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dc.contributor.authorLachyankar, Mahesh B.
dc.contributor.authorCondon, Peter J.
dc.contributor.authorDaou, Marie-Claire
dc.contributor.authorDe, Asit K.
dc.contributor.authorLevine, John B.
dc.contributor.authorObermeier, Axel
dc.contributor.authorRoss, Alonzo H.
dc.date2022-08-11T08:09:00.000
dc.date.accessioned2022-08-23T16:14:56Z
dc.date.available2022-08-23T16:14:56Z
dc.date.issued2002-12-28
dc.date.submitted2008-10-15
dc.identifier.citationJ Neurosci Res. 2003 Jan 15;71(2):157-72. <a href="http://dx.doi.org/10.1002/jnr.10480 ">Link to article on publisher's site</a>
dc.identifier.issn0360-4012 (Print)
dc.identifier.doi10.1002/jnr.10480
dc.identifier.pmid12503079
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33980
dc.description.abstractTo understand the functional interactions between the TrkA and p75 nerve growth factor (NGF) receptors, we stably transfected LAN5 neuroblastoma cells with an expression vector for ET-R, a chimeric receptor with the extracellular domain of the epidermal growth factor receptor (EGFR), and the TrkA transmembrane and intracellular domains. EGF activated the ET-R kinase and induced partial differentiation. NGF, which can bind to endogenous p75, did not induce differentiation but enhanced the EGF-induced response, leading to differentiation of almost all cells. A mutated NGF, 3T-NGF, that binds to TrkA but not to p75 did not synergize with EGF. Enhancement of EGF-induced differentiation required at least nanomolar concentrations of NGF, consistent with the low-affinity p75 binding site. EGF may induce a limited number of neuronal cells because it also enhanced apoptosis. Both NGF and a caspase inhibitor reduced apoptosis and, thereby, enhanced differentiation. NGF seems to enhance survival through the phosphatidylinositol-3 kinase (PI3K) pathway. Consistent with this hypothesis, Akt, a downstream effector of the PI3K pathway, was hyperphosphorylated in the presence of EGF+NGF. These results demonstrate that TrkA kinase initiates differentiation, and p75 enhances differentiation by rescuing differentiating cells from apoptosis via the PI3K pathway. Even though both EGF and NGF are required for differentiation of LAN5/ET-R cells, only NGF is required for survival of the differentiated cells. In the absence of NGF, the cells die by an apoptotic mechanism, involving caspase-3. An anti-p75 antibody blocked the survival effect of NGF. Brain-derived neurotrophic factor also enhanced cell survival, indicating that in differentiated cells, NGF acts through the p75 receptor to prevent apoptosis.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12503079&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1002/jnr.10480
dc.subjectAnimals; Antibodies, Blocking; Apoptosis; Blotting, Western; Brain-Derived Neurotrophic Factor; Carrier Proteins; Caspase 1; Caspase 3; Caspases; Cell Differentiation; Cell Survival; Dose-Response Relationship, Drug; *Drug Synergism; Epidermal Growth Factor; Flow Cytometry; Humans; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Nerve Growth Factor; Neurites; Neuroblastoma; PC12 Cells; PTEN Phosphohydrolase; Phosphoric Monoester Hydrolases; Phosphorylation; Precipitin Tests; Protein Folding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-cbl; Rats; Receptor, Epidermal Growth Factor; Receptor, Nerve Growth Factor; *Receptor, trkA; Receptors, Nerve Growth Factor; Recombinant Fusion Proteins; Time Factors; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins; *Ubiquitin-Protein Ligases
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleNovel functional interactions between Trk kinase and p75 neurotrophin receptor in neuroblastoma cells
dc.typeJournal Article
dc.source.journaltitleJournal of neuroscience research
dc.source.volume71
dc.source.issue2
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/633
dc.identifier.contextkey651103
html.description.abstract<p>To understand the functional interactions between the TrkA and p75 nerve growth factor (NGF) receptors, we stably transfected LAN5 neuroblastoma cells with an expression vector for ET-R, a chimeric receptor with the extracellular domain of the epidermal growth factor receptor (EGFR), and the TrkA transmembrane and intracellular domains. EGF activated the ET-R kinase and induced partial differentiation. NGF, which can bind to endogenous p75, did not induce differentiation but enhanced the EGF-induced response, leading to differentiation of almost all cells. A mutated NGF, 3T-NGF, that binds to TrkA but not to p75 did not synergize with EGF. Enhancement of EGF-induced differentiation required at least nanomolar concentrations of NGF, consistent with the low-affinity p75 binding site. EGF may induce a limited number of neuronal cells because it also enhanced apoptosis. Both NGF and a caspase inhibitor reduced apoptosis and, thereby, enhanced differentiation. NGF seems to enhance survival through the phosphatidylinositol-3 kinase (PI3K) pathway. Consistent with this hypothesis, Akt, a downstream effector of the PI3K pathway, was hyperphosphorylated in the presence of EGF+NGF. These results demonstrate that TrkA kinase initiates differentiation, and p75 enhances differentiation by rescuing differentiating cells from apoptosis via the PI3K pathway. Even though both EGF and NGF are required for differentiation of LAN5/ET-R cells, only NGF is required for survival of the differentiated cells. In the absence of NGF, the cells die by an apoptotic mechanism, involving caspase-3. An anti-p75 antibody blocked the survival effect of NGF. Brain-derived neurotrophic factor also enhanced cell survival, indicating that in differentiated cells, NGF acts through the p75 receptor to prevent apoptosis.</p>
dc.identifier.submissionpathgsbs_sp/633
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages157-72


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