Urokinase receptor explained

The Urokinase receptor, also known as urokinase plasminogen activator surface receptor (uPAR) or CD87 (Cluster of Differentiation 87), is a protein encoded in humans by the PLAUR gene. It is a multidomain glycoprotein tethered to the cell membrane with a (GPI) anchor. uPAR was originally identified as a saturable binding site for urokinase (also known as uPA) on the cell surface.

Molecular characteristics

uPAR consists of three tandem LU domains, which are protein domains of the three-finger protein family.^[1] The structure of uPAR has been solved by X-ray crystallography in complex with a peptide antagonist^[2] and with its native ligand, urokinase.^[3] All three three-finger domains are necessary for high affinity binding of the primary ligand, urokinase. In addition, uPAR also interacts with several other proteins, including vitronectin, the uPAR associated protein (uPARAP) and the integrin family of membrane proteins.

It has been possible to express uPAR recombinantly in CHO-cells and S2 cells from Drosophila melanogaster. 4 out of 5 of the possible glycosylation sites are used in vivo giving the protein a molecular weight of 50–60 kDA.

Physiological significance

uPAR is a part of the plasminogen activation system, which in the healthy body is involved in tissue reorganization events such as mammary gland involution and wound healing. In order to be able to reorganize tissue, the old tissue must be able to be degraded. An important mechanism in this degradation is the proteolysis cascade initiated by the plasminogen activation system. uPAR binds urokinase and thus restricts plasminogen activation to the immediate vicinity of the cell membrane. When urokinase is bound to the receptor, there is cleavage between the GPI-anchor and the uPAR, releasing a soluble form of the protein known as suPAR.^{[4] [5]}

Clinical significance

Soluble urokinase plasminogen activator receptor (suPAR) has been found to be a biomarker of inflammation.^[6] Elevated suPAR is seen in chronic obstructive pulmonary disease, asthma, liver failure, heart failure, cardiovascular disease, and rheumatoid arthritis. Smokers have significantly higher suPAR compared to non-smokers.

Urokinase receptors have been found to be highly expressed on senescent cells, leading researchers to use chimeric antigen receptor T cells to eliminate senescent cells in mice.^{[7] [8]}

The components of the plasminogen activation system have been found to be highly expressed in many malignant tumors, indicating that tumors are able to hijack the system, and use it in metastasis. Thus inhibitors of the various components of the plasminogen activation system have been sought as possible anticancer drugs.^[9]

uPAR has been involved in various other non-proteolytic processes related to cancer, such as cell migration, cell cycle regulation, and cell adhesion.

Interactions

Urokinase receptor has been shown to interact with LRP1.^[10]

See also

• Cancer
• Cluster of differentiation
• Metastasis
• Plasmin
• suPAR
• Urokinase

Further reading

• Ploug M . Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor . Current Pharmaceutical Design . 9 . 19 . 1499–528 . 2003 . 12871065 . 10.2174/1381612033454630 .
• Kjøller L . The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility . Biological Chemistry . 383 . 1 . 5–19 . January 2002 . 11928822 . 10.1515/BC.2002.002 . 6125978 .
• Chavakis T, Kanse SM, May AE, Preissner KT . Haemostatic factors occupy new territory: the role of the urokinase receptor system and kininogen in inflammation . Biochemical Society Transactions . 30 . 2 . 168–73 . April 2002 . 12023845 . 10.1042/BST0300168 .
• Ploug M, Gårdsvoll H, Jørgensen TJ, Lønborg Hansen L, Danø K . Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy . Biochemical Society Transactions . 30 . 2 . 177–83 . April 2002 . 12023847 . 10.1042/BST0300177 .
• Alfano M, Sidenius N, Blasi F, Poli G . The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection . Journal of Leukocyte Biology . 74 . 5 . 750–6 . November 2003 . 12960238 . 10.1189/jlb.0403176 . 8526093 .
• Alfano D, Franco P, Vocca I, Gambi N, Pisa V, Mancini A, Caputi M, Carriero MV, Iaccarino I, Stoppelli MP . The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis . Thrombosis and Haemostasis . 93 . 2 . 205–11 . February 2005 . 15711734 . 10.1160/TH04-09-0592 . 35517406 .

Notes and References

1. Kessler . Pascal . Marchot . Pascale . Silva . Marcela . Servent . Denis . The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions . Journal of Neurochemistry . August 2017 . 142 . 7–18 . 10.1111/jnc.13975. 28326549 . free .
2. Llinas P, Le Du MH, Gårdsvoll H, Danø K, Ploug M, Gilquin B, Stura EA, Ménez A . Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide . The EMBO Journal . 24 . 9 . 1655–63 . May 2005 . 15861141 . 1142576 . 10.1038/sj.emboj.7600635 .
3. Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, Li Y, Yuan C, Bian C, Chen L, Furie B, Furie BC, Cines DB, Huang M . Structure of human urokinase plasminogen activator in complex with its receptor . Science . 311 . 5761 . 656–9 . February 2006 . 16456079 . 10.1126/science.1121143 . 2006Sci...311..656H . 39521660 .
4. Web site: ViroGates. What is suPAR. 2021-09-27. suPARnostic® by ViroGates. en.
5. Thunø M, Macho B, Eugen-Olsen J . suPAR: the molecular crystal ball . Disease Markers . 27 . 3 . 157–72 . 2009 . 19893210 . 3835059 . 10.1155/2009/504294. free .
6. Desmedt S, Desmedt V, Delanghe JR, Speeckaert R, Speeckaert MM . The Intriguing Role of Soluble Urokinase Receptor in Inflammatory Diseases . . 54 . 2 . 117–133 . 2017 . 10.1080/10408363.2016.1269310 . 28084848. 32624995 .
7. Wagner V, Gil J . T Cells Engineered to Target Senescence . . 583 . 7814 . 37–38 . 2020 . 10.1038/d41586-020-01759-x . 32601490. 2020Natur.583...37W . free . 10044/1/80980 . free .
8. Amor C, Feucht J, Lowe SW . Senolytic CAR T cells reverse senescence-associated pathologies . . 583 . 7814 . 127–132 . 2020 . 10.1038/s41586-020-2403-9 . 7583560 . 32555459.
9. Josip Madunić . The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role . . 118 . 12 . 2020–2036 . 2018 . 10.1055/s-0038-1675399 . 30419600. free .
10. Czekay RP, Kuemmel TA, Orlando RA, Farquhar MG . Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity . Molecular Biology of the Cell . 12 . 5 . 1467–79 . May 2001 . 11359936 . 34598 . 10.1091/mbc.12.5.1467 .