Association between Presenilin‐1 and TRAF6 modulates regulated intramembrane proteolysis of the p75<sup>NTR</sup> neurotrophin receptor

Powell, Jennifer; Twomey, Ciara; Jain, Raunak; McCarthy, Justin V.

doi:10.1111/j.1471-4159.2008.05763.x

Cited by 30 publications

(20 citation statements)

References 83 publications

(116 reference statements)

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“…CGNs displayed higher levels of fully processed ICD than HCNs, and this correlated with higher levels of both full-length and proteolytically activated PS-1. In a previous study, NGF-mediated degradation of IkB was found to be compromised in mouse embryo fibroblasts (MEFs) derived from PS-1-knockout mice (Powell et al, 2009), which is in agreement with our DAPT and csec mut results in CGNs. In fact, pharmacological or genetic blockade of p75 NTR cleavage by csecretase in these cells phenocopied the functional profile of HCNs, suggesting that differences in proteolytic processing of p75 NTR might, in part, underlie the divergent signaling activities of this receptor in the two neuronal types.…”

Section: Discussionsupporting

confidence: 75%

“…In our own experiments, we have not been able to detect significant changes in the proteolytic cleavage of p75 NTR in either HCNs or CGNs following NGF treatment (data not shown). Other studies have indicated that several other stimuli can influence the proteolytic processing of p75 NTR , including interaction with sortilin , ubiquitylation and palmitoylation (Powell et al, 2009;, activation of Trk receptors (Ceni et al, 2010;Kanning et al, 2003;Urra et al, 2007), myelin-derived ligands (Domeniconi et al, 2005), b-amyloid peptide (Sotthibundhu et al, 2008) and oxidative stress (Kraemer et al, 2014;Le Moan et al, 2011). Aside from its regulation, most studies are in agreement that proteolytic cleavage can affect p75 NTR -mediated signaling and biological activities.…”

Section: Discussionsupporting

confidence: 50%

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

Vicario

Kisiswa

Tann

et al. 2015

Journal of Cell Science

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 50%

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

Vicario

Kisiswa

Tann

et al. 2015

Journal of Cell Science

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“…Through genetic knock-out of the presenilins, we have further demonstrated the essential role of the presenilins in ␥-secretase cleavage of TNFR1. Although it has been shown that ␥-secretase cleavage of the insulin-like growth factor 1 receptor, Notch, IL-1 receptor I, p75 NTR , or ErbB-4 receptor occurs in the presence of their corresponding ligands (40,50,58,(77)(78)(79), ligand-induced cleavage has not been shown for other receptors, such as the growth hormone receptor. Here we demonstrate that TNF␣ stimulation can induce ectodomain shedding, generation of TNFR1 CTF, and subsequent ␥-secretase cleavage of TNFR1, perhaps pointing to a general mechanism of ligand-mediated regulated intramembrane proteolysis.…”

Section: Discussionmentioning

confidence: 99%

“…Given that the TNFR superfamily member p75 neurotrophin receptor (p75 NTR ) undergoes regulated intramembrane proteolysis (55)(56)(57)(58) and that TNFR1 fits the profile of a ␥-secretase substrate, we screened a number of TNF superfamily members to detect involvement of the ␥-secretase protease in their proteolysis and signaling. Using pharmacological inhibitors and genetic knock-out approaches, in this study, we report the identification of TNFR1 as a ␥-secretase substrate and demonstrate that loss of presenilin expression and ␥-secretase activity antagonized TNF-mediated JNK MAPK activation, reduced pro-apoptotic complex II assembly, and inhibited TNF-induced caspase activation and apoptosis.…”

mentioning

confidence: 99%

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Chhibber‐Goel

Coleman-Vaughan

Agrawal

et al. 2016

Journal of Biological Chemistry

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The ␥-secretase protease and associated regulated intramembrane proteolysis play an important role in controlling receptormediated intracellular signaling events, which have a central role in Alzheimer disease, cancer progression, and immune surveillance. An increasing number of ␥-secretase substrates have a role in cytokine signaling, including the IL-6 receptor, IL-1 receptor type I, and IL-1 receptor type II. In this study, we show that following TNF-converting enzyme-mediated ectodomain shedding of TNF type I receptor (TNFR1), the membranebound TNFR1 C-terminal fragment is subsequently cleaved by ␥-secretase to generate a cytosolic TNFR1 intracellular domain. We also show that clathrin-mediated internalization of TNFR1 C-terminal fragment is a prerequisite for efficient ␥-secretase cleavage of TNFR1. Furthermore, using in vitro and in vivo model systems, we show that in the absence of presenilin expression and ␥-secretase activity, TNF-mediated JNK activation was prevented, assembly of the TNFR1 pro-apoptotic complex II was reduced, and TNF-induced apoptosis was inhibited. These observations demonstrate that TNFR1 is a ␥-secretase substrate and suggest that ␥-secretase cleavage of TNFR1 represents a new layer of regulation that links the presenilins and the ␥-secretase protease to pro-inflammatory cytokine signaling.The biological activities of the tumor necrosis factor-␣ (TNF) pro-inflammatory cytokine are resolved by two distinct cell surface receptors, TNFR1 3 and TNFR2, which elicit a diversity of cellular responses, such as inflammation, cell proliferation, cell differentiation, and initiation of apoptosis (1-10). TNFR1 initiates either pro-inflammatory or pro-apoptotic signaling through the selective recruitment of intracellular adaptor and effector proteins (1,3,6,7,11). Ligand binding and trimerization of TNFR1 enables the recruitment of TNFR1-associated death domain protein (TRADD) (12, 13), which functions as a scaffold enabling the recruitment of receptorinteracting protein kinase 1 (RIPK1) (14 -16), TNF receptorassociated factor 2 (TRAF2) or TRAF5 (12), and the cellular inhibitor of apoptosis proteins (cIAPs) cIAP1 and cIAP2 (11), which collectively form a signaling composite called complex I (17-19). The resulting lysine 63-linked polyubiquitination of RIPK1 by TRAF2 and the cIAPs (20 -24) enables an interaction with the IB kinase complex that mediates the phosphorylation and degradation of IB-inhibitory proteins and activation of the transcription factor NF-B to promote non-apoptotic signaling pathways (25-27). NF-B also increases expression of anti-apoptotic genes, including cIAPs and FLICE inhibitory protein (c-FLIP), further ensuring a non-apoptotic signaling pathway.The importance of receptor internalization as a regulatory mechanism for the segregation and divergence of intracellular signaling pathways is highlighted by studies on internalization of TNFR1 and TNFR2, the Fas receptor (FasR/CD95), IL-1 receptor I, Toll-like receptor 4, and TRAIL receptors (18, 28 -33). The current favored m...

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“…They include SC-1 (36), RhoA (37), and TRAF6 (38,39). In addition, several p75-interacting proteins, such as NRIF (neurotrophin receptor-interacting factor) (21), NADE (p75NTR-associated cell death executor) (40), and NRAGE (neurotrophin receptor-interacting MAGE homolog) (41), contribute to apoptosis in immortalized cell lines.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

Parkhurst

Zampieri

Chao

2010

Journal of Biological Chemistry

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The p75 neurotrophin receptor, a member of the tumor necrosis factor superfamily of receptors, undergoes an ␣-secretase-mediated release of its extracellular domain, followed by a ␥-secretase-mediated intramembrane cleavage. Like amyloid precursor protein and Notch, ␥-secretase cleavage of the p75 receptor releases an intracellular domain (ICD). However, it has been experimentally challenging to determine the precise subcellular localization and functional consequences of the p75 ICD. Here, we utilized a nuclear translocation assay and biochemical fractionation approaches to follow the fate of the ICD. We found that the p75 ICD can translocate to the nucleus to activate a green fluorescent protein reporter gene. Furthermore, the p75 ICD was localized in nuclear fractions. Chromatin immunoprecipitation experiments indicated that nerve growth factor induced the association of endogenous p75 with the cyclin E 1 promoter. Expression of the p75 ICD resulted in modulation of gene expression from this locus. These results suggest that the p75 ICD generated by ␥-secretase cleavage is capable of modulating transcriptional events in the nucleus.The p75 neurotrophin receptor is the founding member of the tumor necrosis factor receptor superfamily that includes the Fas antigen, DR6, CD30, and CD40. This family of receptors is distinguished with multiple cysteine-rich domains for ligand binding, a single transmembrane sequence, and a noncatalytic cytoplasmic domain (1). The intracellular region of the p55 tumor necrosis factor receptor, Fas receptor, and p75 contains a death domain sequence (2). The death domain serves as a proteinprotein docking site and is required for initiating tumor necrosis factor-and Fas-mediated apoptosis (3).The p75 receptor is recognized by all the neurotrophins (NGF, 3 brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4), which promote differentiation, growth, and survival of diverse cell types in the nervous system (4 -6). Neurotrophins also initiate signaling through Trk tyrosine kinase receptors, which are capable of forming high affinity binding sites with p75 to potentiate responses at low concentrations of neurotrophins (7). The precursor form of neurotrophins (proneurotrophins) binds more avidly to p75 than the mature form (8, 9). In the absence of Trk receptors, p75 is capable of independent signaling that activates NF-B, c-Jun N-terminal kinase (JNK), and the sphingomyelin cycle (10). In selected cell types, p75 can initiate cell death (11-13). Alternatively, p75 can serve as a co-receptor for several proteins that modulate axon outgrowth, such as Nogo, neuropilin-1, and plexin-A4 (14 -16). Recently, p75 interaction with ephrin A has been shown to direct targeting of retinal ganglion cells during development (17).Intramembrane cleavage events have been detected for p75 in many cell types (18,19). Proteolysis through presenilin-dependent ␥-secretase activity has emerged as a highly conserved and prevalent mechanism in receptor signaling responsible for the intramembrane c...

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Association between Presenilin‐1 and TRAF6 modulates regulated intramembrane proteolysis of the p75^NTR neurotrophin receptor

Cited by 30 publications

References 83 publications

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

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

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

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Association between Presenilin‐1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR neurotrophin receptor

Cited by 30 publications

References 83 publications

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

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

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

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Association between Presenilin‐1 and TRAF6 modulates regulated intramembrane proteolysis of the p75^NTR neurotrophin receptor