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Human ProNGF: biological effects and binding profiles at TrkA, P75 NTR and sortilin
Author(s) -
Clewes Oliver,
Fahey Mark S.,
Tyler Sue J.,
Watson Judy J.,
Seok Heon,
Catania Caterina,
Cho Kwangwook,
Dawbarn David,
Allen Shelley J.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05698.x
Subject(s) - tropomyosin receptor kinase a , nerve growth factor , low affinity nerve growth factor receptor , neurotrophin , neurite , chemistry , receptor , microbiology and biotechnology , biology , biochemistry , in vitro
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.