Identification of a Urokinase Receptor-Integrin Interaction Site

Daniel I. Simon, Ying Wei, Li Zhang, Navaneetha K. Rao, Hui Xu, Zhiping Chen, Qiumei Liu, Steven Rosenberg, Harold A. Chapman
2000 Journal of Biological Chemistry  
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 ␤ 2 -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
more » ... ound to immobilized M25, binding being promoted by urokinase and blocked by soluble M25, but not a scrambled control or homologous peptides from other ␤ 2 -associated ␣-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 ␤-propeller model of ␣-chain folding, M25 spans an exposed loop on the ligand-binding, upper surface of ␣M, identifying uPAR as an atypical ␣M ligand. Although not blocking ligand binding to Mac-1, M25 (25-100 M) inhibited leukocyte adhesion to fibrinogen, vitronectin, and cytokine-stimulated endothelial cells. M25 also blocked the association of uPAR with ␤ 1 -integrins and impaired ␤ 1integrin-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.
doi:10.1074/jbc.275.14.10228 pmid:10744708 fatcat:pcfaturpczcwzgiihydztqgnza