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Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2

Anne Wiemhoefer1, Anita Stargardt1, Wouter A van der Linden2

  • 1From the ‡Department of Cell Biology and Histology, Academic Medical Centre- University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands;

Molecular & Cellular Proteomics : MCP
|June 5, 2015
PubMed

Insights

Tripeptidyl peptidase II (TPP2) regulates crucial cell functions by controlling ERK1 and ERK2 phosphorylation. Inhibiting TPP2 impacts neuroblastoma cells and brain function, highlighting its importance in normal cellular processes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Tripeptidyl peptidase II (TPP2) is a serine peptidase implicated in diverse biological roles, including antigen processing, cell growth, DNA repair, and neuropeptide signaling.
  • The precise mechanisms by which TPP2 influences these varied cellular processes remain largely unelucidated.

Purpose of the Study:

  • To investigate the functional impact of TPP2 inhibition on cellular signaling pathways.
  • To identify proteomic changes in neuroblastoma cells following TPP2 inhibition.
  • To elucidate the role of TPP2 in neuronal function and synaptic plasticity.

Main Methods:

  • Selective inhibition of TPP2 using both a reversible inhibitor (butabindide) and a novel irreversible peptide phosphonate inhibitor.
  • Proteomic analysis of neuroblastoma cells to identify rapid changes post-inhibition.
  • Assessment of extracellular signal-regulated kinase 1 (ERK1) and ERK2 phosphorylation levels.
  • Evaluation of synaptic plasticity in hippocampal neurons following TPP2 inhibition.

Main Results:

  • TPP2 inhibition led to rapid proteomic alterations in neuroblastoma cells.
  • Inhibition of TPP2 resulted in a decrease in nuclear active, di-phosphorylated ERK1 and ERK2.
  • This reduction in ERK phosphorylation down-regulates signal transduction pathways activated by growth factors and mitogenic stimuli.
  • TPP2 inhibition in hippocampal neurons caused excessive synaptic strengthening, indicating a critical role in brain function.

Conclusions:

  • TPP2 plays a significant role in mediating cellular functions through the regulation of ERK1 and ERK2 phosphorylation.
  • TPP2 activity is essential for maintaining normal brain function, particularly synaptic regulation.
  • Targeting TPP2 may offer therapeutic avenues for conditions involving aberrant cell growth or signaling pathways.

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