title: Selective inhibition by kringle 5 of human plasminogen on endothelial cell migration, an important process in angiogenesis.
abstract: Angiogenesis is a multi-step process that includes endothelial cell proliferation, migration, basement membrane degradation, and new lumen organization. Angiostatin, an internal fragment of plasminogen comprising the first four triple disulfide-linked kringle structures, is one of the most potent endogenous angiogenesis inhibitors described to date. The kringle 5 domain of plasminogen, which shares high sequence homology with the four kringles of angiostatin, was previously shown to antagonize endothelial cell growth. We now describe that the recombinant kringle 5 of human plasminogen inhibits endothelial cell migration with an IC50 (concentration for half maximal inhibition) of approximately 500 nM. We demonstrate that the lysine-binding sites of kringle 5 may not be involved in its anti-migratory activities. The anti-migratory activity of kringle 5 is similar to that of angiostatin. Kringle 5 also shows selective inhibition on endothelial cells as opposed to other cell types. Relative to its native form, reduced kringle 5 displays a significant increase in anti-migratory activity, implying that the kringle conformation may shield kringle 5 from effectively interacting with endothelial cells. This report thus constitutes the first demonstration that kringle 5 of plasminogen is a selective inhibitor for endothelial cell migration.
authors.affiliation: Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceuticals, Inc., Provinceline & Route 206, Princeton, New Jersey, 08543, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Ji
authors.forename: L G
authors.initials: LG
authors.lastname: Barrientos
authors.forename: M
authors.initials: M
authors.lastname: Llinás
authors.forename: H
authors.initials: H
authors.lastname: Gray
authors.forename: X
authors.initials: X
authors.lastname: Villarreal
authors.forename: M E
authors.initials: ME
authors.lastname: DeFord
authors.forename: F J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: R A
authors.initials: RA
authors.lastname: Kramer
authors.forename: P A
authors.initials: PA
authors.lastname: Trail
mesh_terms: D000595:Amino Acid Sequence; D043168:Angiostatins; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D018082:Kringles; D051379:Mice; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen