Limited proteolysis of angiogenin by elastase is regulated by plasminogen.
Human neutrophil elastase cleaves angiogenin at the Ile-29/Met-30 peptide bond to produce two major disulfide-linked fragments with apparent molecular weights of 10,000 and 4000, respectively. Elastase-cleaved angiogenin has slightly increased ribonucleolytic activity, but has lost its ability to undergo nuclear translocation in endothelial cells, a process essential for angiogenic activity. Cleavage appears to alter the cell-binding properties of angiogenin, despite the fact that it occurs some distance from the putative receptor-binding site, since the elastase-cleaved protein fails to compete with its native counterpart for nuclear translocation in endothelial cells. Plasminogen specifically accelerates elastase proteolysis of angiogenin. It does not enhance elastase activity toward ribonuclease A or the synthetic peptide substrate MeOSuc-Ala-Ala-Pro-Val-pNA. Plasminogen-accelerated inactivation of angiogenin by elastase might be a significant event in the process of angiogenin-induced angiogenesis since (i) angiogenin and plasminogen circulate in plasma at high concentrations, (ii) angiogenin, especially when bound to actin, activates tissue plasminogen activator to generate plasmin from plasminogen, and (iii) elastase cleaves plasminogen to produce angiostatin, a potent inhibitor of angiogenesis and metastasis. Interrelationships among angiogenin, plasminogen, plasminogen activators, elastase, and angiostatin may provide a sensitive regulatory system to balance angiogenesis and antiangiogenesis.
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Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. guofuhu@warren.med.harvard.edu
D000595:Amino Acid Sequence; D001665:Binding Sites; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009504:Neutrophils / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism; D010958:Plasminogen / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D012331:RNA, Fungal / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D011994:Recombinant Proteins; D012259:Ribonuclease, Pancreatic; D014469:Umbilical Arteries
D010446:Peptide Fragments; D011506:Proteins; D012331:RNA, Fungal; D011994:Recombinant Proteins; D010958:Plasminogen; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D019272:Leukocyte Elastase