Plasmin-dependent elimination of the growth-factor-like domain in urokinase causes its rapid cellular uptake and degradation

The Biochemical Journal
A A PoliakovV V Stepanova

Abstract

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) act in concert to mediate pericellular proteolysis and to stimulate intracellular signalling responsible for cell migration and proliferation. uPA is composed of three domains, a proteolytic domain (PD), a kringle domain (KD) and a growth-factor-like domain (GFD), the last of which mediates the interaction with uPAR. We demonstrate that uPA, associated with the surface of U937 cells, undergoes plasmin-mediated cleavage of the Lys(46)-Ser(47) bond with elimination of the GFD. Using recombinant forms of uPA, we show that a uPA variant lacking the GFD (r-uPADeltaGFD) and unable to associate with uPAR is rapidly cleared from the cell surface. Binding and internalization of r-uPADeltaGFD are markedly decreased in the presence of 39 kDa receptor-associated protein (RAP), the antagonist of several endocytic receptors of the low-density lipoprotein receptor family, suggesting that this protein clearance pathway is used for r-uPADeltaGFD. In contrast with rapidly internalized r-uPADeltaGFD, the intact recombinant single-chain urokinase with wild-type structure (r-uPAwt) bound to uPAR is retained on the cell surface. Soluble uPAR protects uPA from cleavage by plasmin that...Continue Reading

Citations

Sep 19, 2006·Journal of Molecular Biology·Cyril BarinkaJacek Lubkowski
Aug 2, 2005·Protein Expression and Purification·Vibha Bansal, Pradip K Roychoudhury
Apr 17, 2009·Canadian Journal of Physiology and Pharmacology·Vsevolod A TkachukYelena V Parfyonova
Mar 14, 2008·Blood·Victoria StepanovaDouglas B Cines
Sep 26, 2019·Cellular and Molecular Neurobiology·Rais Reskiawan A Kadir, Ulvi Bayraktutan
Jul 20, 2017·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Juan F SantibanezJelena Krstić
Jun 15, 2021·Frontiers in Molecular Biosciences·Farwa AltafVivi Kasim

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