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Endostatin in the Regulation of Endothelial Cell Œ Helsinki University Biomedical Dissertations No. 51 ENDOSTATIN IN THE REGULATION OF ENDOTHELIAL CELL – MATRIX INTERACTIONS AND PERICELLULAR PROTEOLYSIS Sara A. Wickström Departments of Pathology and Virology, Haartman Institute, Helsinki University Hospital and Biomedicum Helsinki University of Helsinki Finland Academic Dissertation To be presented, with the permission of the Faculty of Medicine, University of Helsinki, for public criticism, in the Lecture Hall 3 of the Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, on March 26th, 2004, at 12 o’clock noon Helsinki 2004 Supervised by: Professor Jorma Keski-Oja Departments of Pathology and Virology Biomedicum and Haartman Institute University of Helsinki Helsinki, Finland Reviewed by: Professor Ismo Virtanen Department of Biomedicine and Anatomy Biomedicum Helsinki University of Helsinki Helsinki, Finland and Docent Raija Soininen Department of Biochemistry Biocenter Oulu University of Oulu Oulu, Finland Opponent: Professor Lena Claesson-Welsh Department of Genetics and Pathology Rudbeck Laboratory University of Uppsala Uppsala, Sweden ISSN 147-8433 ISBN 952-10-1723-6 (nid.) ISBN 952-10-1724-4 (PDF) http://ethesis.helsinki.fi Yliopistopaino Helsinki 2004 4 Contents Original publications ............................................................................................ 7 Abbreviations......................................................................................................... 8 Abstract.................................................................................................................. 9 Introduction......................................................................................................... 10 Cell migration and extracellular matrix ............................................................ 10 Extracellular matrix....................................................................................... 10 Basement membranes................................................................................ 11 Mechanisms of cell motility.......................................................................... 13 Integrins and cell-matrix interactions............................................................ 15 Signaling pathways involved in cell migration............................................. 15 Pericellular proteolysis...................................................................................... 17 Plasminogen activators.................................................................................. 17 Urokinase-type plasminogen activator...................................................... 18 Urokinase receptor .................................................................................... 18 Inhibitors of plasminogen activators......................................................... 19 Interplay between proteolysis, signaling, and migration .............................. 20 Vasculogenesis and angiogenesis ..................................................................... 22 Molecular mechanisms of angiogenesis........................................................ 22 Tumor angiogenesis and the angiogenic switch............................................ 23 Role of integrins in angiogenesis .................................................................. 24 Proteolytic cascades in angiogenesis ............................................................ 25 Basement membrane-derived inhibitors of angiogenesis ................................. 26 Fragments of type IV collagen...................................................................... 26 Endostatin...................................................................................................... 28 Structural features ..................................................................................... 28 Biological roles ......................................................................................... 29 Effects of endostatin on tumor growth...................................................... 30 Cell surface receptors................................................................................ 32 Mechanisms of action ............................................................................... 33 Angiogenesis inhibitors in cancer therapy .................................................... 34 Aims of the present study ................................................................................... 36 Materials and methods ....................................................................................... 37 Cell culture and treatments............................................................................ 37 Expression and characterization of human endostatin.................................. 37 Growth factors, chemicals, and enzymes...................................................... 37 Antibodies ..................................................................................................... 38 SDS-PAGE and immunoblotting .................................................................. 38 Casein zymography and reverse zymography............................................... 38 Immunoprecipitation..................................................................................... 39 Immunofluorescence..................................................................................... 39 Cell adhesion assays...................................................................................... 40 In vitro chemotaxis assay.............................................................................. 40 Isolation of the extracellular matrix .............................................................. 40 5 Isolation of detergent-insoluble membrane fractions.................................... 41 Affinity precipitation of GTP-Rho................................................................ 41 Src family kinase autophosphorylation assay. .............................................. 41 Metabolic labeling......................................................................................... 42 Wound-induced migration assay................................................................... 42 Endothelial cell tube formation assay ........................................................... 42 Results .................................................................................................................. 43 Endostatin regulates levels of secreted soluble uPA/PAI-1 complex and induces changes in cell surface localization of uPA and uPAR (I)................................ 43 Loss of endothelial cell focal adhesions and actin cytoskeleton in endostatin- treated cells (I, II, III)........................................................................................ 44 Association of endostatin with α5β1 integrin and caveolin-1 (II, III)................ 44 Tyrosyl phosphatase-dependent activation of caveolin-1- associated Src regulates endostatin-induced disassembly of cytoskeleton and decreased deposition of fibronectin matrix (II) ................................................................. 44 Endostatin and α5β1 integrin partition in lipid rafts in a heparan sulfate proteoglycan-dependent manner (III) ............................................................... 45 Endostatin downregulates RhoA activity via Src and p190 (III) ...................... 46 Endostatin-derived peptides promote cell adhesion via integrins and induce disassembly of the cytoskeleton (IV)................................................................ 46 Endostatin-derived peptides inhibit endothelial migration and tubular morphogenesis of endothelial cells (IV) ........................................................... 47 Discussion............................................................................................................. 48 Effects of endostatin on endothelial cell pericellular proteolysis ..................... 48 Regulation of actin cytoskeleton and cell migration by endostatin .................. 49 Requirement of integrin α5β1, heparan sulfate proteoglycans and lipid rafts in endostatin signaling........................................................................................... 51 Identification of an integrin-binding peptide within endostatin........................ 52 A model for endostatin-induced signaling ........................................................ 53 Perspective ........................................................................................................... 55 Acknowledgements.............................................................................................. 56 References ............................................................................................................ 58 6 Original publications This thesis is based on the following original articles, which are referred to by their Roman numerals in the text. I. Wickström, S.A., Veikkola, T., Rehn, M., Pihlajaniemi, T., Alitalo, K., and Keski-Oja, J. Endostatin-induced modulation of plasminogen activation with concomitant loss of focal adhesions and actin stress fibers in human endothelial cell cultures. Cancer Res. 61: 6511-6516, 2001. II. Wickström, S.A., Alitalo, K., and Keski-Oja, J. Endostatin associates with α5β1 integrin and caveolin-1 and activates Src via a tyrosyl phosphatase- dependent pathway in human endothelial cells. Cancer Res. 62: 5580-5589, 2002. III. Wickström, S.A., Alitalo, K., and Keski-Oja, J. Endostatin associates with lipid rafts and induces reorganization
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