Regulation of plasminogen activation: a role for melanotransferrin (p97) in cell migration.
We recently reported that human recombinant melanotransferrin (p97) presents a high transport rate across the blood-brain barrier that might involve the low-density lipoprotein receptor-related protein (LRP). We now report new interactions between p97 and another LRP ligand, the urokinase plasminogen activator (uPA) complex. By using biospecific interaction analysis, both pro-uPA and plasminogen are shown to interact with immobilized p97. Moreover, the activation of plasminogen by pro-uPA is increased by soluble p97. Because the uPA system plays a crucial role in cell migration, both in cancer and in angiogenesis, we also measured the impact of both endogenous membrane-bound and exogenous p97 on cell migration. The monoclonal antibody L235 (which recognizes a conformational epitope on p97) inhibited the migration of human microvascular endothelial cells (HMECs-1) and of human melanoma SK-MEL-28 cells, indicating that endogenous membrane-bound p97 could be associated with this process. In addition, low concentrations of exogenous p97 (10 and 100 nM) inhibited HMEC-1 and SK-MEL28 cell migration by more than 50%. These results indicate that membrane-bound and soluble p97 affect the migration capacity of endothelial and melanoma cells and suggest that p97 could be involved in the regulation of plasminogen activation by interacting with pro-uPA and plasminogen.
Demeule
Michel
M
Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-UQAM, CP 8888, Succ Centre-ville, Montréal, QC, Canada H3C 3P8.
Bertrand
Yanick
Y
Michaud-Levesque
Jonathan
J
Jodoin
Julie
J
Rolland
Yannève
Y
Gabathuler
Reinhard
R
Béliveau
Richard
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000951:Antigens, Neoplasm; D001253:Astrocytes / Q000166:cytology; D001812:Blood-Brain Barrier / Q000502:physiology; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008545:Melanoma; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000378:metabolism / Q000493:pharmacokinetics*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism*; D051381:Rats; D012995:Solubility; D014407:Tumor Cells, Cultured / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator