BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome

Mol Neurobiol. 2016 Aug;53(6):4261-4273. doi: 10.1007/s12035-015-9335-7. Epub 2015 Jul 30.

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.

Keywords: Depolarization; ERK1/2; GluN2B; NGF; NT-3; PLCγ; STEP33.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Cerebral Cortex / cytology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hippocampus / cytology
  • Membrane Potentials / drug effects
  • Mice
  • Neostriatum / metabolism
  • Nerve Growth Factor / pharmacology
  • Neurons / metabolism
  • Neurotrophin 3 / pharmacology
  • Phospholipase C gamma / metabolism
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Proteolysis / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Ubiquitination / drug effects

Substances

  • Brain-Derived Neurotrophic Factor
  • NR2B NMDA receptor
  • Neurotrophin 3
  • Receptors, N-Methyl-D-Aspartate
  • Nerve Growth Factor
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ptpn5 protein, mouse
  • Phospholipase C gamma
  • Proteasome Endopeptidase Complex