Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor

Robert W. Colman, Robin A. Pixley, Syeda Najamunnisa, Wuyi Yan, Jieyi Wang, Andrew Mazar, Keith R. McCrae*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

Abstract

The urokinase receptor (uPAR) binds urokinase-type plasminogen activator (u-PA) through specific interactions with uPAR domain 1, and vitronectin through interactions with a site within uPAR domains 2 and 3. These interactions promote the expression of cell surface plasminogen activator activity and cellular adhesion to vitronectin, respectively. High molecular weight kininogen (HK) also stimulates the expression of cell surface plasminogen activator activity through its ability to serve as an acquired receptor for prekallikrein, which, after its activation, may directly activate prourokinase. Here, we report that binding of the cleaved form of HK (HKa) to human umbilical vein endothelial cells (HUVEC) is mediated through zinc-dependent interactions with uPAR. These occur through a site within uPAR domains 2 and 3, since the binding of 125I-HKa to HUVEC is inhibited by vitronectin, anti-uPAR domain 2 and 3 antibodies and soluble, recombinant uPAR (suPAR), but not by antibody 7E3, which recognizes the β chain of the endothelial cell vitronectin receptor (integrin α(v)β3), or fibrinogen, another α(v)β3 ligand. We also demonstrate the formation of a zinc- dependent complex between suPAR and HKa. Interactions of HKa with endothelial cell uPAR may underlie its ability to promote kallikrein-dependent cell surface plasmin generation, and also explain, in part, its anti-adhesive properties.

Original languageEnglish (US)
Pages (from-to)1481-1487
Number of pages7
JournalJournal of Clinical Investigation
Volume100
Issue number6
DOIs
StatePublished - Sep 15 1997

Keywords

  • Integrin α(v)β
  • Plasminogen
  • Prekallikreln
  • Prourokinase
  • Vitronectin

ASJC Scopus subject areas

  • Medicine(all)

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