Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains
- Authors
- Bager, R., Kristensen, T.K., Jensen, J.K., Szczur, A., Christensen, A., Andersen, L.M., Johansen, J.S., Larsen, N., Baatrup, E., Huang, M., Ploug, M., and Andreasen, P.A.
- ID
- ZDB-PUB-120705-7
- Date
- 2012
- Source
- The Journal of biological chemistry 287(33): 27526-27536 (Journal)
- Registered Authors
- Keywords
- evolution, fibrinolysis, plansminogen regulation, serine protease, urokinase receptor, zebrafish
- MeSH Terms
-
- Animals
- Base Sequence
- Cloning, Molecular
- Molecular Sequence Data
- Plasminogen/genetics
- Plasminogen/metabolism*
- Plasminogen Activator Inhibitor 1/genetics
- Plasminogen Activator Inhibitor 1/metabolism*
- Protein Structure, Tertiary
- Urokinase-Type Plasminogen Activator/genetics
- Urokinase-Type Plasminogen Activator/metabolism*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 22733817 Full text @ J. Biol. Chem.
Plasminogen activation catalysed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodelling processes. Since its discovery in the mid-1980s, the cell membrane-anchored urokinase-type plasminogen activator receptor (uPAR) has been believed to be central to the functions of uPA, as uPA-catalysed plasminogen activation activity appeared to be confined to cell surfaces through the binding of uPA to uPAR. However, a functional uPAR has so far only been identified in mammals. We have now cloned, recombinantly produced, and characterised two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyse the activation of fish plasminogen efficiently and both proteases are inhibited rapidly by plasminogen activator inhibitor-1 (PAI-1). But zfuPA-a differs from mammalian uPA by lacking the exon encoding the uPAR-binding epidermal growth factor-like domain; zfuPA-b differs from mammalian uPA by lacking two cysteines of the epidermal growth factor-like domain and a uPAR-binding sequence comparable to that found in mammalian uPA. Accordingly, no zfuPA-b binding activity could be found in fish white blood cells or fish cell lines. We therefore propose that the current consensus of uPA-catalysed plasminogen activation taking place on cell surfaces, derived from observations with mammals, is too narrow. Fish uPAs appear incapable of receptor binding in the manner known from mammals and uPA-catalysed plasminogen activation in fish may occur mainly in solution. Studies with non-mammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation.