Identification of a Urokinase Receptor-Integrin Interaction Site

Adhesion and signaling by integrins require their dynamic association with nonintegrin membrane proteins. One such protein, the glycolipid-anchored urokinase receptor (uPAR), associates with and modifies the function of the β2-integrin Mac-1 (CD11b/CD18). In this study, a critical non-I-domain binding site for uPAR on CD11b (M25; residues 424–440) is identified by homology with a phage display peptide known to bind uPAR. Recombinant soluble uPAR and cells expressing uPAR bound to immobilized M25, binding being promoted by urokinase and blocked by soluble M25, but not a scrambled control or homologous peptides from other β2-associated α-chains. Mac-1, but not a mutated Mac-1 in which M25 was replaced with the homologous sequence of CD11c, co-precipitated with uPAR. In the β-propeller model of α-chain folding, M25 spans an exposed loop on the ligand-binding, upper surface of αM, identifying uPAR as an atypical αM ligand. Although not blocking ligand binding to Mac-1, M25 (25–100 μm) inhibited leukocyte adhesion to fibrinogen, vitronectin, and cytokine-stimulated endothelial cells. M25 also blocked the association of uPAR with β1-integrins and impaired β1-integrin-dependent spreading and migration of human vascular smooth muscle cells on fibronectin and collagen. These observations indicate that uPAR associates with integrins directly and that disruption of this association broadly impairs integrin function, suggesting a novel strategy for regulation of integrins in the settings of inflammation and tumor progression.

• Publication year

  2000

• Venue

  Journal of Biological Chemistry

• Publication date

  2000-04-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.275.14.10228PMID 10744708
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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