Neuron-type-specific signaling by the p75NTR death receptor is regulated by differential proteolytic cleavage

Abstract

Signaling by the p75 neurotrophin receptor (p75NTR, also known as NGFR) is often referred to as cell-context dependent, but neurontype-specific signaling by p75NTR has not been systematically investigated. Here, we report that p75NTR 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 p75NTR proteolytic cleavage. Whereas the p75NTR 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 p75NTR 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 p75NTR, 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.