• Anne Wiemhoefer
  • Anita Stargardt
  • Wouter A van der Linden
  • Maria C Renner
  • Ronald E van Kesteren
  • Jan Stap
  • Marcel A Raspe
  • Birgitta Tomkinson
  • Helmut W Kessels
  • Huib Ovaa
  • Herman S Overkleeft
  • Bogdan Florea
  • Eric A Reits

Tripeptidyl peptidase II (TPP2) is a serine peptidase involved in various biological processes, including antigen processing, cell growth, DNA repair, and neuropeptide mediated signaling. The underlying mechanisms of how a peptidase can influence this multitude of processes still remain unknown. We identified rapid proteomic changes in neuroblastoma cells following selective TPP2 inhibition using the known reversible inhibitor butabindide, as well as a new, more potent, and irreversible peptide phosphonate inhibitor. Our data show that TPP2 inhibition indirectly but rapidly decreases the levels of active, di-phosphorylated extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the nucleus, thereby down-regulating signal transduction downstream of growth factors and mitogenic stimuli. We conclude that TPP2 mediates many important cellular functions by controlling ERK1 and ERK2 phosphorylation. For instance, we show that TPP2 inhibition of neurons in the hippocampus leads to an excessive strengthening of synapses, indicating that TPP2 activity is crucial for normal brain function.

Original languageEnglish
Pages (from-to)2177-93
Number of pages17
JournalMolecular and Cellular Proteomics
Volume14
Issue number8
DOI
Publication statusPublished - Aug 2015

ID: 1446312