Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains

René Bager; Thomas K. Kristensen; Jan Jensen; Agnieszka Szczur; Anni Christensen; Lisbeth Andersen; Jesper Sanderhoff Johansen; Niels Larsen; Erik Baatrup; Mingdong Huang; Michael Ploug; Peter A. Andreasen

doi:10.1074/jbc.M112.369207

Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains

René Bager, Thomas K. Kristensen, Jan Jensen, Agnieszka Szczur, Anni Christensen, Lisbeth Andersen, Jesper Sanderhoff Johansen, Niels Larsen, Erik Baatrup, Mingdong Huang, Michael Ploug, Peter A. Andreasen

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Abstract

Plasminogen activation catalyzed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodeling 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-catalyzed 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 characterized two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyze 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 with 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-catalyzed 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-catalyzed plasminogen activation in fish may occur mainly in solution. Studies with nonmammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation.

Original language	English
Journal	The Journal of Biological Chemistry
Volume	287
Issue number	33
Pages (from-to)	27526-27536
Number of pages	11
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M112.369207
Publication status	Published - 10 Aug 2012

Keywords

Animals
Base Sequence
Cloning, Molecular
Molecular Sequence Data
Plasminogen
Plasminogen Activator Inhibitor 1
Protein Structure, Tertiary
Urokinase-Type Plasminogen Activator
Zebrafish
Zebrafish Proteins

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Bager, R., Kristensen, T. K., Jensen, J., Szczur, A., Christensen, A., Andersen, L., Johansen, J. S., Larsen, N., Baatrup, E., Huang, M., Ploug, M., & Andreasen, P. A. (2012). Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains. The Journal of Biological Chemistry, 287(33), 27526-27536. https://doi.org/10.1074/jbc.M112.369207

Bager, R, Kristensen, TK, Jensen, J, Szczur, A, Christensen, A, Andersen, L, Johansen, JS, Larsen, N, Baatrup, E, Huang, M, Ploug, M & Andreasen, PA 2012, 'Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains', The Journal of Biological Chemistry, vol. 287, no. 33, pp. 27526-27536. https://doi.org/10.1074/jbc.M112.369207

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title = "Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains",

abstract = "Plasminogen activation catalyzed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodeling 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-catalyzed 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 characterized two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyze 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 with 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-catalyzed 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-catalyzed plasminogen activation in fish may occur mainly in solution. Studies with nonmammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation.",

keywords = "Animals, Base Sequence, Cloning, Molecular, Molecular Sequence Data, Plasminogen, Plasminogen Activator Inhibitor 1, Protein Structure, Tertiary, Urokinase-Type Plasminogen Activator, Zebrafish, Zebrafish Proteins",

author = "Ren{\'e} Bager and Kristensen, {Thomas K.} and Jan Jensen and Agnieszka Szczur and Anni Christensen and Lisbeth Andersen and Johansen, {Jesper Sanderhoff} and Niels Larsen and Erik Baatrup and Mingdong Huang and Michael Ploug and Andreasen, {Peter A.}",

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doi = "10.1074/jbc.M112.369207",

language = "English",

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T1 - Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains

AU - Bager, René

AU - Kristensen, Thomas K.

AU - Jensen, Jan

AU - Szczur, Agnieszka

AU - Christensen, Anni

AU - Andersen, Lisbeth

AU - Johansen, Jesper Sanderhoff

AU - Larsen, Niels

AU - Baatrup, Erik

AU - Huang, Mingdong

AU - Ploug, Michael

AU - Andreasen, Peter A.

PY - 2012/8/10

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N2 - Plasminogen activation catalyzed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodeling 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-catalyzed 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 characterized two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyze 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 with 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-catalyzed 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-catalyzed plasminogen activation in fish may occur mainly in solution. Studies with nonmammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation.

AB - Plasminogen activation catalyzed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodeling 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-catalyzed 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 characterized two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyze 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 with 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-catalyzed 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-catalyzed plasminogen activation in fish may occur mainly in solution. Studies with nonmammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation.

KW - Animals

KW - Base Sequence

KW - Cloning, Molecular

KW - Molecular Sequence Data

KW - Plasminogen

KW - Plasminogen Activator Inhibitor 1

KW - Protein Structure, Tertiary

KW - Urokinase-Type Plasminogen Activator

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1074/jbc.M112.369207

DO - 10.1074/jbc.M112.369207

M3 - Journal article

C2 - 22733817

SN - 0021-9258

VL - 287

SP - 27526

EP - 27536

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 33

ER -

Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains

Abstract

Keywords

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