Genetic polymorphism of urokinase-type plasminogen activator is interacting with plasminogen activator inhibitor-1 to raise risk of cervical neoplasia

2012 ◽  
Vol 106 (2) ◽  
pp. 204-208 ◽  
Author(s):  
Yi-Torng Tee ◽  
Po-Hui Wang ◽  
Hsiu-Ting Tsai ◽  
Long-Yau Lin ◽  
Hung-Ting Lin ◽  
...  
Keyword(s):  
Genetic Polymorphism ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Cervical Neoplasia ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Activator Inhibitor

Increased secretion of urokinase-type plasminogen activator by human lung microvascular endothelial cells

1998 ◽  
Vol 275 (1) ◽  
pp. L47-L54 ◽  
Author(s):  
Kimiko Takahashi ◽  
Yasuhide Uwabe ◽  
Yoshio Sawasaki ◽  
Toshio Kiguchi ◽  
Hiroyuki Nakamura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Lung Fibroblasts ◽  
Microvascular Endothelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Microvascular Endothelial ◽  
Activator Inhibitor

Human lung microvascular endothelial cells (HLMECs) secreted 1.5–15 times more urokinase-type plasminogen activator (uPA) antigen than human hepatic microvascular endothelial cells, human umbilical vein endothelial cells (HUVECs), angioma endothelial cells, and lung fibroblasts. All of these cells also secreted a 100-fold greater amount of plasminogen activator inhibitor-1 than of uPA antigen, and uPA activities were not detected in the culture medium. The expression of uPA mRNA in HLMECs was higher (100-fold) compared with HUVECs, angioma endothelial cells, and lung fibroblasts. HLMECs secreted uPA antigen on both the luminal and basal sides of the cells. On the other hand, HLMECs secreted a 10- to 15-fold lower amount of tissue-type plasminogen activator than HUVECs, mostly on the luminal side. After stimulation with interleukin (IL)-1β, HLMECs secreted a six- to ninefold amount of uPA antigen. In contrast, no stimulatory effect was observed in HUVECs even under high IL-1β concentrations. The secretion of uPA and plasminogen activator inhibitor-1 from HLMECs was also enhanced by tumor necrosis factor-α and IL-2. These results suggest that HLMECs may contribute not only to the patency of lung vessels but also to the maintenance of alveolar functions through the production and secretion of uPA, especially in the presence of inflammatory cytokines.

scholarly journals Deep mutational scanning of the plasminogen activator inhibitor-1 functional landscape

2021 ◽  
Author(s):  
Zachary M Huttinger ◽  
Laura M Haynes ◽  
Andrew Yee ◽  
Colin A Kretz ◽  
David R Siemieniak ◽  
...  
Keyword(s):  
Amino Acid ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Single Amino Acid ◽  
Plasminogen Activator Inhibitor 1 ◽  
Missense Variants ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Activator Inhibitor ◽  
Pai 1

The serine protease inhibitor (SERPIN) plasminogen activator inhibitor-1 (PAI-1) is a key regulator of the fibrinolytic system, inhibiting the serine proteases tissue- and urokinase-type plasminogen activator (tPA and uPA, respectively). Missense variants may render PAI-1 non-functional through misfolding, leading to its turnover as a protease substrate, or to a more rapid transition to the latent/inactive state. Deep mutational scanning was performed to evaluate the impact of amino acid sequence variation on PAI-1 inhibition of uPA using an M13 filamentous phage display system. The effects of single amino acid substitutions on PAI-1's functional inhibition of its canonical target proteases, tPA and uPA , have been determined for only a small fraction of potential mutations. To construct a more comprehensive dataset, a mutagenized PAI-1 library, encompassing ~70% of potential single amino acid substitutions, was displayed on M13 filamentous phage. From this library, the relative effects of 27% of all possible missense variants on PAI-1 inhibition of urokinase-type plasminogen activator were determined using high-throughput DNA sequencing with 826 missense variants demonstrating conserved inhibitory activity and 1137 resulting in loss of PAI-1 function. Comparison of these deep mutational scanning results to predictions from PolyPhen-2 and SIFT demonstrate the limitations of these algorithms, consistent with similar reports for other proteins. Comparison to common human PAI-1 gene variants present in the gnomAD database is consistent with evolutionary selection against loss of PAI-1 function. These findings provide insight into structure-function relationships for PAI-1 and other members of the SERPIN superfamily.

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