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Takehiko Tarui, Nobuaki Akakura, Mousumi Majumdar, Nicholas Andronicos, Junichi Takagi, Andrew P. Mazar, Khalil Bdeir, Alice Kuo, Serge V. Yarovoi, Douglas B. Cines, Yoshikazu Takada

Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin v3 induces signal transduction and enhances plasminogen activation

Keywords: Adhesion receptors / integrins, adhesion molecules, cell migration, Angiogenesis and inhibitors, plasminogen activators

It has been questioned whether there are receptors for urokinase-type plasminogen activator (uPA) that facilitate plasminogen activation other than the high affinity uPA receptor (uPAR/CD87) since studies of uPAR knockout mice did not support a major role of uPAR in plasminogen activation. uPA also promotes cell adhesion, chemotaxis, and proliferation besides plasminogen activation. These uPA-induced signaling events are not mediated by uPAR, but mediated by unidentified, lower-affinity receptors for the uPA kringle. We found that uPA binds specifically to integrin v3 on CHO cells depleted of uPAR. The binding of uPA to v3 required the uPA kringle domain. The isolated uPA kringle domain binds specifically to purified, recombinant soluble, and cell surface v3, and other integrins (41 and 91), and induced migration of CHO cells in an v3-dependent manner. The binding of the uPA kringle to v3 and uPA kringle-induced v3-dependent cell migration were blocked by homologous plasminogen kringles 13 or 14 (angiostatin), a known integrin antagonist. We studied whether the binding of uPA to integrin v3 through the kringle domain plays a role in plasminogen activation. On CHO cell depleted of uPAR, uPA enhanced plasminogen activation in a kringle and v3-dependent manner. Endothelial cells bound to and migrated on uPA and uPA kringle in an v3-dependent manner. These results suggest that uPA binding to integrins through the kringle domain plays an important role in both plasminogen activation and uPA-induced intracellular signaling. The uPA kringle-integrin interaction may represent a novel therapeutic target for cancer, inflammation, and vascular remodeling.

Thrombosis and Haemostasis, Schattauer

Print ISSN: 0340-6245
Volume: 95, 03/2006
Pages: 524 - 534

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