Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of receptor-bound urokinase-type plasminogen activator (uPA) in cellular activation of latent transforming growth factor-beta (LTGF-beta) was investigated in a model system of mouse LB6 cells transfected with either a human uPA receptor cDNA (LhuPAR+), a human prouPA cDNA (LhuPA), or a control neomycin-resistance cDNA (Lneo). When LhuPAR+ cells were co-cultured with LhuPA cells, the plasmin-dependent fibrinolytic activity generated was more than that observed in either homotypic cultures with fivefold greater number of LhuPA cells or co-cultures containing LhuPA and Lneo cells instead of the LhuPAR+ cells. The preferential activation of TGF-beta by co-cultures with the greatest plasmin-generation potential, LhuPAR+ and LhuPA cells, was confirmed by three independent bioassays. In the first assay, a 48% decrease in PA activity, a measure of active TGF-beta production, was observed with BAE cells treated with conditioned medium (CM) from co-cultures of LhuPA and LhuPAR+ cells. Inclusion of neutralizing antibodies to TGF-beta abrogated the inhibitory effect of CM on PA activity demonstrating that the inhibitory molecule was TGF-beta. Addition of the amino terminal fragment of uPA (ATF) or omission of plasminogen from co-cultures blocked both the fibrinolytic activity and the generation of TGF-beta activity in the CM. In the second assay, CM from co-cultures of LhuPA and LhuPAR+ cells inhibited the migration of BAE cells in a wound assay. Controls with anti-TGF-beta IgG indicated that the inhibition was due to TGF-beta. In the third assay, proliferation of mink lung epithelial cells was inhibited by CM generated by co-cultures of LhuPA and LhuPAR+ cells as compared to CM from the same cells cultured in the absence of plasminogen or to CM from a co-culture of LhuPA with LhuPAR- cells. Excess mannose-6-phosphate (M6P) blocked the generation of TGF-beta as assayed by both the BAE migration and PA assays, presumably because it interfered with cell-surface localization of LTGF-beta. Additionally, small numbers of LhuPA and LhuPAR+ cells co-cultured with BAE cells inhibited the BAE cell PA activity via the paracrine action of TGF-beta. These results support the conclusion that plasmin-dependent activation LTGF-beta by LB6 cells is promoted by the surface localization of uPA by its receptor.
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PMID:Requirement for receptor-bound urokinase in plasmin-dependent cellular conversion of latent TGF-beta to TGF-beta. 812 64

We studied the expression of insulin-like growth factors I (IGF-I) and II (IGF-II) and their receptors (IGF-R) in 2 related murine mammary adenocarcinoma in vivo lines, M3 and MM3, with different metastasizing ability. We further investigated the effects of IGFs on the secretion of a key enzyme in the metastatic cascade, the urokinase-type plasminogen activator (uPA) in M3 and MM3 cells. M3 is a spontaneous mammary tumor originated in BALB/c mice, with a 40% incidence of lung metastases. MM3 variant, obtained by successive s.c. implants of M3 lung metastases into syngeneic mice, shows a 95% incidence of lung metastases. Similar levels of expression of IGF-I protein were found in M3 and MM3 tumors, whereas IGF-II expression was 4-fold higher im MM3. RNAse protection assays showed similar levels of IGF-I mRNA in M3 and MM3 tumors and revealed a 4-fold increase in IGF-II transcripts in MM3 tumors compared with M3. Authentic IGF-I and II messages were also found in primary cultures of M3 and MM3 cells. IGF-I mRNA levels were similar in both cultures and, as described for solid tumors a 5-fold increase in IGF-II message was detected in MM3 cells. The presence of type I and mannose-6-phosphate (Man-6P)/type II IGF-R was demonstrated in both M3 and MM3 tumors. A 2-fold increase of type I IGF-R was detected in MM3 tumors compared with M3. Man-6P/type II IGF-R levels were 2-fold lower in MM3 tumors than in M3. As observed in tumor membranes, type I IGF-R concentrations were higher and Man-6P/type II IGF-R lower in cultures of MM3 epithelial cells compared with MM3 cells. In addition, we found that IGF-I enhanced secreted uPA activity in both M3 and MM3 cells while IGF-II only stimulated uPA secretion in MM3 cells.
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PMID:Varying patterns of expression of insulin-like growth factors I and II and their receptors in murine mammary adenocarcinomas of different metastasizing ability. 863 97

The B10/B10.A congenic mouse pair serves as a model for identifying specific genes related to morphogenesis and dysmorphogenesis of the embryonic palate and other organs. The present report describes our initial investigation of the Fraser-Juriloff paradigm, which proposes that susceptibility to malformation results from genetically determined differences in normal developmental patterns. Specifically, we evaluated the relationship between Igf2r gene expression, transforming growth factor-beta (TGF-beta) activation, and cdk4 gene expression. By using in situ hybridization, RNase protection assays, indirect immunofluorescence, Western blots, and bioassays, we show 1) the presence of insulin-like growth factor II (IGF-II), IGF-II receptor (IGF-IIR), IGF-IR, TGF-beta, plasminogen, plasminogen activators [urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA)], and Cdk4 in developing palates; 2) on embryonic day 14 (E14), which is a critical day for palatal growth, B10.A embryos have 82% greater IGF-IIR mRNA than B10; 3) on E14, B10.A embryonic palates have a 57% greater level of active TGF-beta2 than B10, although the total TGF-beta2 is nearly identical; and 4) on E14, B10 embryonic palates have a 52% greater level of Cdk4 mRNA than B10.A palates, a measure of cell cycle progression. Because cellular activation of latent TGF-beta appears to require binding to the mannose-6-phosphate (M6P) binding site of the IGF-IIR and is plasmin and plasminogen activator dependent, the positive correlation of IGF-IIR levels and active TGF-beta2 levels seems to be key. Thus, the strain variation of TGF-beta2/IGF-IIR-mediated growth inhibition in late G1 phase would appear to account for the slower growth and development of B10.A palates relative to B10. Elevated corticosteroid (CORT) exposure in E14 B10.A embryos significantly increases TGF-beta levels, 87% of which is TGF-beta2, as well as the levels of active TGF-beta, 64% of which is TGF-beta2. Without exogenous CORT, B10.A embryos do not have clefts; hence, we present an outline of pathogenesis: slower growing B10.A embryos have an up-regulation of IGF-IIR, which serves to sequester IGF-II from the growth-promoting IGF-IR and to bind more CORT-up-regulated, latent TGF-beta2 for subsequent plasmin-dependent activation; higher levels of TGF-beta2 signaling down-regulate Cdk4 and result in greater palatal growth inhibition at a critical stage of palatogenesis and, thus, cleft palate. We present an epigenetic model of information processing related to cell proliferation. The model is a dynamical network that uses continuous logic to learn its rules from changing conditions.
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PMID:Insulin-like growth factor II receptor, transforming growth factor-beta, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis. 943 20

Transforming growth factor-beta1 (TGF-beta1) is a critical cytokine for cell proliferation and differentiation. It is secreted by many cells in a latent pro-form (LTGF-beta1) from which biologically active TGF-beta1 is released by an in vivo mechanism that is not known. Here we show that the mannose-6-phosphate/insulin-like growth factor II-receptor (M6P/IGFII-R), which binds LTGF-beta1, complexes with urokinase (plasminogen activator)-receptor (uPA-R) on the surface of human monocytes and directly binds plasminogen (Plg). Plasmin generated from Plg in the complex mediates release of TGF-beta1 when M6P/IGFII-R is associated with uPA-R. Thus, this interaction of M6P/IGFII-R and uPA-R suggests a potential mechanism for the generation of TGF-beta1 by cells.
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PMID:M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1. 1009 5

Endothelial-to-mesenchymal transition (EndoMT) is a process through which certain subsets of endothelial cells lose endothelial characteristics and transform into mesenchymal or smooth muscle-like cells. Emerging evidence suggests that this process plays an important role during vascular development and in many vascular pathologies. As in epithelial-mesenchymal transition, EndoMT seems to progress through a series of important steps whose interdependence and order are not clear, and that some of them are regulated by soluble growth factors. Insulin-like growth factor II (IGFII), apart from being considered important in cancer, angiogenesis, and atherosclerotic lesions, is also considered as essential to embryonic development. Here, we report that addition of IGFII promoted the EndoMT process in the presence of very low amounts of chicken serum to arrested primary embryonic aortic chicken endothelial cells attached to fibronectin (FN), gelatin, or native type I collagen. This was demonstrated by cell spreading, loss of cell-cell contacts, detachment, migration, and transformation. These cellular events also occurred when IGFII was added to medium containing vitronectin (VN). Additionally, we demonstrated that these proteins were present in the spontaneous intimal thickenings that are observed at day 11-13 of chicken embryo development. We also show that alterations in the distribution of VE-cadherin and beta-catenin occur after IGFII and serum or VN stimulation, and propose that the via VN IGFII effects may be facilitated by interaction of the mannose-6-phosphate/IGFII receptor (M6P/IGFIIR) with the urokinase-type plasminogen activator receptor (uPAR) and its ligand (uPA). Collectively, these findings provide the first evidence for a potential role of the IGFII-VN complex during the EndoMT process. From our observations and previous studies, we postulate a working hypothesis supporting a fundamental role for these molecules during EndoMT.
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PMID:Potential role for insulin-like growth factor II and vitronectin in the endothelial-mesenchymal transition process. 1683 Nov 97

Deregulated apoptosis of MCs (mesangial cells) is associated with a number of kidney diseases including end-stage diabetic nephropathy. Cell death by apoptosis is a tightly orchestrated event, whose mechanisms are not completely defined. In the present study we show that the uPA (urokinase-type plasminogen activator)/uPAR (uPA receptor) system can initiate both cell survival and pro-apoptotic signals in human MCs in response to different apoptotic stimuli. uPA abrogated MC apoptosis induced by serum withdrawal conditions and enhanced apoptosis initiated in MCs by high glucose. Effects of uPA were independent of its proteolytic activity and required uPAR for both pro- and anti-apoptotic effects. Studies on the uPAR interactome provide evidence that the opposing effects of uPA were directed via different uPAR-interacting transmembrane partners. Exposure of MCs to RGD (Arg-Gly-Asp) peptide led to abrogation of the anti-apoptotic effect of uPA, which implies involvement of integrins in this process. A pro-apoptotic effect of uPA under high-glucose conditions was mediated via association of uPAR and the cation-independent M6P (mannose-6-phosphate)/IGF2R (insulin-like growth factor 2 receptor). Both receptors were co-precipitated and co-localized in MCs. Studies on the underlying signalling indicate that the ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt and BAD (Bcl-2/Bcl-X(L)-antagonist, causing cell death) protein were involved in regulation of apoptosis by uPA in MCs. M6P/IGF2R mediated BAD perinuclear localization during apoptosis initiated by uPA and high glucose. In conclusion, we provide evidence that, in MCs, the uPA/uPAR system regulates survival/apoptosis processes in a stimulus-specific fashion via a mitochondria-dependent mechanism and that BAD protein serves as a downstream molecule.
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PMID:Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus. 1856 64