Urokinase-type plasminogen activator receptor (CD87) is a ligand for integrins and mediates cell-cell interaction.
Binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR/CD87) regulates cellular adhesion, migration, and tumor cell invasion. However, it is unclear how glycosyl phosphatidylinositol-anchored uPAR, which lacks a transmembrane structure, mediates signal transduction. It has been proposed that uPAR forms cis-interactions with integrins as an associated protein and thereby transduces proliferative or migratory signals to cells upon binding of uPA. We provide evidence that soluble uPAR (suPAR) specifically binds to integrins alpha4beta1, alpha6beta1, alpha9beta1, and alphavbeta3 on Chinese hamster ovary cells in a cation-dependent manner. Anti-integrin and anti-uPAR antibodies effectively block binding of suPAR to these integrins. Binding of suPAR to alpha4beta1 and alphavbeta3 is blocked by known soluble ligands and by the integrin mutations that inhibit ligand binding. These results suggest that uPAR is an integrin ligand rather than, or in addition to, an integrin-associated protein. In addition, we demonstrate that glycosyl phosphatidylinositol-anchored uPAR on the cell surface specifically binds to integrins on the apposing cells, suggesting that uPAR-integrin interaction may mediate cell-cell interaction (trans-interaction). These previously unrecognized uPAR-integrin interactions may allow uPAR to transduce signals through the engaged integrin without a hypothetical transmembrane adapter and may provide a potential therapeutic target for control of inflammation and cancer.
Tarui
T
T
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Mazar
A P
AP
Cines
D B
DB
Takada
Y
Y
D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D006224:Cricetinae; D004330:Drosophila; D007249:Inflammation / Q000503:physiopathology; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D009369:Neoplasms / Q000503:physiopathology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D016023:Integrins; D008024:Ligands; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins