View source for Plasminogen activator

{{Short description|Type of protein}}
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[[Image:Fibrinolysis.svg|thumb|400px|[[Fibrinolysis]]]]'''Plasminogen activators''' are [[serine protease]]s that catalyze the activation of [[plasmin]] via proteolytic cleavage of its [[zymogen]] form [[plasminogen]]. Plasmin is an important factor in [[fibrinolysis]], the breakdown of [[fibrin]] polymers formed during blood clotting. There are two main plasminogen activators: [[Urokinase|urokinase (uPA)]] and [[Tissue plasminogen activator|tissue plasminogen activator (tPA).]] Tissue plasminogen activators are used to treat medical conditions related to blood clotting including embolic or thrombotic stroke, myocardial infarction, and pulmonary embolism.<ref name=":0" />

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 surfaces cause their conformation to change, allowing them 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.<ref>{{cite journal | vauthors = Law RH, Caradoc-Davies T, Cowieson N, Horvath AJ, Quek AJ, Encarnacao JA, Steer D, Cowan A, Zhang Q, Lu BG, Pike RN, Smith AI, Coughlin PB, Whisstock JC | title = The X-ray crystal structure of full-length human plasminogen | journal = Cell Reports | volume = 1 | issue = 3 | pages = 185–90 | date = March 2012 | pmid = 22832192 | doi = 10.1016/j.celrep.2012.02.012 | doi-access = free }}</ref>
[[File:T-PA.gif|thumb|3-dimensional structure of tPA]]
[[File:Protein PLAU PDB 1c5w.png|thumb|3-dimensional structure of uPA]]

== Inhibition ==
The main inhibitor of tissue plasminogen activator and urokinase is plasminogen activator inhibitor-1 (PAI-1).<ref>{{cite journal | vauthors = Declerck PJ, Gils A | title = Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin | journal = Seminars in Thrombosis and Hemostasis | volume = 39 | issue = 4 | pages = 356–64 | date = June 2013 | pmid = 23504606 | doi = 10.1055/s-0033-1334487 | s2cid = 5190211 }}</ref> Plasminogen activator inhibitor-1 is a serine protease, synthesized by endothelial cells, that specifically inhibits [[tissue plasminogen activator]] (tPA) and [[urokinase]] (uPA). Tissue plasminogen activator and urokinase are the activators of [[plasmin]]ogen and result in the breakdown of blood clots ([[fibrinolysis]]).<ref>{{cite journal | vauthors = Mimuro J | title = [Type 1 plasminogen activator inhibitor: its role in biological reactions] | journal = [Rinsho Ketsueki] the Japanese Journal of Clinical Hematology | volume = 32 | issue = 5 | pages = 487–9 | date = May 1991 | pmid = 1870265 }}</ref>

PAI-1 levels have also been studied in patients and how they influence certain diseases. Elevated serum levels of PAI-1 have been found in obese individuals.<ref name=":1">{{cite journal | vauthors = Carter JC, Church FC | title = Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1 | journal = PPAR Research | volume = 2009 | pages = 345320 | date = 2009-01-01 | pmid = 19672469 | pmc = 2723729 | doi = 10.1155/2009/345320 | doi-access = free }}</ref>  Elevated levels of PAI-1 also seem to increase the risk of atherothrombotic events and may also promote vascular disease.<ref>{{cite journal | vauthors = Vaughan DE | title = PAI-1 and atherothrombosis | journal = Journal of Thrombosis and Haemostasis | volume = 3 | issue = 8 | pages = 1879–83 | date = August 2005 | pmid = 16102055 | doi = 10.1111/j.1538-7836.2005.01420.x | s2cid = 6651339 | doi-access = free }}</ref>

Plasminogen activator inhibitor-2 (PAI-2) is 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.<ref>{{cite journal | vauthors = Mikus P, Urano T, Liljeström P, Ny T | title = Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms | journal = European Journal of Biochemistry | volume = 218 | issue = 3 | pages = 1071–82 | date = December 1993 | pmid = 7506655 | doi=10.1111/j.1432-1033.1993.tb18467.x}}</ref>

== 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.<ref>{{cite journal | vauthors = Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN | title = Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa | journal = The Journal of Biological Chemistry | volume = 283 | issue = 27 | pages = 18655–64 | date = July 2008 | pmid = 18441012 | pmc = 2441546 | doi = 10.1074/jbc.M802275200 | doi-access = free }}</ref> Deficiency in factor XI is known to cause [[hemophilia C]].<ref>{{cite journal | vauthors = Bolton-Maggs PH | title = Factor XI deficiency | journal = Baillière's Clinical Haematology | volume = 9 | issue = 2 | pages = 355–68 | date = June 1996 | pmid = 8800510 | doi=10.1016/s0950-3536(96)80068-0}}</ref>  Factor XIIa is another plasma protein that is involved in the activation of zymogen factor is activated into factor XIa.<ref>{{cite journal | vauthors = Walsh PN | title = Roles of platelets and factor XI in the initiation of blood coagulation by thrombin | journal = Thrombosis and Haemostasis | volume = 86 | issue = 1 | pages = 75–82 | date = July 2001 | doi = 10.1055/s-0037-1616203 | pmid = 11487044 | s2cid = 32572142 }}</ref> 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 [[Thrombotic stroke|thrombotic]] or [[embolic stroke]], [[myocardial infarction]], and [[pulmonary embolism]]. It is manufactured using recombinant techniques and is sold as alteplase, reteplase, and tenecteplase.  Alteplase was the first of these versions to go on the market, and has the same structure as tPA.  Reteplase and tenecteplase both received FDA approval after alteplase, and have nonidentical structures to tPA.<ref name=":0">{{cite web | url = http://emedicine.medscape.com/article/811234-overview#a2|title=Thrombolytic Therapy|last=Rivera-Bou|first=Wanda L |date=15 December 2016|website=MedScape | access-date = 28 February 2017}}</ref> These recombinant forms of tPA have been shown to have a longer half-life in the blood and greater resistance to inhibition, resulting in  an increased capacity to treat thrombolytic diseases.<ref>{{cite journal | vauthors = Gurman P, Miranda OR, Nathan A, Washington C, Rosen Y, Elman NM | title = Recombinant tissue plasminogen activators (rtPA): a review | journal = Clinical Pharmacology and Therapeutics | volume = 97 | issue = 3 | pages = 274–85 | date = March 2015 | pmid = 25670034 | doi = 10.1002/cpt.33 | s2cid = 19937661 }}</ref>

Urokinase is similarly used in the medical field, specifically for the treatment of pulmonary embolism.<ref>{{cite web | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7966 | title = LABEL: KINLYTIC- urokinase injection, powder, lyophilized, for solution |date=8 June 2007|website=DailyMed: US National Library of Medicine }}</ref>

== Plasminogen Activator Role in Breast Cancer ==
{{#invoke:Infobox_gene|getTemplateData|QID=Q18030589}}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 are 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.<ref name=":1" />

== References ==
{{Reflist|33em}}

== External links ==
* {{PDBe-KB2|P00747|Plasminogen}}
{{Antithrombotics}}
{{DEFAULTSORT:Plasminogen Activator}}
[[Category:Hematology]]