Single chain urokinase-type plasminogen activator bound to its receptor is relatively resistant to plasminogen activator inhibitor type 1

Abd A I Roof Higazi, Andrew Mazar, Jieyi Wang, Regina Reilly, Jack Henkin, Douglas Kniss, Douglas Cines

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Urokinase type plasminogen activator (uPA) is synthesized as single chain protein (sou P A) with little intrinsic activity. scuPA is activated when it is converted to two chain urokinase (tcuPA) by plasmin or when it binds as a single chain molecule to its cellular receptor (uPAR) (JBC 270: 17375, 1995). Previous data indicate that complexes between scuPA and its receptor have somewhat higher affinity for plasminogen than does tcuPA. The current study indicates that plasminogen activator activity of scuPA bound to recombinant, soluble uPAR (suPAR) is also five fold less sensitive to inhibition by plasminogen activator type 1 (PAI-1) than is soluble or receptor-bound tcuPA. Binding of PAI-1 to suPAR/scuPA complexes is totally reversible and can be overcome by increasing the concentration of plasminogen, suggesting a competitive mechanism of inhibition (Kj = 18 nM). Binding of scuPA to suPAR also retards its cleavage by plasmin. These results indicates that binding of single chain urokinase to its receptor promotes its activity, retards its inhibition and protects it from conversion to a two chain form of the enzyme, a step that may precede its inactivation and clearance from cell surfaces. These results are consistent with a physiologic role for receptor-bound single chain urokinase as a cellular plasminogen activator.

    Original languageEnglish (US)
    Pages (from-to)30
    Number of pages1
    JournalFibrinolysis
    Volume10
    Issue numberSUPPL. 3
    DOIs
    StatePublished - 1996

    ASJC Scopus subject areas

    • Hematology

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