Expression and Processing of Neurotrophins

Stable Identifier
R-HSA-9036866
Type
Pathway
Species
Homo sapiens
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Neurotrophins function as ligands for receptor tyrosine kinases of the NTRK (TRK) family, as well as the death receptor NGFR (p75NTR). While all four neurotrophins, NGF, BDNF, NTF3 (NT-3) and NTF4 (NT-4, NT-5, NTF5) can bind to and activate NGFR, they show different specificity for NTRKs. NGF exclusively activates NTRK1 (TRKA). BDNF and NTF4 are high affinity ligands for NTRK2 (TRKB). NTF3 is a high affinity ligand for NTRK3 (TRKC) and a low affinity ligand for NTRK2. Neurotrophins play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. For review, please refer to Lessmann et al. 2003, Chao 2003, and Park and Poo 2013.
Human NGF, also knowns as the nerve growth factor, is encoded by a gene on chromosome 1, which produces a single transcript. Nascent NGF protein, pre-pro-NGF, is 241 amino acids long. As pre-pro-NGF enters the endoplasmic reticulum (ER), the signal peptide, consisting of eighteen amino acids at the N-terminus, is cleaved, producing pro-NGF. Two molecules of pro-NGF form homodimers in the ER. After transport of pro-NGF homodimers to the Golgi, 103 amino acids at the N-terminus of pro-NGF are cleaved, producing mature NGF homodimers. Both pro-NGF homodimers and mature NGF homodimers are secreted to the extracellular space. Mature NGF homodimers activate NTRK1 signaling, while NGFR signaling can be activated by both mature and pro-NGF homodimers. Secreted pro-NGF homodimers may be cleaved by extracellular matrix proteases to produce mature NGF homodimers. For review, please refer to Poo 2001, Lu et al. 2005, Skaper et al. 2012, Bradshaw et al. 2015.
Human BDNF, also known as brain-derived neurotrophic factor, is encoded by a gene on chromosome 11, which, through the use of 9 alternative promoters and alternative splicing, produces 17 protein-coding transcripts. Most BDNF transcripts result in the same pre-pro-BDNF protein of 247 amino acids, but alternative promoters and different 5' and 3’UTRs allow to fine-tune regulation of BDNF expression at different developmental stages and at different levels of neuronal activity. Similar to NGF, pre-pro-BDNF is processed by proteolytic cleavage in the ER to produce pro-BDNF homodimers. It is unclear whether proteolytic processing of pro-BDNF, to produce mature BDNF homodimers, occurs in the Golgi or in the secretory granules. Extracellular matrix proteases can also cleave secreted pro-BDNF to produce mature BDNF homodimers. Secreted mature BDNF homodimers can activate NTRK2 signaling, while secreted pro-BDNF homodimers can activate NGFR signaling. For review, please refer to Poo 2001, Lu et al. 2005, Skaper et al. 2012, Park and Poo 2013.
Human NTF4, also known as neurotrophin-4, is transcribed from a gene on chromosome 19. A single experimentally confirmed transcript produces a pre-pro-NTF4 protein of 210 amino acids. After proteolytic processing in the ER and Golgi, mature NTF4 homodimers are secreted and can activate NTRK2 signaling (Hibbert et al. 2003). For review, please refer to Poo 2001, Skaper et al. 2012.
Human NTF3, also known as neurotrophin-3, is transcribed from a gene on chromosome 12. Two NTF3 transcripts have been experimentally confirmed, but only the longer NTF3 splice variant of 270 amino acids has been studied. After proteolytic processing in the ER and Golgi, mature NTF3 homodimers are secreted and can activate NTRK3 signaling (Seidah et al. 1996, Farhadi et al. 2000). For review, please refer to Poo 2001, Skaper et al. 2012.

Literature References
PubMed ID Title Journal Year
16062169 The yin and yang of neurotrophin action

Lu, B, Pang, PT, Woo, NH

Nat. Rev. Neurosci. 2005
23254191 Neurotrophin regulation of neural circuit development and function

Park, H, Poo, MM

Nat. Rev. Neurosci. 2013
12671646 Neurotrophins and their receptors: a convergence point for many signalling pathways

Chao, MV

Nat Rev Neurosci 2003
25491371 NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling

Bradshaw, RA, Pundavela, J, Biarc, J, Chalkley, RJ, Burlingame, AL, Hondermarck, H

Adv Biol Regul 2015
22367796 The neurotrophin family of neurotrophic factors: an overview

Skaper, SD

Methods Mol. Biol. 2012
8603699 Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases

Seidah, NG, Benjannet, S, Pareek, S, Chrétien, M, Murphy, RA

FEBS Lett. 1996
12787574 Neurotrophin secretion: current facts and future prospects

Lessmann, V, Gottmann, K, Malcangio, M

Prog Neurobiol 2003
12970359 Neurotrophin-4, alone or heterodimerized with brain-derived neurotrophic factor, is sorted to the constitutive secretory pathway

Hibbert, AP, Morris, SJ, Seidah, NG, Murphy, RA

J. Biol. Chem. 2003
10818141 Neurotrophin-3 sorts to the constitutive secretory pathway of hippocampal neurons and is diverted to the regulated secretory pathway by coexpression with brain-derived neurotrophic factor

Farhadi, HF, Mowla, SJ, Petrecca, K, Morris, SJ, Seidah, NG, Murphy, RA

J. Neurosci. 2000
11253356 Neurotrophins as synaptic modulators

Poo, MM

Nat. Rev. Neurosci. 2001
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