title: Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation.
abstract: 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 alpha v beta 3 on CHO cells depleted of uPAR. The binding of uPA to alpha v beta 3 required the uPA kringle domain. The isolated uPA kringle domain binds specifically to purified, recombinant soluble, and cell surface alpha v beta 3, and other integrins (alpha 4 beta 1 and alpha 9 beta 1), and induced migration of CHO cells in an alpha v beta 3-dependent manner. The binding of the uPA kringle to alpha v beta 3 and uPA kringle-induced alpha v beta 3-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 alpha v beta 3 through the kringle domain plays a role in plasminogen activation. On CHO cell depleted of uPAR, uPA enhanced plasminogen activation in a kringle and alpha v beta 3-dependent manner. Endothelial cells bound to and migrated on uPA and uPA kringle in an alpha v beta 3-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.
authors.affiliation: Department of Dermatology, UC Davis Medical Center, Research III, Sacramento, CA 95817, USA.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Tarui
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Akakura
authors.forename: Mousumi
authors.initials: M
authors.lastname: Majumdar
authors.forename: Nicholas
authors.initials: N
authors.lastname: Andronicos
authors.forename: Junichi
authors.initials: J
authors.lastname: Takagi
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.forename: Alice
authors.initials: A
authors.lastname: Kuo
authors.forename: Serge V
authors.initials: SV
authors.lastname: Yarovoi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D043168:Angiostatins / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000187:drug effects / Q000648:ultrastructure; D039302:Integrin alphaVbeta3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018082:Kringles; D010958:Plasminogen / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000172:deficiency; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator