title: A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo.
abstract: Nerve growth factor (NGF) is generated from a precursor, proNGF, that is proteolytically processed. NGF preferentially binds a trophic tyrosine kinase receptor, TrkA, while proNGF binds a neurotrophin receptor (NTR), p75(NTR), that can have neurotoxic activity. Previously, we along with others showed that the soluble protein α2-macroglobulin (α2M) is neurotoxic. Toxicity is due in part to α2M binding to NGF and inhibiting trophic activity, presumably by preventing NGF binding to TrkA. However, the mechanisms remained unclear. Here, we show ex vivo and in vivo three mechanisms for α2M neurotoxicity. First, unexpectedly the α2M-NGF complexes do bind TrkA receptors but do not induce TrkA dimerization or activation, resulting in deficient trophic support. Second, α2M makes stable complexes with proNGF, conveying resistance to proteolysis that results in more proNGF and less NGF. Third, α2M-proNGF complexes bind p75(NTR) and are more potent agonists than free proNGF, inducing tumor necrosis factor alpha (TNF-α) production. Hence, α2M regulates proNGF/p75(NTR) positively and mature NGF/TrkA negatively, causing neuronal death ex vivo. These three mechanisms are operative in vivo, and α2M causes neurodegeneration in a p75(NTR)- and proNGF-dependent manner. α2M could be exploited as a therapeutic target, or as a modifier of neurotrophin signals.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Department of Oncology and the Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Barcelona
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada Department of Oncology and the Cancer Center, McGill University, Montreal, Quebec, Canada uri.saragovi@mcgill.ca.
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011498:Protein Precursors / Q000502:physiology; D055550:Protein Stability; D059748:Proteolysis; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000502:physiology*
chemical_list: C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor; D000511:alpha-Macroglobulins; D020932:Nerve Growth Factor; D020917:Receptor, trkA