NGF processing (Homo sapiens)
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Description
All neurotrophins (NTs) are generated as pre-pro-neurotrophin precursors. The signal peptide is cleaved off as NT is associated with the endoplasmic reticulum (ER). The resulting pro-NT can form a homodimer spontaneously which then transits to the Golgi apparatus and then onto the trans-Golgi network (TGN). Resident protein convertases (PCs) can cleave off the pro-sequence and mature NT is is targeted to constitutively released vesicles. The pro-NT form can also be released to the extracellular region.
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convertase (Calcium
dependant)receptor-mediated
signallingA peculiarity of p75NTR is the ability to bind the pro-neurotrophins proNGF and proBDNF. Proneurotrophins do not associate with TRK receptors, whereas they efficiently signal cell death by apoptosis through p75NTR. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR, mediating apoptosis, and mature forms activating TRK receptors, to promote survival. Moreover, the two receptors are utilised to differentially modulate neuronal plasticity. For instance, proBDNF-p75NTR signalling facilitates LTD, long term depression, in the hippocampus (Woo NH, et al, 2005), while BDNF-TRKB signalling promotes LTP (long term potentiation). Many biological observations indicate a functional interaction between p75NTR and TRKA signaling pathways.
Annotated Interactions
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.
The signal peptide is cleaved off immediately after sequestration into the ER. Therefore, expression of either NGF transcript gives rise to an apparently identical intracellular glycosylated precursor formed by cleavage of the primary gene product after the signal peptide.
convertase (Calcium
dependant)