Competition between plasminogen and tissue plasminogen activator for cellular binding sites

Félez, Jordi; Chanquía, C.J.; Fàbregas, Pere; Plow, Edward F.; Miles, Lindsey A.

doi:10.1182/blood.v82.8.2433.2433

Cited by 71 publications

(32 citation statements)

References 56 publications

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“…Vascular endothelial cells can assemble plasmino gen and tissue-type plasminogen activator (t-PA) on their surfaces, mediated by their cellular receptors, which is of great importance in the regulation of the cellular fibri nolytic system. Several candidate molecules for plas minogen receptors (Plg-Rs) and t-PA receptors (t-PARs), such as a-enolase, 9,10,11 cytokeratin 8, 12 actin, 13 gangliosides, 14 annexin II (Ann-II), 15 or other molecule 16 have been demonstrated on several cell types, some of which can bind both plasminogen and t-PA with the common 17 or two different regions 15 in the molecules. However, lit tle is known about the effects of these receptors on the plasminogen activation system except that Ann-II en hances significantly plasminogen activation by t-PA. 18 We have isolated a novel endothelial t-PAR with a molecular weight (MW) of 20 kDa from human en dothelial cells 19 which is neither the Ann-II nor plas minogen binding proteins reported so far.…”

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confidence: 99%

Analysis of Tissue-Type Plasminogen Activator Receptor (t-PAR) in Human Endothelial Cells

Fukao

Matsuo²

1998

Semin Thromb Hemost

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Vascular endothelial cells regulate the fibrinolytic system in blood by expressing cell-surface receptors for plasminogen and plasminogen activators (PAs) as well as secreting PAs and their inhibitors. Although several receptors for plasminogen and PAs have been identified in many cell types, little is known about tissue-type PA (t-PA)-specific receptor (t-PAR) on endothelial cells except a few reports. By using suspended human umbilical vein endothelial cells (HUVEC), which are free from the formation of extracellular matrix (ECM)--where type-1 plasminogen activator inhibitor (PAI-1) preferably accumulates and interacts with t-PA with high affinity--we demonstrated a relatively low affinity binding site for t-PA on the cells and identified a novel t-PAR. The isolation and characterization of HUVEC-derived t-PAR was performed in the present study. A 20-kDa t-PAR was successively isolated and purified by high performance liquid chromatography system from HUVEC which specifically binds t-PA and not plasminogen forming a 90-kDa complex with t-PA. When t-PA binds the immobilized t-PAR stoichiometrically 1:1, the enzymatic activity of t-PA was enhanced 90-fold. Thus, it is suggested that the t-PAR may function as a t-PA-enhancing molecule expressed on the surface of endothelial cells.

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confidence: 99%

Analysis of Tissue-Type Plasminogen Activator Receptor (t-PAR) in Human Endothelial Cells

Fukao

Matsuo²

1998

Semin Thromb Hemost

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“…It is noteworthy that plasminogen and tPA share binding sites on the cell surface, based on cross-competition studies. 123 Both Plg-R KT and S100A10 have been demonstrated to directly bind tPA. 79,[124][125][126] Despite potentially sharing binding sites on Plg-R KT and S10010, the relative concentrations of tPA and plasminogen in the circulation should permit simultaneous binding of both ligands to the cell surface, and each tPA molecule should be bound proximally to several plasminogen molecules.…”

Section: Role Of Colocalization Of Plasminogen and Plasminogen Activamentioning

confidence: 99%

“…79,[124][125][126] Despite potentially sharing binding sites on Plg-R KT and S10010, the relative concentrations of tPA and plasminogen in the circulation should permit simultaneous binding of both ligands to the cell surface, and each tPA molecule should be bound proximally to several plasminogen molecules. 123…”

Section: Role Of Colocalization Of Plasminogen and Plasminogen Activamentioning

confidence: 99%

Plasminogen Receptors: The First Quarter Century

Miles

Parmer

2013

Semin Thromb Hemost

104

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The interaction of plasminogen with cell surfaces results in promotion of plasmin formation and retention on the cell surface. This results in arming cell surfaces with the broad spectrum proteolytic activity of plasmin. Over the past quarter century, key functional consequences of the association of plasmin with the cell surface have been elucidated. Physiologic and pathophysiologic processes with plasmin-dependent cell migration as a central feature include inflammation, wound healing, oncogenesis, metastasis, myogenesis, and muscle regeneration. Cell surface plasmin also participates in neurite outgrowth, and prohormone processing. Furthermore, plasmin-induced cell signaling also affects the functions of inflammatory cells, via production of cytokines, reactive oxygen species, and other mediators. Finally, plasminogen receptors regulate fibrinolysis. In this review we highlight emerging data that shed light on long-standing controversies and raise new issues in the field. We focus on 1) the impact of the recent X-ray crystal structures of plasminogen and the development of antibodies that recognize cell-induced conformational changes in plasminogen, on our understanding of the interaction of plasminogen with cells; 2) the relationship between apoptosis and plasminogen binding to cells; 3) the current status of our understanding of the molecular identitity of plasminogen receptors and the discovery of a structurally unique novel plasminogen receptor, Plg-RKT; 4) the determinants of the interplay between distinct plasminogen receptors and cellular functions; and 5) new insights into the role of co-localization of plasminogen and plasminogen activator receptors on the cell surface.

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“…Receptors for tPA have also been identified and appear to fall into the category of medium to low affinity (39,(46)(47)(48)(49)(50). Previously high affinity binding was studied, but later work has suggested this was extracellular matrixassociated PAI-1 (51).…”

Section: Tpa Receptorsmentioning

confidence: 99%

Plasminogen activation on the cell surface

Longstaff¹

2002

Front Biosci

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The plasminogen activation system appears to be widely involved in many biological processes in health and disease, but the regulation of plasmin generation or the mechanisms of stimulation by cell surface receptors are not well understood. Cell surface plasminogen activation requires binding sites for plasminogen substrate and activator enzyme before enhancement of plasmin generation rate is observed. The cell surface moieties involved in binding these reactants appear to be a mixed group of proteins and other molecules, many of which have been extensively investigated. The binding of plasminogen in particular is characterized by heterogeneous receptor molecules, present in high number but generally with low affinity for plasminogen. The low affinity of the interaction, with Kd values around 10(-6) M, presents considerable technical difficulties when studying and quantitating plasminogen binding to cells or isolated receptors. Studying plasminogen activation kinetics in the presence of cells also presents technical difficulties and raises difficult questions on interpretation of results. However, approaches developed to study enzyme activation systems in other areas of hemostasis may also be applied to the problems associated with pericellular proteolysis. Models should be developed that match In vitro experimental data and help us understand the meaning of kinetic constants derived from these systems. In this way it should be possible to better understand the regulation of plasminogen activation around the cell under normal conditions and in a variety of disease states where cell-associated plasminogen activation is believed to be up-regulated. Ultimately, a sound understanding of theses regulatory mechanisms will enable us to devise strategies for modulating proteolytic activity, test these approaches in well designed In vitro systems and relate these results to the in vivo situation.

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Competition between plasminogen and tissue plasminogen activator for cellular binding sites

Cited by 71 publications

References 56 publications

Analysis of Tissue-Type Plasminogen Activator Receptor (t-PAR) in Human Endothelial Cells

Analysis of Tissue-Type Plasminogen Activator Receptor (t-PAR) in Human Endothelial Cells

Plasminogen Receptors: The First Quarter Century

Plasminogen activation on the cell surface

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