Selective inhibition by kringle 5 of human plasminogen on endothelial cell migration, an important process in angiogenesis.
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.
Ji
W R
WR
Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceuticals, Inc., Provinceline & Route 206, Princeton, New Jersey, 08543, USA.
Barrientos
L G
LG
Llinás
M
M
Gray
H
H
Villarreal
X
X
DeFord
M E
ME
Castellino
F J
FJ
Kramer
R A
RA
Trail
P A
PA
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
D017931:DNA Primers; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen