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David J. Loskutoff - One of the best experts on this subject based on the ideXlab platform.

  • the low density lipoprotein receptor related protein is a motogenic receptor for Plasminogen Activator inhibitor 1
    Journal of Biological Chemistry, 2004
    Co-Authors: Bernard Degryse, Ralf-peter Czekay, Yuichi Kamikubo, Jaap G Neels, Kathleen Aertgeerts, David J. Loskutoff
    Abstract:

    Although Plasminogen Activator Inhibitor-1 (PAI-1) is known to stimulate cell migration, little is known about underlying mechanisms. We show that both active and inactive (e.g. cleaved) PAI-1 can activate the Jak/Stat signaling system and stimulate cell migration in chemotaxis, haptotaxis, chemokinesis, and wound healing assays. Moreover, antibodies to the LDL receptor-related protein (LRP) and an LRP antagonist (RAP) blocked these motogenic effects of PAI-1, while a PAI-1 mutant that did not bind to LRP failed to activate the Jak/Stat signaling pathway or to stimulate cell migration. PAI-1 had no chemotactic effect on LRP-deficient cells. These results indicate that LRP is a signaling molecule, that it mediates the migration-promoting activity of PAI-1, and that this activity does not require intact, biologically active PAI-1. Activation of this LRP-dependent signaling pathway by PAI-1 may begin to explain how the inhibitor stimulates cell migration in a variety of normal and pathological processes.

  • Plasminogen Activator inhibitor 1 regulates cell adhesion by binding to the somatomedin b domain of vitronectin
    Journal of Cellular Physiology, 2001
    Co-Authors: Gary Deng, Scott A Curriden, Geng Hu, Ralf-peter Czekay, David J. Loskutoff
    Abstract:

    Plasminogen Activator Inhibitor-1 (PAI-1) binds to the somatomedin B (SMB) domain of vitronectin. It inhibits the adhesion of U937 cells to vitronectin by competing with the urokinase receptor (uPAR; CD87) on these cells for binding to the same domain. Although the inhibitor also blocks integrin-mediated cell adhesion, the molecular basis of this effect is unclear. In this study, the effect of the inhibitor on the adhesion of a variety of cells (e.g., U937, MCF7, HT-1080, and HeLa) to vitronectin was assessed, and the importance of the SMB domain in these interactions was determined. Although PAI-1 blocked the adhesion of all of these cells to vitronectin-coated wells, it did not block adhesion to a variant of vitronectin which lacked the SMB domain. Interestingly, HT-1080 and U937 cells attached avidly to microtiter wells coated with purified recombinant SMB (which does not contain the RGD sequence), and this adhesion was again blocked by the inhibitor. These results affirm that PAI-1 can inhibit both uPAR- and integrin-mediated cell adhesion, and demonstrate that the SMB domain of vitronectin is required for these effects. They also show that multiple cell types can employ uPAR as an adhesion receptor. The use of purified recombinant SMB should help to further define this novel adhesive pathway, and to delineate its relationship with integrin-mediated adhesive events. © 2001 Wiley-Liss, Inc.

  • Plasminogen Activator inhibitor 1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice
    Circulation, 2001
    Co-Authors: Stavros Konstantinides, Katrin Schafer, T Thinnes, David J. Loskutoff
    Abstract:

    Background—The origin and contribution of Plasminogen Activator Inhibitor-1 (PAI-1) and its cofactor vitronectin (VN) to arterial thrombosis/thrombolysis in vivo is controversial. Methods and Resul...

Bernard Degryse - One of the best experts on this subject based on the ideXlab platform.

  • vitronectin inhibits Plasminogen Activator inhibitor 1 induced signalling and chemotaxis by blocking Plasminogen Activator inhibitor 1 binding to the low density lipoprotein receptor related protein
    The International Journal of Biochemistry & Cell Biology, 2009
    Co-Authors: Yuichi Kamikubo, Jaap G Neels, Bernard Degryse
    Abstract:

    We have previously reported that the serpin Plasminogen Activator Inhibitor-1 activates the Janus kinase (Jak)/signal transducer and Activator of transcription (Stat) signalling pathway and stimulates cell migration by binding to the low-density lipoprotein receptor-related protein. All the free forms (cleaved, latent or active) of this inhibitor were shown to be motogenic. However, the Plasminogen Activator Inhibitor-1 can also interact with vitronectin which acts as a cofactor by increasing the half-life of the active form of the serpin. Since vitronectin influences most of the biological functions of the Plasminogen Activator Inhibitor-1, we explored the effects of vitronectin on signalling and cell migration induced by this serpin. We found that the interaction between vitronectin and the Plasminogen Activator Inhibitor-1 suppressed signalling and cell migration. In fact, a purified vitronectin(1-97)/Plasminogen Activator Inhibitor-1 complex was not chemotactic. Vitronectin interaction with the Plasminogen Activator Inhibitor-1 blocks the binding of this serpin to its motogenic receptor, the low-density lipoprotein receptor-related protein. Consequently, vitronectin inhibits the activation of the Janus kinase/signal transducer and Activator of transcription signalling pathway by the Plasminogen Activator Inhibitor-1 and subsequent cell migration. In conclusion, we have unveiled a new inhibitory role of vitronectin, which turns off the intracellular signalling and migration-promoting activity of the Plasminogen Activator Inhibitor-1. Thus, the motogenic (cleaved, latent or active) and non-motogenic (in complex with vitronectin) forms of the Plasminogen Activator Inhibitor-1 have different properties that may explain the rather contrasting physiological and pathological roles of this serpin.

  • the low density lipoprotein receptor related protein is a motogenic receptor for Plasminogen Activator inhibitor 1
    Journal of Biological Chemistry, 2004
    Co-Authors: Bernard Degryse, Ralf-peter Czekay, Yuichi Kamikubo, Jaap G Neels, Kathleen Aertgeerts, David J. Loskutoff
    Abstract:

    Although Plasminogen Activator Inhibitor-1 (PAI-1) is known to stimulate cell migration, little is known about underlying mechanisms. We show that both active and inactive (e.g. cleaved) PAI-1 can activate the Jak/Stat signaling system and stimulate cell migration in chemotaxis, haptotaxis, chemokinesis, and wound healing assays. Moreover, antibodies to the LDL receptor-related protein (LRP) and an LRP antagonist (RAP) blocked these motogenic effects of PAI-1, while a PAI-1 mutant that did not bind to LRP failed to activate the Jak/Stat signaling pathway or to stimulate cell migration. PAI-1 had no chemotactic effect on LRP-deficient cells. These results indicate that LRP is a signaling molecule, that it mediates the migration-promoting activity of PAI-1, and that this activity does not require intact, biologically active PAI-1. Activation of this LRP-dependent signaling pathway by PAI-1 may begin to explain how the inhibitor stimulates cell migration in a variety of normal and pathological processes.

Yuichi Kamikubo - One of the best experts on this subject based on the ideXlab platform.

  • vitronectin inhibits Plasminogen Activator inhibitor 1 induced signalling and chemotaxis by blocking Plasminogen Activator inhibitor 1 binding to the low density lipoprotein receptor related protein
    The International Journal of Biochemistry & Cell Biology, 2009
    Co-Authors: Yuichi Kamikubo, Jaap G Neels, Bernard Degryse
    Abstract:

    We have previously reported that the serpin Plasminogen Activator Inhibitor-1 activates the Janus kinase (Jak)/signal transducer and Activator of transcription (Stat) signalling pathway and stimulates cell migration by binding to the low-density lipoprotein receptor-related protein. All the free forms (cleaved, latent or active) of this inhibitor were shown to be motogenic. However, the Plasminogen Activator Inhibitor-1 can also interact with vitronectin which acts as a cofactor by increasing the half-life of the active form of the serpin. Since vitronectin influences most of the biological functions of the Plasminogen Activator Inhibitor-1, we explored the effects of vitronectin on signalling and cell migration induced by this serpin. We found that the interaction between vitronectin and the Plasminogen Activator Inhibitor-1 suppressed signalling and cell migration. In fact, a purified vitronectin(1-97)/Plasminogen Activator Inhibitor-1 complex was not chemotactic. Vitronectin interaction with the Plasminogen Activator Inhibitor-1 blocks the binding of this serpin to its motogenic receptor, the low-density lipoprotein receptor-related protein. Consequently, vitronectin inhibits the activation of the Janus kinase/signal transducer and Activator of transcription signalling pathway by the Plasminogen Activator Inhibitor-1 and subsequent cell migration. In conclusion, we have unveiled a new inhibitory role of vitronectin, which turns off the intracellular signalling and migration-promoting activity of the Plasminogen Activator Inhibitor-1. Thus, the motogenic (cleaved, latent or active) and non-motogenic (in complex with vitronectin) forms of the Plasminogen Activator Inhibitor-1 have different properties that may explain the rather contrasting physiological and pathological roles of this serpin.

  • the low density lipoprotein receptor related protein is a motogenic receptor for Plasminogen Activator inhibitor 1
    Journal of Biological Chemistry, 2004
    Co-Authors: Bernard Degryse, Ralf-peter Czekay, Yuichi Kamikubo, Jaap G Neels, Kathleen Aertgeerts, David J. Loskutoff
    Abstract:

    Although Plasminogen Activator Inhibitor-1 (PAI-1) is known to stimulate cell migration, little is known about underlying mechanisms. We show that both active and inactive (e.g. cleaved) PAI-1 can activate the Jak/Stat signaling system and stimulate cell migration in chemotaxis, haptotaxis, chemokinesis, and wound healing assays. Moreover, antibodies to the LDL receptor-related protein (LRP) and an LRP antagonist (RAP) blocked these motogenic effects of PAI-1, while a PAI-1 mutant that did not bind to LRP failed to activate the Jak/Stat signaling pathway or to stimulate cell migration. PAI-1 had no chemotactic effect on LRP-deficient cells. These results indicate that LRP is a signaling molecule, that it mediates the migration-promoting activity of PAI-1, and that this activity does not require intact, biologically active PAI-1. Activation of this LRP-dependent signaling pathway by PAI-1 may begin to explain how the inhibitor stimulates cell migration in a variety of normal and pathological processes.

Daniel B Rifkin - One of the best experts on this subject based on the ideXlab platform.

  • an assay for transforming growth factor β using cells transfected with a Plasminogen Activator inhibitor 1 promoter luciferase construct
    Analytical Biochemistry, 1994
    Co-Authors: Mayumi Abe, John G Harpel, C N Metz, Irene Nunes, D J Loskutoff, Daniel B Rifkin
    Abstract:

    Transforming growth factor-beta (TGF-beta) is a potent regulator of cellular differentiation, proliferation, migration, and protein expression. These properties have been exploited to create a variety of bioassays for detecting the mature growth factor. In this paper, we describe a highly sensitive and specific, nonradioactive quantitative bioassay for TGF-beta based on its ability to induce Plasminogen Activator Inhibitor-1 (PAI-1) expression. Mink lung epithelial cells (MLEC) were stably transfected with an expression construct containing a truncated PAI-1 promoter fused to the firefly luciferase reporter gene. Addition of TGF-beta (0.2 to > 30 pM) to the transfectants resulted in a dose-dependent increase in luciferase activity in the cell lysates. Although responsive to TGF-beta, this promoter fragment was only minimally influenced by other known inducers of PAI-1 expression. When compared to the widely used MLEC assay, this assay demonstrated greater sensitivity and specificity, allowing quantification of TGF-beta in complex biological solutions.

  • an assay for transforming growth factor β using cells transfected with a Plasminogen Activator inhibitor 1 promoter luciferase construct
    Analytical Biochemistry, 1994
    Co-Authors: John G Harpel, C N Metz, Irene Nunes, D J Loskutoff, Daniel B Rifkin
    Abstract:

    Abstract Transforming growth factor-β (TGF-β) is a potent regulator of cellular differentiation, proliferation, migration, and protein expression. These properties have been exploited to create a variety of bioassays for detecting the mature growth factor. In this paper, we describe a highly sensitive and specific, nonradioactive quantitative bioassay for TGF-β based on its ability to induce Plasminogen Activator Inhibitor-1 (PAI-1) expression. Mink lung epithelial cells (MLEC) were stably transfected with an expression construct containing a truncated PAI-1 promoter fused to the firefly luciferase reporter gene. Addition of TGF-β (0.2 to >30 pM) to the transfectants resulted in a dose-dependent increase in luciferase activity in the cell lysates. Although responsive to TGF-β, this promoter fragment was only minimally influenced by other known inducers of PAI-1 expression. When compared to the widely used MLEC assay, this assay demonstrated greater sensitivity and specificity, allowing quantification of TGF-β in complex biological solutions.

Jesús Avila - One of the best experts on this subject based on the ideXlab platform.

  • expression of Plasminogen Activator inhibitor 1 by olfactory ensheathing glia promotes axonal regeneration
    Glia, 2011
    Co-Authors: Diana Simon, Filip Lim, Erika Pastrana, Javier Diaznido, Maria Jesus Martinbermejo, Maria Teresa Gallegohernandez, Vega Garciaescudero, Ana Garciagomez, Jesús Avila
    Abstract:

    Olfactory ensheathing glia (OEG) cells are known to facilitate repair following axotomy of adult neurons, although the molecular mechanisms involved are not fully understood. We previously identified Plasminogen Activator Inhibitor-1 (PAI-1), proteinase-activated receptor-1 (PAR-1), and thrombomodulin (TM) as candidates to regulate rat OEG-dependent axonal regeneration. In this study, we have validated the involvement of these proteins in promoting axonal regeneration by immortalized human OEGs. We studied the effect of silencing these proteins in OEGs on their capacity to promote the regeneration of severed adult retinal ganglion cells (RGCs) axons. Our results support the role of glial PAI-1 as a downstream effector of PAR-1 in promoting axon regeneration. In contrast, we found that TM inhibits OEG induced-axonal regeneration. We also assessed the signaling pathways downstream of PAR-1 that might modulate PAI-1 expression, observing that specifically inhibiting Gα(i), Rho kinase, or PLC and PKC downregulated the expression of PAI-1 in OEGs, with a concomitant reduction in OEG-dependent axon regeneration in adult RGCs. Our findings support an important role for the thrombin system in regulating adult axonal regeneration by OEGs.