NGF processing (Homo sapiens)

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Bibliography

1. Seidah NG, Benjannet S, Pareek S, Savaria D, Hamelin J, Goulet B, Laliberte J, Lazure C, Chrétien M, Murphy RA.; ''Cellular processing of the nerve growth factor precursor by the mammalian pro-protein convertases.''; PubMed Europe PMC Scholia
2. Sofroniew MV, Howe CL, Mobley WC.; ''Nerve growth factor signaling, neuroprotection, and neural repair.''; PubMed Europe PMC Scholia
3. Friedman WJ, Greene LA.; ''Neurotrophin signaling via Trks and p75.''; PubMed Europe PMC Scholia
4. Reichardt LF.; ''Neurotrophin-regulated signalling pathways.''; PubMed Europe PMC Scholia
5. Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMed Europe PMC Scholia
6. Kaplan DR, Miller FD.; ''Neurotrophin signal transduction in the nervous system.''; PubMed Europe PMC Scholia
7. Chao MV.; ''Neurotrophins and their receptors: a convergence point for many signalling pathways.''; PubMed Europe PMC Scholia
8. Huang EJ, Reichardt LF.; ''Trk receptors: roles in neuronal signal transduction.''; PubMed Europe PMC Scholia
9. Lessmann V, Gottmann K, Malcangio M.; ''Neurotrophin secretion: current facts and future prospects.''; PubMed Europe PMC Scholia
10. Arévalo JC, Wu SH.; ''Neurotrophin signaling: many exciting surprises!''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
FURIN	Protein	P09958 (Uniprot-TrEMBL)
NGF	Protein	P01138 (Uniprot-TrEMBL)
NGF(1-241)	Protein	P01138 (Uniprot-TrEMBL)
NGF(19-241)	Protein	P01138 (Uniprot-TrEMBL)
NGF(19-241)	Protein	P01138 (Uniprot-TrEMBL)
PCSK5(115-913)	Protein	Q92824 (Uniprot-TrEMBL)
PCSK6	Protein	P29122 (Uniprot-TrEMBL)
Signaling by NTRK1 (TRKA)	Pathway	R-HSA-187037 (Reactome)	Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins.
Subtilisin/kexin convertase (Calcium dependant)	Complex	R-HSA-166611 (Reactome)
mature beta-NGF homodimer	Complex	R-HSA-187017 (Reactome)
mature beta-NGF homodimer	Complex	R-HSA-187031 (Reactome)
p75 NTR receptor-mediated signalling	Pathway	R-HSA-193704 (Reactome)	Besides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a number of downstream signalling events controlling survival, death, proliferation, and axonogenesis, according to the cellular context. p75NTR is devoid of enzymatic activity, and signals by recruiting other proteins to its own intracellular domain. p75 interacting proteins include NRIF, TRAF2, 4, and 6, NRAGE, necdin, SC1, NADE, RhoA, Rac, ARMS, RIP2, FAP and PLAIDD. Here we annotate only the proteins for which a clear involvement in p75NTR signalling was demonstrated. A 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.
pro-beta-NGF homodimer	Complex	R-HSA-166554 (Reactome)
pro-beta-NGF homodimer	Complex	R-HSA-187028 (Reactome)
pro-beta-NGF homodimer	Complex	R-HSA-187029 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
NGF(1-241)			R-HSA-187045 (Reactome)
	NGF(19-241)	Arrow	R-HSA-187045 (Reactome)
NGF(19-241)			R-HSA-167047 (Reactome)
			R-HSA-167014 (Reactome)	From the endoplasmic reticulum, the pro-neurotrophins transit to the golgi apparatus, most likely via intermediate non-clathrin-coated transport vesicles, and finally accumulate in the trans-golgi network (TGN). In the TGN, two different types of secretory vesicles can be generated and filled with neurotrophins: regulated and constitutive secretory vesicles.
			R-HSA-167047 (Reactome)	The pro-neurotrophin (pro-NGF: 27 kDa) spontaneously forms stable, non-covalent dimers directly in the ER. The homodimer is associated by noncovalent forces, with an equilibrium dissociation constant of 10 pM. The neurotrophin pro- domain is important for proper folding and intracellular sorting. Heterodimers of different neurotrophin monomers can also be generated at the ER.
			R-HSA-187020 (Reactome)	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.
			R-HSA-187035 (Reactome)	Both mature neurotrophin and pro-neurotrophin are released extracellularly and are biologically active. The precursor proNGF, instead of mNGF (mature NGF), is the molecular form preferentially released by neurons in an activity-dependent manner. Neurotrophins are secreted in low amounts from several tissues, mainly from target tissues of innervating neurons. In the nervous system, they are secreted by neurons, astrocytes and microglia. Neurotrophin secretion can be both constitutive and regulated. Constitutive release is observed in cells lacking a regulated pathway, and additional stimulus-dependent regulated secretion is evident in those cells where this route is available. Secretion is regulated by a number of stimuli, including neurotrophins themselves. In neurons, regulated secretion appears to be the prevalent pathway. NGF is secreted from the cell soma and the dendrites, while it is unclear whether it can also be secreted by axons. Constitutive secretion of NGF is observed only from the soma and the most proximal dendrites. Similar considerations hold for the other neurotrophins as well.
			R-HSA-187045 (Reactome)	Pre-pro- precursors of the neurotrophins NGF, BDNF, NT-3, NT-4/5 are synthesized in various cell types by endoplasmic reticulum (ER) attached ribosomes, leading to sequestration of the newly formed polypeptide chain into the ER. The mouse NGF gene gives rise to two major transcripts that contain NGF (12.5 kDa) at the C-terminus and differ by alternative splicing of an N-terminal exon, so that the large precursor (34 kDa) has 67 amino acids upstream of an internal signal peptide and the smaller precursor (27 kDa) has this signal peptide at its N-terminus. The transcript for the large precursor predominates in the submaxillary gland, whereas the transcript for the smaller precursor predominates in virtually all other tissues. 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.
Subtilisin/kexin convertase (Calcium dependant)		mim-catalysis	R-HSA-187020 (Reactome)
	mature beta-NGF homodimer	Arrow	R-HSA-187020 (Reactome)
	mature beta-NGF homodimer	Arrow	R-HSA-187035 (Reactome)
mature beta-NGF homodimer			R-HSA-187035 (Reactome)
	pro-beta-NGF homodimer	Arrow	R-HSA-167014 (Reactome)
	pro-beta-NGF homodimer	Arrow	R-HSA-167047 (Reactome)
	pro-beta-NGF homodimer	Arrow	R-HSA-187035 (Reactome)
pro-beta-NGF homodimer			R-HSA-167014 (Reactome)
pro-beta-NGF homodimer			R-HSA-187020 (Reactome)
pro-beta-NGF homodimer			R-HSA-187035 (Reactome)