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Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150 Deacetylation by Axonal HDAC1.
Pathak A, Stanley EM, Hickman FE, Wallace N, Brewer B, Li D, Gluska S, Perlson E, Fuhrmann S, Akassoglou K, Bronfman F, Casaccia P, Burnette DT, Carter BD
(2018) Dev Cell 46: 376-387.e7
MeSH Terms: Animals, Axonal Transport, Axons, Dynactin Complex, Histone Deacetylase 1, Microtubule-Associated Proteins, Neurons, Rats, Sprague-Dawley, Receptor, Nerve Growth Factor
Show Abstract · Added March 27, 2019
During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150 deacetylation as a unique mechanism regulating axonal transport.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
3 Members
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MeSH Terms
The biological functions and signaling mechanisms of the p75 neurotrophin receptor.
Kraemer BR, Yoon SO, Carter BD
(2014) Handb Exp Pharmacol 220: 121-64
MeSH Terms: Adaptor Proteins, Vesicular Transport, Animals, Apoptosis, Cell Cycle, Cell Survival, Humans, JNK Mitogen-Activated Protein Kinases, Myelin Sheath, NF-kappa B, Neuronal Plasticity, Protein Precursors, Receptor, Nerve Growth Factor, Receptor, trkA, Signal Transduction
Show Abstract · Added January 22, 2015
The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including programmed cell death, axonal growth and degeneration, cell proliferation, myelination, and synaptic plasticity. The multiplicity of cellular functions governed by the receptor arises from the variety of ligands and co-receptors which associate with p75(NTR) and regulate its signaling. P75(NTR) promotes survival through interactions with Trk receptors, inhibits axonal regeneration via partnerships with Nogo receptor (Nogo-R) and Lingo-1, and promotes apoptosis through association with Sortilin. Signals downstream of these interactions are further modulated through regulated intramembrane proteolysis (RIP) of p75(NTR) and by interactions with numerous cytosolic partners. In this chapter, we discuss the intricate signaling mechanisms of p75(NTR), emphasizing how these signals are differentially regulated to mediate these diverse cellular functions.
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1 Members
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14 MeSH Terms
p75 neurotrophin receptor cleavage by α- and γ-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells.
Forsyth PA, Krishna N, Lawn S, Valadez JG, Qu X, Fenstermacher DA, Fournier M, Potthast L, Chinnaiyan P, Gibney GT, Zeinieh M, Barker PA, Carter BD, Cooper MK, Kenchappa RS
(2014) J Biol Chem 289: 8067-85
MeSH Terms: Amyloid Precursor Protein Secretases, Brain, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques, Glioma, Humans, Mutation, Neoplastic Stem Cells, Nerve Growth Factors, Receptor, Nerve Growth Factor
Show Abstract · Added March 17, 2014
Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.
0 Communities
2 Members
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12 MeSH Terms
A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons.
Perdigoto AL, Chaudhry N, Barnes GN, Filbin MT, Carter BD
(2011) Mol Cell Neurosci 46: 235-44
MeSH Terms: Animals, CHO Cells, Cells, Cultured, Cerebral Cortex, Coculture Techniques, Cricetinae, Cricetulus, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelin-Associated Glycoprotein, Neurites, Neurons, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, Receptor, Nerve Growth Factor, rho GTP-Binding Proteins, rho-Associated Kinases
Show Abstract · Added March 5, 2014
Axonal regeneration in the central nervous system is prevented, in part, by inhibitory proteins expressed by myelin, including myelin-associated glycoprotein (MAG). Although injury to the corticospinal tract can result in permanent disability, little is known regarding the mechanisms by which MAG affects cortical neurons. Here, we demonstrate that cortical neurons plated on MAG expressing CHO cells, exhibit a striking reduction in process outgrowth. Interestingly, none of the receptors previously implicated in MAG signaling, including the p75 neurotrophin receptor or gangliosides, contributed significantly to MAG-mediated inhibition. However, blocking the small GTPase Rho or its downstream effector kinase, ROCK, partially reversed the effects of MAG on the neurons. In addition, we identified the lipid phosphatase PTEN as a mediator of MAG's inhibitory effects on neurite outgrowth. Knockdown or gene deletion of PTEN or overexpression of activated AKT in cortical neurons resulted in significant, although partial, rescue of neurite outgrowth on MAG-CHO cells. Moreover, MAG decreased the levels of phospho-Akt, suggesting that it activates PTEN in the neurons. Taken together, these results suggest a novel pathway activated by MAG in cortical neurons involving the PTEN/PI3K/AKT axis.
Copyright © 2010 Elsevier Inc. All rights reserved.
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1 Members
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20 MeSH Terms
Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor.
Vilar M, Charalampopoulos I, Kenchappa RS, Reversi A, Klos-Applequist JM, Karaca E, Simi A, Spuch C, Choi S, Friedman WJ, Ericson J, Schiavo G, Carter BD, Ibáñez CF
(2009) J Cell Sci 122: 3351-7
MeSH Terms: Amino Acid Sequence, Animals, Axons, COS Cells, Caspase 3, Cell Death, Chlorocebus aethiops, Cross-Linking Reagents, Disulfides, Humans, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Ligands, Molecular Sequence Data, Mutant Proteins, NF-kappa B, Nerve Growth Factors, Protein Multimerization, Protein Transport, Rats, Receptor, Nerve Growth Factor, Receptor-Interacting Protein Serine-Threonine Kinase 2, Signal Transduction, TNF Receptor-Associated Factor 6
Show Abstract · Added March 5, 2014
Dimerization is recognized as a crucial step in the activation of many plasma membrane receptors. However, a growing number of receptors pre-exist as dimers in the absence of ligand, indicating that, although necessary, dimerization is not always sufficient for signaling. The p75 neurotrophin receptor (p75(NTR)) forms disulfide-linked dimers at the cell surface independently of ligand binding through Cys257 in its transmembrane domain. Here, we show that crosslinking of p75(NTR) dimers by cysteine-scanning mutagenesis results in constitutive, ligand-independent activity in several pathways that are normally engaged upon neurotrophin stimulation of native receptors. The activity profiles of different disulfide-crosslinked p75(NTR) mutants were similar but not identical, suggesting that different configurations of p75(NTR) dimers might be endowed with different functions. Interestingly, crosslinked p75(NTR) mutants did not mimic the effects of the myelin inhibitors Nogo or MAG, suggesting the existence of ligand-specific activation mechanisms. Together, these results support a conformational model of p75(NTR) activation by neurotrophins, and reveal a genetic approach to generate gain-of-function receptor variants with distinct functional profiles.
0 Communities
1 Members
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24 MeSH Terms
Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers.
Vilar M, Charalampopoulos I, Kenchappa RS, Simi A, Karaca E, Reversi A, Choi S, Bothwell M, Mingarro I, Friedman WJ, Schiavo G, Bastiaens PI, Verveer PJ, Carter BD, Ibáñez CF
(2009) Neuron 62: 72-83
MeSH Terms: Animals, Animals, Newborn, Binding Sites, Cell Death, Cells, Cultured, Chlorocebus aethiops, Cysteine, Green Fluorescent Proteins, Humans, Membrane Proteins, Mice, Mutation, NF-kappa B, Nerve Growth Factor, Nerve Tissue Proteins, Neurons, Oligopeptides, Protein Binding, Protein Conformation, Protein Multimerization, RNA, Small Interfering, Rats, Receptor, Nerve Growth Factor, Receptors, Growth Factor, Receptors, Nerve Growth Factor, Signal Transduction, Superior Cervical Ganglion, Transfection, rhoA GTP-Binding Protein
Show Abstract · Added March 5, 2014
Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75(NTR)), but the mechanism of receptor activation has remained elusive. Here, we show that p75(NTR) forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys(257) in its transmembrane domain. Mutation of Cys(257) abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75(NTR)/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75(NTR). FRET experiments revealed a close association of p75(NTR) intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys(257) did not alter the oligomeric state of p75(NTR), the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75(NTR) by a mechanism involving rearrangement of disulphide-linked receptor subunits.
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1 Members
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29 MeSH Terms
Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures.
Volosin M, Trotter C, Cragnolini A, Kenchappa RS, Light M, Hempstead BL, Carter BD, Friedman WJ
(2008) J Neurosci 28: 9870-9
MeSH Terms: Animals, Apoptosis, Cell Survival, Cells, Cultured, DNA-Binding Proteins, Disease Models, Animal, Electrophoretic Mobility Shift Assay, Embryo, Mammalian, Female, Fluoresceins, Hippocampus, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Nerve Growth Factor, Nerve Growth Factors, Neurons, Organic Chemicals, Pilocarpine, Pregnancy, Protein Precursors, Rats, Receptor, Nerve Growth Factor, Seizures, Time Factors
Show Abstract · Added March 5, 2014
Seizure-induced damage elicits a loss of hippocampal neurons mediated to a great extent by the p75 neurotrophin receptor (NTR). Proneurotrophins, which are potent apoptosis-inducing ligands for p75(NTR), were increased in the hippocampus, particularly in astrocytes, by pilocarpine-induced seizures; and infusion of anti-pro-NGF dramatically attenuated neuronal loss after seizures. The p75(NTR) is expressed in many different cell types in the nervous system, and can mediate a variety of different cellular functions by recruiting specific intracellular binding proteins to activate distinct signaling pathways. In this study, we demonstrate that neurotrophin receptor-interacting factor (NRIF) mediates apoptotic signaling via p75(NTR) in hippocampal neurons in vitro and in vivo. After seizure-induced injury, NRIF(-/-) mice showed an increase in p75(NTR) expression in the hippocampus; however, these neurons failed to undergo apoptosis in contrast to wild-type mice. Treatment of cultured hippocampal neurons with proneurotrophins induced association of NRIF with p75(NTR) and subsequent translocation of NRIF to the nucleus, which was dependent on cleavage of the receptor. Neurons lacking NRIF were resistant to p75(NTR)-mediated apoptosis in vitro and in vivo. In addition, we demonstrate some mechanistic differences in p75(NTR) signaling in hippocampal neurons compared with other cell types. Overall, these studies demonstrate the requirement for NRIF to signal p75(NTR)-mediated apoptosis of hippocampal neurons and that blocking pro-NGF can inhibit neuronal loss after seizures.
0 Communities
1 Members
0 Resources
26 MeSH Terms
NRAGE, a p75NTR adaptor protein, is required for developmental apoptosis in vivo.
Bertrand MJ, Kenchappa RS, Andrieu D, Leclercq-Smekens M, Nguyen HN, Carter BD, Muscatelli F, Barker PA, De Backer O
(2008) Cell Death Differ 15: 1921-9
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Fertility, Gene Targeting, Hair Follicle, Mice, Mice, Knockout, Motor Neurons, Mutation, Neoplasm Proteins, Receptor, Nerve Growth Factor, Sympathetic Nervous System, Trigeminal Ganglion
Show Abstract · Added March 5, 2014
NRAGE (also known as Maged1, Dlxin) is a member of the MAGE gene family that may play a role in the neuronal apoptosis that is regulated by the p75 neurotrophin receptor (p75NTR). To test this hypothesis in vivo, we generated NRAGE knockout mice and found that NRAGE deletion caused a defect in developmental apoptosis of sympathetic neurons of the superior cervical ganglia, similar to that observed in p75NTR knockout mice. Primary sympathetic neurons derived from NRAGE knockout mice were resistant to apoptosis induced by brain-derived neurotrophic factor (BDNF), a pro-apoptotic p75NTR ligand, and NRAGE-deficient sympathetic neurons show attenuated BDNF-dependent JNK activation. Hair follicle catagen is an apoptosis-like process that is dependent on p75NTR signaling; we show that NRAGE and p75NTR show regulated co-expression in the hair follicle and that identical defects in hair follicle catagen are present in NRAGE and p75NTR knockout mice. Interestingly, NRAGE knockout mice have severe defects in motoneuron apoptosis that are not observed in p75NTR knockout animals, raising the possibility that NRAGE may facilitate apoptosis induced by receptors other than p75NTR. Together, these studies demonstrate that NRAGE plays an important role in apoptotic-signaling in vivo.
0 Communities
1 Members
0 Resources
14 MeSH Terms
NRIF is a regulator of neuronal cholesterol biosynthesis genes.
Korade Z, Kenchappa RS, Mirnics K, Carter BD
(2009) J Mol Neurosci 38: 152-8
MeSH Terms: Acyl Coenzyme A, Animals, Cell Line, Cholesterol, DNA-Binding Proteins, Gene Expression Regulation, Enzymologic, Hippocampus, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Mice, Mice, Knockout, Neuroblastoma, Neurons, Oxidoreductases Acting on CH-CH Group Donors, RNA, Small Interfering, Receptor, Nerve Growth Factor
Show Abstract · Added March 5, 2014
Cholesterol is a critical component of neuronal membranes, required for normal signal transduction. We showed previously that adult hippocampal neurons co-express high levels of cholesterogenic enzymes, and that their expression is under the control of the p75 neurotrophin receptor (p75NTR). Most of the cellular effects of p75NTR are mediated via interacting proteins, including neurotrophin receptor interacting factor (NRIF). In this study, we tested the hypothesis that p75NTR-dependent regulation of cholesterol and lipid biosynthesis genes is mediated by NRIF. We found that in vitro down regulation of NRIF expression decreased the mRNA for two main cholesterogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr; EC 2.3.3.10) and 7-dehydrocholesterol reductase (Dhcr7; EC 1.3.1.21). Further analyses revealed that NRIF-dependent and Dhcr7-dependent transcriptional changes show a high degree of overlap, and that NRIF reduction resulted in reduced expression of sterol-sensing domain protein SCAP, followed by a decrease in mRNA levels of SRE-motif containing genes (HMGCR, FASN, SREBP2, S1P, and SQS1). Finally, a reduction in cholesterol biosynthesis-related gene expression was also observed in hippocampal tissue of mice with NRIF deletion. Our combined in vitro and in vivo studies suggest that hippocampal neuronal cholesterol biosynthesis is regulated through the p75NTR interacting factor NRIF.
0 Communities
2 Members
0 Resources
16 MeSH Terms
Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors tropomyosin-related kinase A and p75.
Hoard JL, Hoover DB, Mabe AM, Blakely RD, Feng N, Paolocci N
(2008) Neuroscience 156: 129-42
MeSH Terms: Acetylcholine, Animals, Autonomic Pathways, Dopamine beta-Hydroxylase, Fluorescent Antibody Technique, Ganglia, Parasympathetic, Heart, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Neurons, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Phenotype, Receptor, Nerve Growth Factor, Receptor, trkA, Stellate Ganglion, Synaptic Transmission, Tyrosine 3-Monooxygenase, Vesicular Acetylcholine Transport Proteins, Vesicular Monoamine Transport Proteins
Show Abstract · Added July 10, 2013
Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e. synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine beta-hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs), like those of humans, have a complex neurochemical phenotype that goes beyond the classical view of cardiac parasympathetic neurons. They also suggest that neurotrophins and local NE synthesis might have important effects on neurons of the mouse ICG.
1 Communities
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23 MeSH Terms