity of the receptor is the same as that of endometrial cells. However, the number of receptor per cell is about half of that for endometrium. Estradiol increases the number of EGF receptors in endometrial cells which may explain the mitogenic effect of estradiol in the face of EGF. However, stimulatory effect of estradiol for EGF receptors is less pronounced in endometriotic cells. Mitogenic action of EGF is suggested to be mediated by phosphorylation of tyrosine residues of 170 kd protein in the tissues. EGF increases the production of tissue plasminogen activator (t-PA) and activates the aromatase activity of the both cell types. However, the stimulatory action of EGF on progestin receptor is observed only in endometrial cells. 3. Biochemical characterization of endometriotic cells in comparison with endometrial cells. Endometriotic tissues accumulate less amount of glycogen and XIII factor of blood coagulation as compared to endometrial tissues. The ability of endometriotic cells to release prostaglandin is also weaker, suggesting suppressed differentiated function of endometriotic cell. Endometriotic cells produce the same amount of CA125 as endometrial cells. Danazol and EGF inhibit the release of CA125 into culture media when standardized per cell. Therefore, normalization of CA125 levels during the treatment dose not always mean the reduction of the lesions but reflect the suppressed function of the endometriotic tissues. 4. Altered microenvironment of endometriotic tissues. An analysis of peritoneal fluid. The amount of peritoneal fluid (PF) with endometriosis increased throughout the menstrual cycle. A number of macrophage is reported to increase in PF with endometriosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Fundamental and clinical studies on biochemical properties of endometriosis in comparison with endometrium]. 250 2

The pronounced synovial hyperplasia often found in the joints of patients with rheumatoid arthritis could be explained partially by the action of monocyte-macrophage polypeptides (monokines). This report demonstrates that two cytokines which may be derived from monocyte-macrophage populations, namely platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), stimulate the DNA synthesis and proliferation of human synovial fibroblast-like cells cultured in low (i.e., 1%) fetal bovine serum. Epidermal growth factor, insulin-like growth factor-I, insulin-like growth factor-II (multiplication stimulating activity) and substance P were inactive. Unlike IL-1, PDGF and FGF do not also stimulate PGE2, plasminogen activator, and hyaluronic acid levels. Thus PDGF and FGF, arising from stimulated monocyte-macrophages, may play a role in the stimulation of mesenchymal cell proliferation that often accompanies chronic inflammatory arthritic disease. The synovial cells respond to a variety of cytokines in different ways suggesting multiple-signaling pathways.
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PMID:Stimulation of human synovial fibroblast DNA synthesis by platelet-derived growth factor and fibroblast growth factor. Differences to the activation by IL-1. 270 21

Cultured human embryonic lung fibroblasts were used as a model to study the effects of transforming growth factor-beta (TGF beta) on the plasminogen activator (PA) activity released by nontumorigenic cells into the culture medium. The cells were exposed to TGF beta under serum-free conditions, and the changes in PA activity and protein metabolism were analyzed by caseinolysis-in-agar assays, zymography, and polypeptide analysis. Treatment of the cells with TGF beta caused a significant decrease in the PA activity of the culture medium as analyzed by the caseinolysis-in-agar assays. The quantitatively most prominent effect of TGF beta on confluent cultures of cells was the induction of an Mr 47,000 protein, as detected by metabolic labeling. The Mr 47,000 protein was a PA inhibitor as judged by reverse zymography. It was antigenically related to a PA inhibitor secreted by HT-1080 tumor cells as demonstrated with monoclonal antibodies. The induced Mr 47,000 inhibitor was deposited into the growth substratum of the cells, as detected by metabolic labeling, immunoblotting analysis, and reverse zymography assays of extracellular matrix preparations. TGF beta also decreased the amounts of urokinase-type and tissue-type PAs accumulated in the conditioned medium, as detected by zymography. Epidermal growth factor antagonized the inhibitory effects of TGF beta by enhancing the amounts of the PAs. These results indicate that growth factors modulate the proteolytic balance of cultured cells by altering the amounts of PAs and their inhibitors.
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PMID:Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta. 349 Oct 81

Adult human skin fibroblasts were used as a model to study the effects of transforming growth factor beta (TGF beta) on the secreted plasminogen activator (PA) activity of cultured cells. TGF beta, at nanogram concentrations, enhanced the secretion of pro-PA from two fibroblast strains in a time- and dose-dependent manner. The induced enzymatic activity was inhibited by anti-urokinase antibodies and it co-migrated with purified urokinase in polyacrylamide gels. The secretion of PA activity was abolished when cycloheximide (0.1 microgram/ml) was added to the cultures. The activity was thus dependent on protein synthesis rather than just on direct activation of a plasminogen proactivator. TGF beta had only a slight mitogenic effect on the test cells. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and insulin were ineffective alone in inducing PA. Insulin, on the contrary, had an inhibitory effect on the TGF beta-induced PA activity. In addition to its effects on the secretion of PA, TGF beta enhanced the production of a proteinase inhibitor by these cells. The results suggest a role for TGF beta in the regulation of PA activity and pericellular proteolysis in fibroblastic cells.
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PMID:Transforming growth factor beta alters plasminogen activator activity in human skin fibroblasts. 351 51

Epidermal growth factor-binding protein (EGF-BP) is a serine proteinase that reversibly associates with epidermal growth factor (EGF). We analyzed the reaction of EGF-BP with urokinase type plasminogen activator (u-PA), a serine proteinase that promotes pericellular proteolysis and cellular migration. EGF-BP cleaved single chain u-PA (scu-PA) between Lys158 and Ile159, converting the zymogen into enzymatically active two-chain u-PA (tcu-PA), as shown by SDS-PAGE, N-terminal sequence analysis, and enzymatic assay. The kcat and Km of the activation reaction were (5.6 +/- 0.6) x 10(-2)s-1 and 2.0 +/- 0.3 microM, yielding a catalytic efficiency of 2.8 x 10(4) M-1.s-1. EGF-BP also activated scu-PA bound to receptors on U937 monocytes as demonstrated by the generation of amidase activity against a tcu-PA-specific fluorogenic substrate. By activating scu-PA, EGF-BP may initiate u-PA-dependent cell surface proteolysis and therefore enhance EGF activities that require cellular migration and/or tissue remodeling.
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PMID:Epidermal growth factor-binding protein activates soluble and receptor-bound single chain urokinase-type plasminogen activator. 749 36

Epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) stimulated cell migration, chemotaxis, and the expression of tissue-type plasminogen activator (t-PA) in human omental microvascular endothelial (HOME) cells. Hepatocyte growth factor (HGF) stimulated cell proliferation, but had a negligible stimulatory effect on cell migration, the expression of t-PA and tube-like formation into collagen gel in HOME cells. Basic fibroblast growth factor stimulated cell proliferation, cell migration, tubulogenesis and the expression of urokinase-type plasminogen activator (u-PA) in bovine aortic endothelial (BAE) cells. HOME and BAE cells had both high- and low-affinity receptors for HGF. In BAE cells, u-PA activity and tube-like structures in collagen gel were induced in the presence of HGF alone. In contrast, in HOME cells, t-PA activity and tube-like structures were induced in the presence of TGF-alpha alone, but not in the presence of HGF alone. However, we observed a marked induction of tube formation by HOME cells when both t-PA and HGF were added simultaneously. In the model system for tumor angiogenesis, when HOME cells were co-cultured with a renal cancer cell line, KPK13, tube-like structures were induced in the presence of HGF:KPK13 cells expressed large amounts of t-PA mRNA. Our present study suggested that HGF in concert with active t-PA could be angiogenic in HOME cells.
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PMID:Cooperative roles of hepatocyte growth factor and plasminogen activator in tubular morphogenesis by human microvascular endothelial cells. 750 7


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