title: Biological activity of nerve growth factor precursor is dependent upon relative levels of its receptors.
abstract: Nerve growth factor (NGF) is produced as a precursor called pro-nerve growth factor (proNGF), which is secreted by many tissues and is the predominant form of NGF in the central nervous system. In Alzheimer disease brain, cholinergic neurons degenerate and can no longer transport NGF as efficiently, leading to an increase in untransported NGF in the target tissue. The protein that accumulates in the target tissue is proNGF, not the mature form. The role of this precursor is controversial, and both neurotrophic and apoptotic activities have been reported for recombinant proNGFs. Differences in the protein structures, protein expression systems, methods used for protein purification, and methods used for bioassay may affect the activity of these proteins. Here, we show that proNGF is neurotrophic regardless of mutations or tags, and no matter how it is purified or in which system it is expressed. However, although proNGF is neurotrophic under our assay conditions for primary sympathetic neurons and for pheochromocytoma (PC12) cells, it is apoptotic for unprimed PC12 cells when they are deprived of serum. The ratio of tropomyosin-related kinase A to p75 neurotrophin receptor is low in unprimed PC12 cells compared with primed PC12 cells and sympathetic neurons, altering the balance of proNGF-induced signaling to favor apoptosis. We conclude that the relative level of proNGF receptors determines whether this precursor exhibits neurotrophic or apoptotic activity.
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Raheleh
authors.initials: R
authors.lastname: Masoudi
authors.forename: Maria S
authors.initials: MS
authors.lastname: Ioannou
authors.forename: Michael D
authors.initials: MD
authors.lastname: Coughlin
authors.forename: Promila
authors.initials: P
authors.lastname: Pagadala
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Neet
authors.forename: Oliver
authors.initials: O
authors.lastname: Clewes
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Allen
authors.forename: David
authors.initials: D
authors.lastname: Dawbarn
authors.forename: Margaret
authors.initials: M
authors.lastname: Fahnestock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016367:Baculoviridae / Q000235:genetics; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D018411:Spodoptera; D013564:Sympathetic Nervous System / Q000166:cytology
chemical_list: D016895:Culture Media, Serum-Free; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C489226:pro-nerve growth factor, mouse; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases