title: Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation.
abstract: BACKGROUND
  The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R).
  
  
  OBJECTIVE
  Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system.
  
  
  RESULTS
  By using specific inhibitors and RNA interference, we show that the tumor necrosis factor α convertase (TACE, ADAM-17) mediates the release of the ectodomain of M6P/IGF2R from human endothelial cells. We demonstrate further that sM6P/IGF2R binds plasminogen (Plg) and thereby prevents Plg from binding to the cell surface and uPA, ultimately inhibiting in this manner Plg activation. Furthermore, peptide 18-36 derived from the Plg-binding site of M6P/IGF2R mimics sM6P/IGF2R in the inhibition of Plg activation and blocks cancer cell invasion in vitro, endothelial cell invasion in vivo, and tumor growth in vivo.
  
  
  CONCLUSIONS
  The interaction of sM6P/IGF2R with Plg may be an important regulatory mechanism to inhibit migration of cells using the uPA/uPAR system.
authors.affiliation: Molecular Immunology Unit, Pathophysiology, Infectiology & Immunology, Medical University of Vienna, Austria. vladimir.leksa@meduniwien.ac.at
authors.forename: Vladimir
authors.initials: V
authors.lastname: Leksa
authors.forename: Robert
authors.initials: R
authors.lastname: Loewe
authors.forename: Brigitte
authors.initials: B
authors.lastname: Binder
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Schiller
authors.forename: Paul
authors.initials: P
authors.lastname: Eckerstorfer
authors.forename: Florian
authors.initials: F
authors.lastname: Forster
authors.forename: Ana
authors.initials: A
authors.lastname: Soler-Cardona
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ondrovicová
authors.forename: Eva
authors.initials: E
authors.lastname: Kutejová
authors.forename: Eva
authors.initials: E
authors.lastname: Steinhuber
authors.forename: Johannes
authors.initials: J
authors.lastname: Breuss
authors.forename: Johannes
authors.initials: J
authors.lastname: Drach
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
authors.forename: Hannes
authors.initials: H
authors.lastname: Stockinger
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002678:Chimera; D042783:Endothelial Cells / Q000502:physiology*; D006128:Growth; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010958:Plasminogen / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D012995:Solubility; D014471:Umbilical Veins; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D017527:Receptor, IGF Type 2; D055293:Receptors, Urokinase Plasminogen Activator; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse