Activation of pro-BDNF by the pericellular serine protease plasmin

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.

Abbreviations: BDNF, brain-derived neurotrophic factor, wtBDNF, wild-type BDNF, mtBDNF, mutated BDNF, NGF, nerve growth factor, uPA, urokinase plasminogen activator, uPAR, uPA receptor, Dec-RVKR-CMK, decanoyl-Arg-Val-Lys-Arg-chloromethylketone

Keywords: BDNF, Furin, Neurotrophin, Plasmin, Proteolytic processing