Plasminogen Receptors in Human Malignancies: Effects on Prognosis and Feasibility as Targets for Drug Development

2020 ◽  
Vol 21 (7) ◽  
pp. 647-656
Author(s):  
Steven L. Gonias ◽  
Carlotta Zampieri
Keyword(s):  
Growth Factors ◽  
Drug Development ◽  
Plasminogen Activator ◽  
Human Cancer ◽  
Annexin A2 ◽  
The Cancer Genome Atlas ◽  
Tissue Type ◽  
Cell Surfaces ◽  
Ecm Proteins ◽  
Type Plasminogen Activator

The major proteases that constitute the fibrinolysis system are tightly regulated. Protease inhibitors target plasmin, the protease responsible for fibrin degradation, and the proteases that convert plasminogen into plasmin, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). A second mechanism by which fibrinolysis is regulated involves exosite interactions, which localize plasminogen and its activators to fibrin, extracellular matrix (ECM) proteins, and cell surfaces. Once plasmin is generated in association with cell surfaces, it may cleave transmembrane proteins, activate growth factors, release growth factors from ECM proteins, remodel ECM, activate metalloproteases, and trigger cell-signaling by cleaving receptors in the Proteaseactivated Receptor (PAR) family. These processes are all implicated in cancer. It is thus not surprising that a family of structurally diverse but functionally similar cell-surface proteins, called Plasminogen Receptors (PlgRs), which increase the catalytic efficiency of plasminogen activation, have received attention for their possible function in cancer and as targets for anticancer drug development. In this review, we consider four previously described PlgRs, including: α-enolase, annexin-A2, Plg-RKT, and cytokeratin-8, in human cancer. To compare the PlgRs, we mined transcriptome profiling data from The Cancer Genome Atlas (TCGA) and searched for correlations between PlgR expression and patient survival. In glioma, the expression of specific PlgRs correlates with tumor grade. In a number of malignancies, including glioblastoma and liver cancer, increased expression of α-enolase or annexin-A2 is associated with an unfavorable prognosis. Whether these correlations reflect the function of PlgRs as receptors for plasminogen or other activities is discussed.

The role of the annexin A2 heterotetramer in vascular fibrinolysis

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 4789-4797 ◽  
Author(s):  
Patricia A. Madureira ◽  
Alexi P. Surette ◽  
Kyle D. Phipps ◽  
Michael A. S. Taboski ◽  
Victoria A. Miller ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Plasminogen Activator ◽  
Vascular Endothelial Cells ◽  
Annexin A2 ◽  
Tissue Type ◽  
Plasmin Activity ◽  
Endothelial Cell Surface ◽  
Type Plasminogen Activator ◽  
And Function ◽  
Annexin A2 Heterotetramer

Abstract The vascular endothelial cells line the inner surface of blood vessels and function to maintain blood fluidity by producing the protease plasmin that removes blood clots from the vasculature, a process called fibrinolysis. Plasminogen receptors play a central role in the regulation of plasmin activity. The protein complex annexin A2 heterotetramer (AIIt) is an important plasminogen receptor at the surface of the endothelial cell. AIIt is composed of 2 molecules of annexin A2 (ANXA2) bound together by a dimer of the protein S100A10. Recent work performed by our laboratory allowed us to clarify the specific roles played by ANXA2 and S100A10 subunits within the AIIt complex, which has been the subject of debate for many years. The ANXA2 subunit of AIIt functions to stabilize and anchor S100A10 to the plasma membrane, whereas the S100A10 subunit initiates the fibrinolytic cascade by colocalizing with the urokinase type plasminogen activator and receptor complex and also providing a common binding site for both tissue-type plasminogen activator and plasminogen via its C-terminal lysine residue. The AIIt mediated colocalization of the plasminogen activators with plasminogen results in the rapid and localized generation of plasmin to the endothelial cell surface, thereby regulating fibrinolysis.

A

2020 ◽  
pp. 55-126
Author(s):  
Sean Ainsworth
Keyword(s):  
Growth Factors ◽  
Adverse Effects ◽  
Acetylsalicylic Acid ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Vascular Endothelial Growth Factors ◽  
Vascular Endothelial ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Endothelial Growth Factors

This chapter presents information on neonatal drugs that begin with A, including use, pharmacology, adverse effects, fetal and infant implications of maternal treatment, treatment, and supply of Abacavir, Acetylcysteine (N-acetylcysteine), Aciclovir = Acyclovir (USAN), Adenosine, Adrenaline = Epinephrine (rINN), Albendazole, Alginate compounds (Gaviscon®), Alimemazine (trimeprazine— former BAN and USAN), Alteplase (tissue-type plasminogen activator [rt-PA]), Amikacin, Amiodarone, Amlodipine, Amodiaquine with artesunate, Amoxicillin = Amoxycillin (former BAN), Amphotericin B, Ampicillin, Anti-vascular endothelial growth factors (for ROP), Arginine (L-arginine), Artemether with lumefantrine, Aspirin = acetylsalicylic acid (INN), Atosiban, Atracurium, Atropine, and Azithromycin

Coupling Tissue Type Plasminogen Activator to Carrier Erythrocyte Protects Against Plasma Inhibitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1881-1881
Author(s):  
Kumkum Ganguly ◽  
Douglas B. Cines ◽  
Vladimir R. Muzykantov
Keyword(s):  
Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Tissue Type ◽  
Cell Surfaces ◽  
Mouse Blood ◽  
Type Plasminogen Activator ◽  
Α2 Macroglobulin ◽  
Tissue Plasminogen ◽  
Pai 1

Abstract Conjugating tissue plasminogen activator (tPA) to carrier red blood cells (RBC) restricts its permeation into tissues and pre-existing hemostatic clots, minimizing side effects, and prolongs its circulation, which permits it to be incorporated within nascent clot which it lyses from inside. We now report that RBC/tPA dissolves clots formed from mouse blood more effectively than free tPA, while they were equipotent against clots formed in vitro from PAI-1 KO mouse blood. To test whether tPA acquires resistance to plasma inhibitors when conjugated to RBC, we compared the activity of RBC/tPA vs free tPA in the presence of purified PAI-1, α2 macroglobulin (α2M) and α1anti-trypsin (α1AT). At equimolar concentrations, PAI-1 completely inhibited the activity of soluble tPA in vitro, whereas RBC/tPA retained 100% and 75% of its amidolytic and fibrinolytic activity, respectively. RBC/tPA, but not free tPA, was also resistant to equimolar concentrations of α2M and α1AT. However, tPA coupled to RBC pre-incubated with a mixture of hyaluronidase, heparinase and neuraminidase was as susceptible to inactivation by PAI-1, α2M and α1AT as free tPA. Further, tPA coupled to glycocalyx-stripped RBC bound two-fold more 125I-labeled PAI-1 than tPA coupled to naïve RBC. We conclude that the RBC glycocalyx protects tPA from inactivation by PA inhibitors, likely by steric hindrance. This unexpected benefit may enhance the utility of RBC/tPA in thromboprophylaxis and suggests a previous under-appreciated role for the glycocalyx in modulating PA activity on the vasculature and other cell surfaces.

Structural Studies of Fibrinolysis by Electron and Light Microscopy

1999 ◽  
Vol 82 (08) ◽  
pp. 277-282 ◽  
Author(s):  
Yuri Veklich ◽  
Jean-Philippe Collet ◽  
Charles Francis ◽  
John W. Weisel
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Plasminogen Activator ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Degradation Products ◽  
Molecular Model ◽  
Three Dimensional ◽  
Tissue Type ◽  
Type Plasminogen Activator

IntroductionMuch is known about the fibrinolytic system that converts fibrin-bound plasminogen to the active protease, plasmin, using plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then cleaves fibrin at specific sites and generates soluble fragments, many of which have been characterized, providing the basis for a molecular model of the polypeptide chain degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments has provided a wealth of information that may be useful in understanding how various proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6 Both the rate of fibrinolysis and the structures of soluble derivatives are determined in part by the fibrin network structure itself. Furthermore, the activation of plasminogen by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction is also affected by the structure of the fibrin. For example, clots made of thin fibers have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding of mechanisms of fibrinolysis (Matsuda, this volume).14,15 To account for these diverse observations and more fully understand the molecular basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix that precede solubilization is required. In this report, we summarize recent experiments utilizing transmission and scanning electron microscopy and confocal light microscopy to provide information about the structural changes occurring in polymerized fibrin during fibrinolysis. Many of the results of these experiments were unexpected and suggest some aspects of potential molecular mechanisms of fibrinolysis, which will also be described here.

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