Conformational regulation of urokinase receptor function: impact of receptor occupancy and epitope-mapped monoclonal antibodies on lamellipodia induction

Henrik Gårdsvoll, Benedikte Jacobsen, Mette C Kriegbaum, Niels Behrendt, Lars Engelholm, Søren Østergaard, Michael Ploug

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    Abstrakt

    The urokinase-type plasminogen activator receptor (uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the β-hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the β-hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.
    OriginalsprogEngelsk
    TidsskriftJournal of Biological Chemistry
    Vol/bind286
    Udgave nummer38
    Sider (fra-til)33544-56
    Antal sider13
    ISSN0021-9258
    DOI
    StatusUdgivet - 2011

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