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Related Experiment Videos

Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1.

Y Wei1, J A Eble, Z Wang

  • 1Respiratory Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Molecular Biology of the Cell
|October 13, 2001
PubMed
Summary

The urokinase receptor (uPAR) binds to the alpha3beta1 integrin, influencing cell adhesion and signaling pathways. This interaction is crucial for cell migration and is modulated by urokinase (uPA).

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Integrin Signaling

Background:

  • The urokinase receptor (uPAR) mediates cellular migration via pericellular proteolysis, integrin regulation, and cell signaling upon urokinase (uPA) binding.
  • uPAR was recently identified as a ligand for the beta2 integrin CD11b/CD18 (Mac-1), but its interactions with beta1 integrins were less defined.

Purpose of the Study:

  • To identify the specific beta1 integrin partner involved in uPAR/uPA signaling.
  • To elucidate the role of this integrin in uPAR-mediated cell adhesion and signaling pathways.

Main Methods:

  • Co-complexing analysis of uPAR with alpha3beta1 integrin in transfected cells.
  • Surface plasmon resonance to quantify soluble uPAR binding to recombinant alpha3beta1.
  • Inhibition studies using antibodies and peptides targeting alpha3beta1.

Related Experiment Videos

  • Cellular adhesion, spreading, and focal adhesion kinase phosphorylation assays.
  • Analysis of uPA signaling in alpha3-deficient epithelial cells.

    • Main Results:

    • uPAR predominantly complexes with alpha3beta1 integrin (>90%) in uPAR-transfected cells.
    • uPA-dependent binding of soluble uPAR to recombinant alpha3beta1 was observed (K(d) < 20 nM), inhibited by an alpha3beta1-specific peptide.
    • uPAR and alpha3beta1 colocalized in MDA-MB-231 cells; uPA enhanced cell spreading and FAK phosphorylation on fibronectin and collagen in an alpha3beta1-dependent manner.
    • Studies in alpha3-deficient mice confirmed the critical role of alpha3beta1 in uPA signaling.

    Conclusions:

    • uPAR preferentially forms complexes with alpha3beta1 integrin, mediating both direct (vitronectin) and indirect (fibronectin, collagen) cell adhesion.
    • The signaling pathways involving alpha3beta1 and other beta1 integrins are dependent on heterotrimeric G proteins.
    • This interaction highlights a novel mechanism for uPAR in regulating cell adhesion and migration through alpha3beta1 integrin.