Activation of pro-BDNF by the pericellular serine protease plasmin.
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.
Gray
Kelly
K
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Ellis
Vincent
V
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism*; D045683:Furin / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D011994:Recombinant Proteins; C426674:brain-derived neurotrophic factor precursor; D020813:Receptor, trkB; D005341:Fibrinolysin; D045683:Furin