Plasminogen activator

Plasminogen activators are serine proteases 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 (uPA) and 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.[1]

Fibrinolysis

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]

3-dimensional structure of tPA

3-dimensional structure of uPA

Inhibition

The main inhibitor of tissue plasminogen activator and urokinase is plasminogen activator inhibitor-1 (PAI-1).[3] 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 plasminogen and results in the breakdown of blood clots (fibrinolysis).[4]

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.[8] Deficiency in factor XI is known to cause hemophilia C.[9] Factor XIIa is another plasma protein that is involved in the activation of zymogen factor is activated into factor XIa.[10] 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 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 exact structure as tPA. Reteplase and tenecteplase both received FDA approval after alteplase, and have nonidentical structures to tPA.[1] These recombinant forms of tPA have been shown to have a longer half-life in the blood and a greater resistance to inhibition, resulting in an increased capacity to treat thrombolytic diseases.[11]

Urokinase is similarly used in the medical field, specifically for the treatment of pulmonary embolism.[12]

Plasminogen Activator Role in Breast Cancer

PLG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1B2I, 1BML, 1BUI, 1CEA, 1CEB, 1DDJ, 1HPJ, 1HPK, 1I5K, 1KI0, 1KRN, 1L4D, 1L4Z, 1PK4, 1PKR, 1PMK, 1QRZ, 1RJX, 2DOH, 2DOI, 2KNF, 2L0S, 2PK4, 3UIR, 4A5T, 4CIK, 4DCB, 4DUR, 4DUU, 5HPG
Identifiers
Aliases	PLG, plasminogen, plasmin
External IDs	OMIM: 173350 MGI: 97620 HomoloGene: 55452 GeneCards: PLG
Gene location (Human) Chr. Chromosome 6 (human)[13] Band 6q26 Start 160,702,238 bp[13] End 160,753,315 bp[13]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[14] Band 17 A1|17 8.5 cM Start 12,378,608 bp[14] End 12,419,385 bp[14]
RNA expression pattern More reference expression data
Gene ontology Molecular function • apolipoprotein binding • protein domain specific binding • peptidase activity • GO:0001948 protein binding • serine-type peptidase activity • receptor binding • hydrolase activity • serine-type endopeptidase activity • chaperone binding • proteasome core complex binding • protein antigen binding • endopeptidase activity • enzyme binding • kinase binding Cellular component • blood microparticle • extracellular region • cell surface • extrinsic component of external side of plasma membrane • extracellular exosome • platelet alpha granule lumen • extracellular • cell membrane • extrinsic component of plasma membrane • intracellular membrane-bounded organelle • collagen-containing extracellular matrix Biological process • hemostasis • negative regulation of cell-substrate adhesion • cellular protein metabolic process • negative regulation of fibrinolysis • negative regulation of cell-cell adhesion mediated by cadherin • platelet degranulation • extracellular matrix disassembly • positive regulation of fibrinolysis • tissue remodeling • negative regulation of cell proliferation • blood coagulation • proteolysis • fibrinolysis • positive regulation of blood vessel endothelial cell migration • tissue regeneration • myoblast differentiation • muscle cell cellular homeostasis • proteolysis involved in cellular protein catabolic process • trophoblast giant cell differentiation • labyrinthine layer blood vessel development • mononuclear cell migration Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5340	18815
Ensembl	ENSG00000122194	ENSMUSG00000059481
UniProt	P00747	P20918
RefSeq (mRNA)	NM_001168338 NM_000301	NM_008877
RefSeq (protein)	NP_000292 NP_001161810	NP_032903
Location (UCSC)	Chr 6: 160.7 – 160.75 Mb	Chr 17: 12.38 – 12.42 Mb
PubMed search	[15]	[16]
Wikidata
View/Edit Human View/Edit Mouse

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

1. Rivera-Bou WL (15 December 2016). "Thrombolytic Therapy". MedScape. Retrieved 28 February 2017.
2. 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 (March 2012). "The X-ray crystal structure of full-length human plasminogen". Cell Reports. 1 (3): 185–90. doi:10.1016/j.celrep.2012.02.012. PMID 22832192.
3. Declerck PJ, Gils A (June 2013). "Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin". Seminars in Thrombosis and Hemostasis. 39 (4): 356–64. doi:10.1055/s-0033-1334487. PMID 23504606.
4. Mimuro J (May 1991). "[Type 1 plasminogen activator inhibitor: its role in biological reactions]". [Rinsho Ketsueki] the Japanese Journal of Clinical Hematology. 32 (5): 487–9. PMID 1870265.
5. Carter JC, Church FC (2009-01-01). "Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1". PPAR Research. 2009: 345320. doi:10.1155/2009/345320. PMC 2723729. PMID 19672469.
6. Vaughan DE (August 2005). "PAI-1 and atherothrombosis". Journal of Thrombosis and Haemostasis. 3 (8): 1879–83. doi:10.1111/j.1538-7836.2005.01420.x. PMID 16102055.
7. Mikus P, Urano T, Liljeström P, Ny T (December 1993). "Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms". European Journal of Biochemistry. 218 (3): 1071–82. doi:10.1111/j.1432-1033.1993.tb18467.x. PMID 7506655.
8. Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN (July 2008). "Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa". The Journal of Biological Chemistry. 283 (27): 18655–64. doi:10.1074/jbc.M802275200. PMC 2441546. PMID 18441012.
9. Bolton-Maggs PH (June 1996). "Factor XI deficiency". Baillière's Clinical Haematology. 9 (2): 355–68. doi:10.1016/s0950-3536(96)80068-0. PMID 8800510.
10. Walsh PN (July 2001). "Roles of platelets and factor XI in the initiation of blood coagulation by thrombin". Thrombosis and Haemostasis. 86 (1): 75–82. PMID 11487044.
11. Gurman P, Miranda OR, Nathan A, Washington C, Rosen Y, Elman NM (March 2015). "Recombinant tissue plasminogen activators (rtPA): a review". Clinical Pharmacology and Therapeutics. 97 (3): 274–85. doi:10.1002/cpt.33. PMID 25670034.
12. "LABEL: KINLYTIC- urokinase injection, powder, lyophilized, for solution". DailyMed: US National Library of Medicine. 8 June 2007.
13. GRCh38: Ensembl release 89: ENSG00000122194 - Ensembl, May 2017
14. GRCm38: Ensembl release 89: ENSMUSG00000059481 - Ensembl, May 2017
15. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
16. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

External links

• Overview of all the structural information available in the PDB for UniProt: P00747 (Plasminogen) at the PDBe-KB.