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

被引：72

作者：

Clewes, Oliver ^{[1
]}

Fahey, Mark S. ^{[1
]}

Tyler, Sue J. ^{[1
]}

Watson, Judy J. ^{[1
]}

Seok, Heon ^{[1
]}

Catania, Caterina ^{[1
]}

Cho, Kwangwook ^{[1
]}

Dawbarn, David ^{[1
]}

Allen, Shelley J. ^{[1
]}

机构：

[1] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England

来源：

JOURNAL OF NEUROCHEMISTRY | 2008年 / 107卷 / 04期

基金：

英国生物技术与生命科学研究理事会;

关键词：

nerve growth factor; neurotrophin; p75(NTR); pro nerve growth factor; sortilin; tyrosine kinase receptor A;

D O I：

10.1111/j.1471-4159.2008.05698.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

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.

引用

页码：1124 / 1135

页数：12

共 37 条

[1]

Recombinant human nerve growth factor for clinical trials: protein expression, purification, stability and characterisation of binding to infusion pumps [J].