Urokinase receptor
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The Urokinase receptor, also known as uPA receptor or uPAR, is multidomain glycoprotein tethered to the cell membrane with a glycosylphosphotidylinositol (GPI) anchor. uPAR was originally identified as a saturable binding site for urokinase on the cell surface.
Molecular characteristics
uPAR consists of three different domains of the Ly-6/uPAR/alpha-neurotoxin family. All three domains are necessary for high affinity binding of the primary ligand, urokinase. It has been possible to express uPAR recombinantly i 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. Recently the structure of uPAR was solved by X-ray crystallography [#endnote_llinas] in complex with an peptide antagonist.Besides the primary ligand urokinase, uPAR interacts with several other proteins, amoing others: vitronectin, the uPAR associated protein (uPARAP) and the integrin family of membrane proteins.
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 it is important, that the old tissue can 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. Thus uPAR seems to be an important player in the regulation of this process.However the components of the plasminogen activation system have been found to be highly expressed in many malignant tumors, indicating that tumors are able to the system, and use it in metastasis. Thus inhibitors of the various components of the plasminogen activation system has been sought as possible anticancer drugs.
uPAR has been involved in various other non-proteolytical processes related to cancer, such as cell migration, cell cycle regulation and cell adhesion.
See also
Plasminogen activation systemReferences
- ↑ Structure-Function Relationships in the Interaction Between the Urokinase-Type Plasminogen Activator and its Receptor. Ploug, M. Curr Pharm Des. 2003;9(19):1499-528.(full text article online: Entrez PubMed [12871065]).
- ↑ Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide. Llinas P, Le Du MH, Gardsvoll H, Dano K, Ploug M, Gilquin B, Stura EA, Menez A. EMBO J. 2005 May 4;24(9):1655-63. Epub 2005 Apr 7. (full text article online: Entrez PubMed [15861141]).
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