Urokinase

PLAU

Available structures

Ortholog search: PDBe RCSB

List of PDB id codes

1C5W, 1C5X, 1C5Y, 1C5Z, 1EJN, 1F5K, 1F5L, 1F92, 1FV9, 1GI7, 1GI8, 1GI9, 1GJ7, 1GJ8, 1GJ9, 1GJA, 1GJB, 1GJC, 1GJD, 1KDU, 1LMW, 1O3P, 1O5A, 1O5B, 1O5C, 1OWD, 1OWE, 1OWH, 1OWI, 1OWJ, 1OWK, 1SC8, 1SQA, 1SQO, 1SQT, 1U6Q, 1VJA, 1W0Z, 1W10, 1W11, 1W12, 1W13, 1W14, 2FD6, 2NWN, 2O8T, 2O8U, 2O8W, 2R2W, 2VIN, 2VIO, 2VIP, 2VIQ, 2VIV, 2VIW, 2VNT, 3BT1, 3BT2, 3IG6, 3KGP, 3KHV, 3KID, 3M61, 3MHW, 3MWI, 3OX7, 3OY5, 3OY6, 3QN7, 3U73, 4DVA, 4DW2, 4FU7, 4FU8, 4FU9, 4FUB, 4FUC, 4FUD, 4FUE, 4FUF, 4FUG, 4FUH, 4FUI, 4FUJ, 4GLY, 4H42, 4JK5, 4JK6, 1URK, 4JNI, 4JNL, 4K24, 4MNV, 4MNW, 4MNX, 4MNY, 4OS1, 4OS2, 4OS4, 4OS5, 4OS6, 4OS7, 4X1N, 4X1Q, 4X1R, 4ZHL, 4ZHM, 4X0W, 4X1P, 4XSK, 4X1S, 5HGG, 4ZKO, 2I9B, 4ZKR, 4ZKS, 2I9A, 4ZKN

Identifiers

Aliases

PLAU, uPA, Urokinase-type plasminogen activator, Kinlytic, Abbokinase, ATF, BDPLT5, QPD, UPA, URK, u-PA, plasminogen activator, urokinase

External IDs

OMIM: 191840 MGI: 97611 HomoloGene: 55670 GeneCards: PLAU

Gene ontology
Molecular function	• peptidase activity • hydrolase activity • serine-type peptidase activity • protein binding • serine-type endopeptidase activity
Cellular component	• extracellular exosome • extracellular region • focal adhesion • cell surface • plasma membrane • extracellular fluid
Biological process	• response to hypoxia • signal transduction • regulation of cell proliferation • smooth muscle cell migration • regulation of wound healing • chemotaxis • regulation of cell adhesion mediated by integrin • regulation of smooth muscle cell migration • regulation of receptor activity • hemostasis • regulation of smooth muscle cell-matrix adhesion • fibrinolysis • proteolysis • blood coagulation • positive regulation of cell migration
Sources:Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

Entrez


5328


18792

Ensembl


ENSG00000122861


ENSMUSG00000021822

UniProt


P00749


P06869

RefSeq (mRNA)


NM_001145031 NM_002658 NM_001319191


NM_008873

RefSeq (protein)


NP_001138503.1 NP_002649.1 NP_001306120.1


NP_032899.1

Location (UCSC)

Chr 10: 73.91 – 73.92 Mb

Chr 14: 20.84 – 20.84 Mb

PubMed search

^[1]

^[2]

Wikidata

View/Edit Human

View/Edit Mouse

Urokinase
Clinical data
AHFS/Drugs.com	Monograph
ATC code	B01AD04 (WHO)
Identifiers
CAS Number	9039-53-6^Y
DrugBank	DB00013^N
ChemSpider	none
UNII	83G67E21XI^N
KEGG	D03341^Y
ChEMBL	CHEMBL1201420^N
ECHA InfoCard	100.029.913
Chemical and physical data
Formula	C₁₃₇₆H₂₁₄₅N₃₈₃O₄₀₆S₁₈
Molar mass	31126.5 g/mol
^NY (what is this?) (verify)

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947.^[3] Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.^[4]

Urokinase is encoded in humans by the PLAU gene, which stands for "plasminogen activator, urokinase".^[5] The same symbol represents the gene in other animal species.

Function

The PLAU gene encodes a serine protease (EC 3.4.21.73) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor.^[6]

Structure

Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond.

Interaction partners

The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor.

uPa also interacts with protein C inhibitor.^[7]^[8]

Urokinase and cancer

Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents.^[9]^[10] However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular mitotic pathways.

As of December 7, 2012, Mesupron, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.^[11] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.^[12]

Clinical applications

Urokinase is used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, pulmonary embolism, myocardial infarction, and occluded intravenous or dialysis cannulas. It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Abbokinase or Kinlytic and competes with recombinant tissue plasminogen activator (e.g., alteplase) as a thrombolytic drug in infarction. However, urokinase is not very selective for clot-bound plasminogen, unlike tissue plasminogen activator (TPA) which preferentially interacts with clot-bound plasminogen. Because urokinase binds about equally to freely circulating plasminogen and clot-bound plasminogen, it causes significant fibrinogenolysis and clot fibrinolysis making its use less favorable than TPA.^[13]

References

↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ Degryse, Bernard (1 June 2011). "The urokinase receptor system as strategic therapeutic target: challenges for the 21st century". Current Pharmaceutical Design. 17 (19): 1872–1873. doi:10.2174/138161211796718161.
↑ Tang, Linlin; Han, Xiuzhen (March 2013). "The urokinase plasminogen activator system in breast cancer invasion and metastasis". Biomedicine & Pharmacotherapy. 67 (2): 179–182. doi:10.1016/j.biopha.2012.10.003.
↑ Nagai M, Hiramatsu R, Kanéda T, Hayasuke N, Arimura H, Nishida M, Suyama T (Dec 1985). "Molecular cloning of cDNA coding for human preprourokinase". Gene. 36 (1-2): 183–8. doi:10.1016/0378-1119(85)90084-8. PMID 2415429.
↑ "Entrez Gene: PLAU plasminogen activator, urokinase".
↑ Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR (Aug 1989). "Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo". Blood. 74 (2): 722–8. PMID 2752144.
↑ España F, Berrettini M, Griffin JH (Aug 1989). "Purification and characterization of plasma protein C inhibitor". Thromb. Res. 55 (3): 369–84. doi:10.1016/0049-3848(89)90069-8. PMID 2551064.
↑ Jankun J, Skrzypczak-Jankun E (July 1999). "Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride". Cancer Biochem. Biophys. 17 (1-2): 109–23. PMID 10738907.
↑ Matthews H, Ranson M, Kelso MJ (November 2011). "Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty?". Int. J. Cancer. 129 (9): 2051–61. doi:10.1002/ijc.26156. PMID 21544803.
↑ "Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery". ClinicalTrials.gov.
↑ "Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer". Press Release. Temple University Health System.
↑ http://www.cvpharmacology.com/thrombolytic/thrombolytic

Ploug M, Gårdsvoll H, Jørgensen TJ, Lønborg Hansen L, Danø K (2002). "Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy.". Biochem. Soc. Trans. 30 (2): 177–83. doi:10.1042/BST0300177. PMID 12023847.
Alfano M, Sidenius N, Blasi F, Poli G (2004). "The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection.". J. Leukoc. Biol. 74 (5): 750–6. doi:10.1189/jlb.0403176. PMID 12960238.
Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M (2004). "Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer.". Thromb. Haemost. 91 (3): 450–6. doi:10.1160/TH03-12-0798. PMID 14983219.
Gilabert-Estelles J, Ramon LA, España F, Gilabert J, Castello R, Estelles A (2006). "Expression of the fibrinolytic components in endometriosis.". Pathophysiol. Haemost. Thromb. 35 (1-2): 136–40. doi:10.1159/000093556. PMID 16855359.

Proteins involved in coagulation

Coagulation factors

Primary hemostasis	vWF platelet membrane glycoproteins: Ib (A B IX) IIb/IIIa (IIb IIIa) VI

Intrinsic pathway	HMWK/Bradykinin Prekallikrein/Kallikrein XII "Hageman" XI IX VIII

Extrinsic pathway	III "Tissue factor" VII

Common pathway	X V II "(Pro)thrombin" I "Fibrin" Fibrinogen (FGA, FGG) XIII

Coagulation inhibitors

Thrombolysis/fibrinolysis

Antithrombotics (thrombolytics, anticoagulants and antiplatelet drugs) (B01)

Antiplatelet drugs

Glycoprotein IIb/IIIa inhibitors	Abciximab Eptifibatide Orbofiban Roxifiban Sibrafiban^§ Tirofiban

ADP receptor/P2Y₁₂ inhibitors	Thienopyridines Clopidogrel Prasugrel Ticlopidine Nucleotide/nucleoside analogs Cangrelor Elinogrel Ticagrelor

Prostaglandin analogue (PGI2)	Beraprost Iloprost Prostacyclin Treprostinil

COX inhibitors	Acetylsalicylic acid/Aspirin^# Aloxiprin Carbasalate calcium Indobufen Triflusal

Thromboxane inhibitors	Thromboxane synthase inhibitors Dipyridamole (+ aspirin) Picotamide Terbogrel Receptor antagonists Terbogrel Terutroban^§

Phosphodiesterase inhibitors	Cilostazol Dipyridamole Triflusal

Other	Cloricromen Ditazole Vorapaxar

Anticoagulants

Vitamin K antagonists
(inhibit II, VII, IX, X)

Factor Xa inhibitors
(with some II inhibition)

Heparin group/ glycosaminoglycans/ (bind antithrombin)	Low molecular weight heparin Bemiparin Certoparin Dalteparin Enoxaparin Nadroparin Parnaparin Reviparin Tinzaparin^‡ Oligosaccharides Fondaparinux Idraparinux^§ Heparinoids Danaparoid Dermatan sulfate Sulodexide

Direct Xa inhibitors ("xabans")	Apixaban Betrixaban^† Darexaban^§ Edoxaban Otamixaban^§ Rivaroxaban

Direct thrombin (IIa) inhibitors

Other

Thrombolytic drugs/
fibrinolytics

Non-medicinal

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21)

Digestive enzymes	Enteropeptidase Trypsin Chymotrypsin Elastase Neutrophil Pancreatic

Coagulation	factors: Thrombin Factor VIIa Factor IXa Factor Xa Factor XIa Factor XIIa Kallikrein PSA KLK1 KLK2 KLK3 KLK4 KLK5 KLK6 KLK7 KLK8 KLK9 KLK10 KLK11 KLK12 KLK13 KLK14 KLK15 fibrinolysis: Plasmin Plasminogen activator Tissue plasminogen activator Urinary plasminogen activator

Complement system	Factor B Factor D Factor I MASP MASP1 MASP2 C3-convertase

Other immune system	Chymase Granzyme Tryptase Proteinase 3/Myeloblastin

Venombin	Ancrod Batroxobin

Other	Acrosin Prolyl endopeptidase Pronase Proprotein convertases 1 2 Prostasin Reelin Subtilisin/Furin Streptokinase S1P Cathepsin A G

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

PDB gallery

1c5w: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR

1c5x: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR

1c5y: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR

1c5z: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR

1ejn: UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN INHIBITOR COMPLEX

1f5k: UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-BENZAMIDINE COMPLEX

1f5l: UROKINASE PLASMINOGEN ACTIVATOR B-CHAIN-AMILORIDE COMPLEX

1f92: UROKINASE PLASMINOGEN ACTIVATOR B CHAIN-UKI-1D COMPLEX

1fv9: Crystal structure of human microurokinase in complex with 2-amino-5-hydroxy-benzimidazole

1gi7: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE

1gi8: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE

1gi9: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE

1gj7: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1gj8: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1gj9: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1gja: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1gjb: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1gjc: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1gjd: ENGINEERING INHIBITORS HIGHLY SELECTIVE FOR THE S1 SITES OF SER190 TRYPSIN-LIKE SERINE PROTEASE DRUG TARGETS

1kdu: SEQUENTIAL 1H NMR ASSIGNMENTS AND SECONDARY STRUCTURE OF THE KRINGLE DOMAIN FROM UROKINASE

1lmw: LMW U-PA STRUCTURE COMPLEXED WITH EGRCMK (GLU-GLY-ARG CHLOROMETHYL KETONE)

1o3p: Elaborate Manifold of Short Hydrogen Bond Arrays Mediating Binding of Active Site-Directed Serine Protease Inhibitors

1o5a: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)

1o5b: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)

1o5c: Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)

1owd: Substituted 2-Naphthamidine inhibitors of urokinase

1owe: Substituted 2-Naphthamidine inhibitors of urokinase

1owh: Substituted 2-Naphthamidine Inhibitors of Urokinase

1owi: Substituted 2-Naphthamidine Inhibitors of Urokinase

1owj: Substituted 2-Naphthamidine Inhibitors of Urokinase

1owk: Substituted 2-Naphthamidine Inhibitors of Urokinase

1sc8: Urokinase Plasminogen Activator B-Chain-J435 Complex

1sqa: Substituted 2-Naphthamidine Inhibitors of Urokinase

1sqo: Substituted 2-Naphthamidine Inhibitors of Urokinase

1sqt: Substituted 2-Naphthamidine Inhibitors of Urokinase

1u6q: Substituted 2-Naphthamadine inhibitors of Urokinase

1urk: SOLUTION STRUCTURE OF THE AMINO TERMINAL FRAGMENT OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR

1vj9: Urokinase Plasminogen Activator B-Chain-JT464 Complex

1vja: Urokinase Plasminogen Activator B-Chain-JT464 Complex

2fd6: Structure of Human Urokinase Plasminogen Activator in Complex with Urokinase Receptor and an anti-upar antibody at 1.9 A

2i9a: Crystal structure of the free aminoterminal fragment of urokinase type plasminogen activator (ATF)

2i9b: Crystal structure of ATF-urokinase receptor complex

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