Human ProNGF: biological effects and binding profiles at TrkA, P75NTR and sortilin

O Clewes, MS Fahey, SJ Tyler, JJ Watson, H Seok, C Catania, K Cho, D Dawbarn, S J Allen

Research output: Contribution to journalArticle (Academic Journal)

62 Citations (Scopus)

Abstract

Nerve growth factor (NGF) promotes cell survival via binding to the tyrosine kinase receptor A (TrkA). Its precursor, proNGF, binds to p75(NTR) and sortilin receptors to initiate apoptosis. Current disagreement exists over whether proNGF acts neurotrophically following binding to TrkA. As in Alzheimer's disease the levels of proNGF increase and TrkA decrease, it is important to clarify the properties of proNGF. Here, wild-type and cleavage-resistant mutated forms (M) of proNGF were engineered and their binding characteristics determined. M-proNGF and NGF bound to p75(NTR) with similar affinities, whilst M-proNGF had a lower affinity than NGF for TrkA. M-proNGF behaved neurotrophically, albeit less effectively than NGF. M-proNGF addition resulted in phosphorylation of TrkA and ERK1/2, and in PC12 cells elicited neurite outgrowth and supported cell survival. Conversely, M-proNGF addition to cultured cortical neurons initiated caspase 3 cleavage. Importantly, these biological effects were shown to be mediated by unprocessed M-proNGF. Surprisingly, binding of the pro region alone to TrkA, at a site other than that of NGF, caused TrkA and ERK1/2 phosphorylation. Our data show that M-proNGF stimulates TrkA to a lesser degree than NGF, suggesting that in Alzheimer brain the increased proNGF : NGF and p75(NTR) : TrkA ratios may permit apoptotic effects to predominate over neurotrophic effects.
Translated title of the contributionHuman ProNGF: biological effects and binding profiles at TrkA, P75NTR and sortilin
Original languageEnglish
Pages (from-to)1124 - 1135
Number of pages12
JournalJournal of Neurochemistry
Volume107
Issue number4
Early online date20 Sep 2008
DOIs
Publication statusPublished - Nov 2008

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    Clewes, O., Fahey, MS., Tyler, SJ., Watson, JJ., Seok, H., Catania, C., Cho, K., Dawbarn, D., & Allen, S. J. (2008). Human ProNGF: biological effects and binding profiles at TrkA, P75NTR and sortilin. Journal of Neurochemistry, 107(4), 1124 - 1135. https://doi.org/10.1111/j.1471-4159.2008.05698.x