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

    53 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    JournalJournal of Biological Chemistry
    Volume286
    Issue number38
    Pages (from-to)33544-56
    Number of pages13
    ISSN0021-9258
    DOIs
    Publication statusPublished - 2011

    Keywords

    • Amino Acid Sequence
    • Animals
    • Antibodies, Monoclonal
    • Cell Line
    • Drosophila melanogaster
    • Epitope Mapping
    • Humans
    • Inhibitory Concentration 50
    • Kinetics
    • Ligands
    • Mice
    • Models, Molecular
    • Molecular Sequence Data
    • Molecular Weight
    • Peptides
    • Protein Structure, Secondary
    • Protein Structure, Tertiary
    • Pseudopodia
    • Receptors, Urokinase Plasminogen Activator
    • Structure-Activity Relationship
    • Transfection
    • Urokinase-Type Plasminogen Activator
    • Vitronectin

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