title: BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome.
abstract: Brain-derived neurotrophic factor (BDNF) promotes synaptic strengthening through the regulation of kinase and phosphatase activity. Conversely, striatal-enriched protein tyrosine phosphatase (STEP) opposes synaptic strengthening through inactivation or internalization of signaling molecules. Here, we investigated whether BDNF regulates STEP levels/activity. BDNF induced a reduction of STEP61 levels in primary cortical neurons, an effect that was prevented by inhibition of tyrosine kinases, phospholipase C gamma, or the ubiquitin-proteasome system (UPS). The levels of pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204), two STEP substrates, increased in BDNF-treated cultures, and blockade of the UPS prevented STEP61 degradation and reduced BDNF-induced GluN2B and ERK1/2 phosphorylation. Moreover, brief or sustained cell depolarization reduced STEP61 levels in cortical neurons by different mechanisms. BDNF also promoted UPS-mediated STEP61 degradation in cultured striatal and hippocampal neurons. In contrast, nerve growth factor and neurotrophin-3 had no effect on STEP61 levels. Our results thus indicate that STEP61 degradation is an important event in BDNF-mediated effects.
authors.affiliation: Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Saavedra
authors.affiliation: Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Puigdellívol
authors.affiliation: Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Shiraz
authors.initials: S
authors.lastname: Tyebji
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kurup
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ginés
authors.affiliation: Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.affiliation: Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT, 06520, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: Departament de Biologia Cel · lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Catalonia, Spain. estherperez@ub.edu.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain. estherperez@ub.edu.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. estherperez@ub.edu.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D017072:Neostriatum / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D020933:Neurotrophin 3 / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C121001:NR2B NMDA receptor; D020933:Neurotrophin 3; D016194:Receptors, N-Methyl-D-Aspartate; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse; D051966:Phospholipase C gamma; D046988:Proteasome Endopeptidase Complex
keywords: Depolarization; ERK1/2; GluN2B; NGF; NT-3; PLCγ; STEP33