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Mol Cell Proteomics. 2015 Aug;14(8):2177-93. doi: 10.1074/mcp.M114.043331. Epub 2015 Jun 3.

Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2.

Author information

1
From the ‡Department of Cell Biology and Histology, Academic Medical Centre- University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands;
2
§Department of Pathology, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324;
3
¶Netherlands Institute for Neuroscience, Meibergdreef 47, 1105BA Amsterdam, The Netherlands;
4
‖Center for Neurogenomics and Cognitive Research, VU University Amsterdam, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
5
**Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands;
6
‡‡Department of Medical Biochemistry and Microbiology, University of Uppsala, Husargatan 3, 75123 Uppsala, Sweden;
7
§§Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.
8
From the ‡Department of Cell Biology and Histology, Academic Medical Centre- University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands; e.a.reits@amc.uva.nl.

Abstract

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.

PMID:
26041847
PMCID:
PMC4528246
DOI:
10.1074/mcp.M114.043331
[Indexed for MEDLINE]
Free PMC Article

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