Abstract
Brain-derived neurotrophic factor (BDNF) is secreted as either a mature furin-processed form or an unprocessed pro-form. Here, we characterise the extracellular processing of pro-BDNF by the serine protease plasmin. Using recombinant BDNF, maintained in the pro-form by site-directed mutagenesis or inhibition of furin, we demonstrate that plasmin (but not related proteases) is a specific and efficient activator of pro-BDNF. The proteolytic cleavage site is identified as Arg125-Val, within the consensus furin-cleavage motif (RVRR), generating an active form that stimulated neurite outgrowth on TrkB-transfected PC12 cells. Furthermore, we demonstrate that this processing can also occur in the pericellular environment by the action of cell-associated plasminogen activators.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain-Derived Neurotrophic Factor / chemistry
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism*
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Cell Membrane / metabolism
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Fibrinolysin / chemistry
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Fibrinolysin / metabolism*
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Furin / antagonists & inhibitors
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Furin / chemistry
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Humans
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Male
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Mutagenesis, Site-Directed
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Neurites / drug effects
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Neurites / physiology
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PC12 Cells
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Protein Precursors / chemistry
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Protein Precursors / genetics
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Protein Precursors / metabolism*
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Rats
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Receptor, trkB / agonists
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Receptor, trkB / genetics
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Receptor, trkB / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Protein Precursors
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Recombinant Proteins
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brain-derived neurotrophic factor precursor
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Receptor, trkB
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Fibrinolysin
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Furin