Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin αvβ3 induces signal transduction and enhances plasminogen activation

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

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58 引文 斯高帕斯(Scopus)

摘要

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 αvβ3 on CHO cells depleted of uPAR. The binding of uPA to αvβ3 required the uPA kringle domain. The isolated uPA kringle domain binds specifically to purified, recombinant soluble, and cell surface αvβ3, and other integrins (α4β1 and α9β1), and induced migration of CHO cells in an αvβ3-dependent manner. The binding of the uPA kringle to αvβ3 and uPA kringle-induced αvβ3-dependent cell migration were blocked by homologous plasminogen kringles 1-3 or 1-4 (angiostatin), a known integrin antagonist. We studied whether the binding of uPA to integrin αvβ3 through the kringle domain plays a role in plasminogen activation. On CHO cell depleted of uPAR, uPA enhanced plasminogen activation in a kringle and αvβ3-dependent manner. Endothelial cells bound to and migrated on uPA and uPA kringle in an αvβ3-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.

原文英語
頁(從 - 到)524-534
頁數11
期刊Thrombosis and Haemostasis
95
發行號3
DOIs
出版狀態已發佈 - 三月 2006
對外發佈

ASJC Scopus subject areas

  • 血液學

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