The pro-neurotrophins are rapidly cleaved intra-cellularly by furin or the pro-protein convertases at a highly conserved site, to produce the mature protein of 12-14 kDa in size (mature NGF or beta-NGF: 12.5 kDa). Furin, PACE4 and PC7 belong to the constitutive secretory pathway; NEC1/PC1, NEC2/PC2, PC4 and PC5 are instead targeted to regulated secretory granules. Furin is expressed ubiquitously in all tissues, whereas NEC1 and NEC2 are the dominant pro-protein convertases in neurons. The mature neurotrophins can be stored within neurons and released extra-cellularly upon stimulation.
Cells, however, appear to have a limited capacity to process pro-neurotrophins, a capacity that may be exhausted when they are produced in excess (Matsumoto T et al, 2008). In this case, the proforms of NGF and BDNF are secreted and cleaved extracellularly by the serine protease plasmin and by selective matrix metalloproteinases (MMPs). The signalling capacities of pro-neurotrophins and mature neurotrophins are markedly different. The pro-neurotrophins are high affinity ligands for p75NTR and can induce p75NTR dependent apoptosis in cultured neurons with minimal activation of TRK receptor mediated differentiation or survival. The biological action of neurotrophins may thus be regulated by proteolytic cleavage, with proforms preferentially activating p75NTR to mediate apoptosis and mature forms activating TRK receptors to promote survival.
It is possible that pro-neurotrophins may somehow be released during development and eliminate neurons in a p75NTR dependent fashion. Substantial quantities of proNGF are found in the cerebrospinal fluid of adult rodents after brain injury, perhaps following NGF expression by inflammatory cells that may not efficiently process pro-neurotrophins. When proBDNF is added as recombinant protein, activation of p75NTR by proBDNF facilitates hippocampal long-term depression (LTD; Woo NH et al, 2005). However, it is unclear whether proBDNF plays any role in LTD under physiological conditions.