Critical role of integrin α5β1 in urokinase (uPA)/urokinase receptor (uPAR, CD87) signaling

Takehiko Tarui, Nicholas Andronicos, Ralf Peter Czekay, Andrew P. Mazar, Khalil Bdeir, Graham C. Parry, Alice Kuo, David J. Loskutoff, Douglas B. Cines, Yoshikazu Takada*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Urokinase-type plasminogen activator (uPA) induces cell adhesion and chemotactic movement. uPA signaling requires its binding to uPA receptor (uPAR/CD87), but how glycosylphosphatidylinositol-anchored uPAR mediates signaling is unclear. uPAR is a ligand for several integrins (e.g. α5β1) and supports cell-cell interaction by binding to integrins on apposing cells (in trans). We studied whether binding of uPAR to α5β1 in cis is involved in adhesion and migration of Chinese hamster ovary cells in response to immobilized uPA. This process was temperature-sensitive and required mitogen-activated protein kinase activation. Anti-uPAR antibody or depletion of uPAR blocked, whereas overexpression of uPAR enhanced, cell adhesion to uPA. Adhesion to usa was also blocked by deletion of the growth factor domain (GFD) of usa and by anti-GFD antibody, whereas neither the isolated usa kringle nor serine protease domain supported adhesion directly. Interestingly, anti-α5 antibody, RGD peptide, and function-blocking mutations in α5β1 blocked adhesion to usa. usa-induced cell migration also required GFD, uPAR, and α5β1, but α5β1 alone did not support usa-induced adhesion and migration. Thus, binding of usa causes uPAR to act as a ligand for α5β1 to induce cell adhesion, intracellular signaling, and cell migration. We demonstrated that usa induced RGD-dependent binding of uPAR to α5β1 in solution. These results suggest that usa-induced adhesion and migration of Chinese hamster ovary cells occurs as a consequence of (a) usa binding to uPAR through GFD, (b) the subsequent binding of a usa·uPAR complex to α5β1 via uPAR, and (c) signal transduction through α5β1.

Original languageEnglish (US)
Pages (from-to)29863-29872
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number32
DOIs
StatePublished - Aug 8 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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