TY - JOUR
T1 - Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2
AU - Wiemhoefer, Anne
AU - Stargardt, Anita
AU - van der Linden, Wouter A.
AU - Renner, Maria C.
AU - van Kesteren, Ronald E.
AU - Stap, Jan
AU - Raspe, Marcel A.
AU - Tomkinson, Birgitta
AU - Kessels, Helmut W.
AU - Ovaa, Huib
AU - Overkleeft, Herman S.
AU - Florea, Bogdan
AU - Reits, Eric A.
PY - 2015
Y1 - 2015
N2 - 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
AB - 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
U2 - https://doi.org/10.1074/mcp.M114.043331
DO - https://doi.org/10.1074/mcp.M114.043331
M3 - Article
C2 - 26041847
SN - 1535-9476
VL - 14
SP - 2177
EP - 2193
JO - Molecular & cellular proteomics
JF - Molecular & cellular proteomics
IS - 8
ER -