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Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6.
Hickman FE, Stanley EM, Carter BD
(2018) J Neurosci 38: 5606-5619
MeSH Terms: ADP-Ribosylation Factors, Animals, Nerve Tissue Proteins, Neurogenesis, Neurons, Neurotrophin 3, Rats, Rats, Sprague-Dawley, Receptor, trkA, Receptors, Growth Factor, Receptors, Nerve Growth Factor, Sympathetic Nervous System
Show Abstract · Added April 4, 2019
The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is upregulated, resulting in formation of TrkA-p75 complexes, which are high-affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 guanine nucleotide exchange factors. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth, whereas the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system. p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface availability may provide insight into how and why neurodegenerative processes manifest and reveal new therapeutic targets. Results from this study indicate a novel mechanism by which p75NTR can be rapidly shuttled to the cell surface from existing intracellular pools and explores a unique pathway by which NGF regulates the sympathetic innervation of target tissues, which has profound consequences for the function of these organs.
Copyright © 2018 the authors 0270-6474/18/385606-14$15.00/0.
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12 MeSH Terms
P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.
Dillon LM, Bean JR, Yang W, Shee K, Symonds LK, Balko JM, McDonald WH, Liu S, Gonzalez-Angulo AM, Mills GB, Arteaga CL, Miller TW
(2015) Oncogene 34: 3968-76
MeSH Terms: Animals, Breast Neoplasms, Cell Survival, Feedback, Physiological, Female, Guanine Nucleotide Exchange Factors, Humans, MAP Kinase Signaling System, MCF-7 Cells, Mice, Inbred NOD, Mice, SCID, Mutation, Neoplasm Transplantation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptors, Growth Factor, rac GTP-Binding Proteins
Show Abstract · Added October 21, 2014
Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.
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17 MeSH Terms
A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress.
Kraemer BR, Snow JP, Vollbrecht P, Pathak A, Valentine WM, Deutch AY, Carter BD
(2014) J Biol Chem 289: 21205-16
MeSH Terms: Animals, Apoptosis, Axons, Cells, Cultured, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Oxidative Stress, Rats, Rats, Sprague-Dawley, Receptors, Growth Factor, Receptors, Nerve Growth Factor, Visual Field Tests
Show Abstract · Added January 22, 2015
The p75 neurotrophin receptor (p75(NTR)) mediates the death of specific populations of neurons during the development of the nervous system or after cellular injury. The receptor has also been implicated as a contributor to neurodegeneration caused by numerous pathological conditions. Because many of these conditions are associated with increases in reactive oxygen species, we investigated whether p75(NTR) has a role in neurodegeneration in response to oxidative stress. Here we demonstrate that p75(NTR) signaling is activated by 4-hydroxynonenal (HNE), a lipid peroxidation product generated naturally during oxidative stress. Exposure of sympathetic neurons to HNE resulted in neurite degeneration and apoptosis. However, these effects were reduced markedly in neurons from p75(NTR-/-) mice. The neurodegenerative effects of HNE were not associated with production of neurotrophins and were unaffected by pretreatment with a receptor-blocking antibody, suggesting that oxidative stress activates p75(NTR) via a ligand-independent mechanism. Previous studies have established that proteolysis of p75(NTR) by the metalloprotease TNFα-converting enzyme and γ-secretase is necessary for p75(NTR)-mediated apoptotic signaling. Exposure of sympathetic neurons to HNE resulted in metalloprotease- and γ-secretase-dependent cleavage of p75(NTR). Pharmacological blockade of p75(NTR) proteolysis protected sympathetic neurons from HNE-induced neurite degeneration and apoptosis, suggesting that cleavage of p75(NTR) is necessary for oxidant-induced neurodegeneration. In vivo, p75(NTR-/-) mice exhibited resistance to axonal degeneration associated with oxidative injury following administration of the neurotoxin 6-hydroxydopamine. Together, these data suggest a novel mechanism linking oxidative stress to ligand-independent cleavage of p75(NTR), resulting in axonal fragmentation and neuronal death.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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3 Members
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13 MeSH Terms
The p75 neurotrophin receptor evades the endolysosomal route in neuronal cells, favouring multivesicular bodies specialised for exosomal release.
Escudero CA, Lazo OM, Galleguillos C, Parraguez JI, Lopez-Verrilli MA, Cabeza C, Leon L, Saeed U, Retamal C, Gonzalez A, Marzolo MP, Carter BD, Court FA, Bronfman FC
(2014) J Cell Sci 127: 1966-79
MeSH Terms: Animals, Endosomes, Exosomes, Lysosomes, Microscopy, Fluorescence, Multivesicular Bodies, Nerve Tissue Proteins, Neurons, PC12 Cells, RNA Interference, Rats, Receptors, Growth Factor, Receptors, Nerve Growth Factor
Show Abstract · Added March 17, 2014
The p75 neurotrophin receptor (p75, also known as NGFR) is a multifaceted signalling receptor that regulates neuronal physiology, including neurite outgrowth, and survival and death decisions. A key cellular aspect regulating neurotrophin signalling is the intracellular trafficking of their receptors; however, the post-endocytic trafficking of p75 is poorly defined. We used sympathetic neurons and rat PC12 cells to study the mechanism of internalisation and post-endocytic trafficking of p75. We found that p75 internalisation depended on the clathrin adaptor protein AP2 and on dynamin. More surprisingly, p75 evaded the lysosomal route at the level of the early endosome, instead accumulating in two different types of endosomes, Rab11-positive endosomes and multivesicular bodies (MVBs) positive for CD63, a marker of the exosomal pathway. Consistently, depolarisation by KCl induced the liberation of previously endocytosed full-length p75 into the extracellular medium in exosomes. Thus, p75 defines a subpopulation of MVBs that does not mature to lysosomes and is available for exosomal release by neuronal cells.
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13 MeSH Terms
Isolation and characterization of node/notochord-like cells from mouse embryonic stem cells.
Winzi MK, Hyttel P, Dale JK, Serup P
(2011) Stem Cells Dev 20: 1817-27
MeSH Terms: Animals, Antigens, Differentiation, Benzamides, Cell Differentiation, Cell Line, Cell Proliferation, Chick Embryo, Dioxoles, Embryonic Stem Cells, Green Fluorescent Proteins, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Intercellular Signaling Peptides and Proteins, Mice, Notochord, Organizers, Embryonic, Peptide Hormones, Pyrroles, Receptors, Growth Factor, Recombinant Fusion Proteins, Signal Transduction, Tissue Culture Techniques, Transplantation, Heterologous
Show Abstract · Added May 13, 2013
The homeobox gene Noto is expressed in the node and its derivative the notochord. Here we use a targeted Noto-GFP reporter to isolate and characterize node/notochord-like cells derived from mouse embryonic stem cells. We find very few Noto-expressing cells after spontaneous differentiation. However, the number of Noto-expressing cells was increased when using Activin A to induce a Foxa2- and Brachyury-expressing progenitor population, whose further differentiation into Noto-expressing cells was improved by simultaneous inhibition of BMP, Wnt, and retinoic acid signaling. Noto-GFP(+) cells expressed the node/notochord markers Noto, Foxa2, Shh, Noggin, Chordin, Foxj1, and Brachyury; showed a vacuolarization characteristic of notochord cells; and can integrate into midline structures when grafted into Hensen's node of gastrulating chicken embryos. The ability to generate node/notochord-like cells in vitro will aid the biochemical characterization of these developmentally important structures.
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23 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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29 MeSH Terms
Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder.
Campbell DB, Li C, Sutcliffe JS, Persico AM, Levitt P
(2008) Autism Res 1: 159-68
MeSH Terms: Alleles, Autistic Disorder, Exons, Genotype, Hepatocyte Growth Factor, Humans, Linkage Disequilibrium, Plasminogen Activator Inhibitor 1, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-met, Receptors, Growth Factor, Receptors, Urokinase Plasminogen Activator, Signal Transduction
Show Abstract · Added February 20, 2014
A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5' promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12-3.31) for genotype TT and 2.42 (95% CI: 1.38-4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.
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13 MeSH Terms
Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions.
Campbell DB, Buie TM, Winter H, Bauman M, Sutcliffe JS, Perrin JM, Levitt P
(2009) Pediatrics 123: 1018-24
MeSH Terms: Alleles, Autistic Disorder, Child, Comorbidity, Female, Gastrointestinal Diseases, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Male, Phenotype, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-met, Receptors, Growth Factor, Risk Factors, Signal Transduction
Show Abstract · Added February 20, 2014
OBJECTIVE - In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder-associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions.
PATIENTS AND METHODS - Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder-associated MET promoter variant rs1858830 were determined. Family-based association test and chi(2) analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions.
RESULTS - In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. chi(2) analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls.
CONCLUSION - These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.
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18 MeSH Terms
Disruption of cerebral cortex MET signaling in autism spectrum disorder.
Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, Persico AM
(2007) Ann Neurol 62: 243-50
MeSH Terms: Autistic Disorder, Blotting, Western, Cerebral Cortex, Child, DNA, Databases, Factual, Female, Genotype, Hepatocyte Growth Factor, Humans, Male, Nerve Net, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-met, RNA, Messenger, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Temporal Lobe, Tissue Banks, Transcription, Genetic
Show Abstract · Added May 19, 2014
OBJECTIVE - Multiple genes contribute to autism spectrum disorder (ASD) susceptibility. One particularly promising candidate is the MET gene, which encodes a receptor tyrosine kinase that mediates hepatocyte growth factor (HGF) signaling in brain circuit formation, immune function, and gastrointestinal repair. The MET promoter variant rs1858830 allele "C" is strongly associated with ASD and results in reduced gene transcription. Here we examined expression levels of MET and members of the MET signaling pathway in postmortem cerebral cortex from ASD cases and healthy control subjects.
METHODS - Protein, total RNA, and DNA were extracted from postmortem temporal cortex gray matter samples (BA 41/42, 52, or 22) belonging to eight pairs of ASD cases and matched control subjects. MET protein expression was determined by Western blotting; messenger RNA expression of MET and other related transcripts was assayed by microarray and quantitative reverse transcriptase polymerase chain reaction.
RESULTS - MET protein levels were significantly decreased in ASD cases compared with control subjects. This was accompanied in ASD brains by increased messenger RNA expression for proteins involved in regulating MET signaling activity. Analyses of coexpression of MET and HGF demonstrated a positive correlation in control subjects that was disrupted in ASD cases.
INTERPRETATION - Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.
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23 MeSH Terms
A genetic variant that disrupts MET transcription is associated with autism.
Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P
(2006) Proc Natl Acad Sci U S A 103: 16834-9
MeSH Terms: Alleles, Autistic Disorder, Base Sequence, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 7, DNA, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-met, Receptors, Growth Factor, Transcription Factors, Transcription, Genetic
Show Abstract · Added February 20, 2014
There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.
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21 MeSH Terms