Plasminogen activator
Plasminogen activators are inhibited by plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, and protein C inhibitor.
Function
Produced mainly in the liver, plasminogen is the inactive zymogen form of plasmin, and circulates in plasma in a closed conformation that cannot be activated. Binding clots or cell surface causes its conformation to change, allowing it to be activated by plasminogen activators. Plasminogen activators do so by cleaving the R561/V562 peptide bond, producing the active protein plasmin, which catalyzes the degradation of fibrin polymers that make up the structure of blood clots.[2]
Inhibition
The main inhibitor of tissue plasminogen activator and urokinase is plasminogen activator inhibitor-1 (PAI-1).
PAI-1 levels has also been studied in patients and how they influence certain diseases. Elevated serum levels of PAI-1 have been found in obese individuals.[5] Elevated levels of PAI-1 also seem to increase the risk of atherothrombotic events and may also promote vascular disease.[6]
Plasminogen activator inhibitor-2 (PAI-2) is also a serine protease that inactivates tPA and uPA. PAI-2 is produced by the placenta and only found in high quantities in the blood during pregnancy.[7]
Factors
Factor XIa and XIIa are two main factors involved in the plasminogen activator. Factor XI (FXI) is a serine protase produced by the liver and circulates in its inactive form. This activation is important to the coagulation cascade.
Applications
Due to its contribution to fibrinolysis, tissue plasminogen activator is used medically to treat blood clot-related disorders including
Urokinase is similarly used in the medical field, specifically for the treatment of pulmonary embolism.[12]
Plasminogen Activator Role in Breast Cancer
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| Location (UCSC) | Chr 6: 160.7 – 160.75 Mb | Chr 17: 12.6 – 12.64 Mb | |||||||
| PubMed search | [15] | [16] | |||||||
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Plasminogen activator inhibitor-1 not only functions as an inhibitor, but other roles of PAI-1 could suggest it could contribute to cancer. The other roles of PAI-1 include, cell de-adhesion, cell proliferation, apoptosis, and cell signaling. These roles could suggest that PAI-1 expression in the tumor microenvironment enhances tumor cell progression. Urokinase cleaves the zymogen plasminogen into serine protease plasmin. The elevated levels of uPA is an indicator of cancer which could be found in the carcinoma of the breast. Plasmin can activate matrix metalloproteases (MMP's) in the extracellular matrix (ECM). MMP activation contributes to tumor cell invasion and metastasis by degradation of ECM components.[5]
References
- ^ a b Rivera-Bou WL (15 December 2016). "Thrombolytic Therapy". MedScape. Retrieved 28 February 2017.
- PMID 22832192.
- S2CID 5190211.
- PMID 1870265.
- ^ PMID 19672469.
- S2CID 6651339.
- PMID 7506655.
- PMID 18441012.
- PMID 8800510.
- S2CID 32572142.
- S2CID 19937661.
- ^ "LABEL: KINLYTIC- urokinase injection, powder, lyophilized, for solution". DailyMed: US National Library of Medicine. 8 June 2007.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000122194 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000059481 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.