title: Potential role of kringle-integrin interaction in plasmin and uPA actions (a hypothesis).
abstract: We previously showed that the kringle domains of plasmin and angiostatin, the N-terminal four kringles (K1-4) of plasminogen, directly bind to integrins. Angiostatin blocks tumor-mediated angiogenesis and has great therapeutic potential. Angiostatin binding to integrins may be related to the antiinflammatory action of angiostatin. We reported that plasmin induces signals through protease-activated receptor (PAR-1), and plasmin-integrin interaction may be required for enhancing plasmin concentration on the cell surface, and enhances its signaling function. Angiostatin binding to integrin does not seem to induce proliferative signals. One possible mechanism of angiostatin's inhibitory action is that angiostatin suppresses plasmin-induced PAR-1 activation by competing with plasmin for binding to integrins. Interestingly, plasminogen did not interact with αvβ3, suggesting that the αvβ3-binding sites in the kringle domains of plasminogen are cryptic. The kringle domain of urokinase-type plasminogen activator (uPA) also binds to integrins. The uPA-integrin interaction enhances uPA concentrations on the cell surface and enhances plasminogen activation on the cell surface. It is likely that integrins bind to the kringle domain, and uPAR binds to the growth factor-like domain (GFD) of uPA simultaneously, making the uPAR-uPA-integrin ternary complex. We present a docking model of the ternary complex.
authors.affiliation: Department of Dermatology, and Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Research III Suite 3300, 4645 Second Avenue, Sacramento, CA 95817, USA. ytakada@ucdavis.edu
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D005341:Fibrinolysin / Q000737:chemistry* / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D018082:Kringles; D008954:Models, Biological; D008958:Models, Molecular; D018375:Neutrophil Activation; D011485:Protein Binding; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D039302:Integrin alphaVbeta3; D016023:Integrins; D055293:Receptors, Urokinase Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator