title: Neuron-type-specific signaling by the p75NTR death receptor is regulated by differential proteolytic cleavage.
abstract: Signaling by the p75 neurotrophin receptor (p75(NTR), also known as NGFR) is often referred to as cell-context dependent, but neuron-type-specific signaling by p75(NTR) has not been systematically investigated. Here, we report that p75(NTR) signals very differently in hippocampal neurons (HCNs) and cerebellar granule neurons (CGNs), and we present evidence indicating that this is partly controlled by differential proteolytic cleavage. Nerve growth factor (NGF) induced caspase-3 activity and cell death in HCNs but not in CGNs, whereas it stimulated NFκB activity in CGNs but not in HCNs. HCNs and CGNs displayed different patterns of p75(NTR) proteolytic cleavage. Whereas the p75(NTR) carboxy terminal fragment (CTF) was more abundant than the intracellular domain (ICD) in HCNs, CGNs exhibited fully processed ICD with very little CTF. Pharmacological or genetic blockade of p75(NTR) cleavage by γ-secretase abolished NGF-induced upregulation of NFκB activity and enabled induction of CGN death, phenocopying the functional profile of HCNs. Thus, the activities of multifunctional receptors, such as p75(NTR), can be tuned into narrower activity profiles by cell-type-specific differences in intracellular processes, such as proteolytic cleavage, leading to very different biological outcomes.
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vicario
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kisiswa
authors.affiliation: Life Sciences Institute, Department of Physiology, National University of Singapore, Singapore 117456, Singapore.
authors.forename: Jason Y
authors.initials: JY
authors.lastname: Tann
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Kelly
authors.affiliation: Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden Life Sciences Institute, Department of Physiology, National University of Singapore, Singapore 117456, Singapore Department of Physiology, National University of Singapore, Singapore 117597, Singapore carlos.ibanez@ki.se.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ibáñez
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death; D002531:Cerebellum / Q000166:cytology; D048749:Cytokinesis; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D059748:Proteolysis; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D053829:Amyloid Precursor Protein Secretases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Cell death; NF‐κB; Nerve growth factor; Presenilin‐1; γ‐secretase