Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2

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. Molecular & Cellular

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5

“…By comparing the transcriptomic and proteomic analyses, we observed three independent responses to the drug: i) an acute phase with genes/proteins induced or repressed in response to sunitinib with a subsequent trend to return to initial values, ii) a stable phase with genes/proteins that are induced/repressed to an equivalent level after short or long exposure to sunitinib, iii) a progressive phase with genes that were induced/repressed by sunitinib and even further induced/repressed in resistant cells ( Figure 5 and 6 ). Only three genes were consistently up-regulated at the mRNA and protein levels; stanniocalcin 2 (STC2, https://www.ncbi.nlm.nih.gov/gene/8614), a secreted, homodimeric glycoprotein, which promotes cell proliferation and cisplatin resistance in cervical cancer 38; connective tissue growth factor (CTGF, https://www.ncbi.nlm.nih.gov/gene/1490), a mitogen related to platelet-derived growth factor that promotes the proliferation, migration and invasion of squamous cell carcinoma 39; tripeptidyl peptidase 1 (TTP1, https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch& Term=1200), a lysosomal serine protease shown to positively regulate Extracellular Signal Regulated Kinase (ERK)/MAP Kinase activity and therefore cell proliferation 40. Whereas STC2 and CTGF belong to “Stable or Progressive” genes at the mRNA and protein levels, TPP1 belongs to “Stable” genes at the mRNA level but to “Progressive” genes at the protein level.…”

Proteomic analysis identifies highly expressed plasma membrane proteins for detection and therapeutic targeting of specific breast cancer subtypes

“…Consistent with this idea, decreased AHNAK expression is associated with a poor outcome in melanoma patients [ 56 ]. SK-BR-3 and DT22 cells also share high expression of TPP2 (tripeptidyl-peptidase 2; 119 and 150 SCs, respectively), a multi-functional enzyme that controls of ERK1 and ERK2 phosphorylation [ 57 ].…”

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

“…Therefore, all negative results obtained using butabindide as the inhibitor [30] must be treated very warily so that AAF--cmk has better transitional potential for any clinical application. Recently, a novel selective, irreversible membrane permeable inhibitor of TPPII, B6, was reported but up to now it is not commercially available [31]. Furthermore, siRNA-based inhibitory strategies are also no perfect for TPPII silencing because they allow to obtain a downregulation of TPPII expression only up to sixty percent [29].…”

“…However, autophagy is not the general mechanism for clearance of such protein aggregates [47]. Previous investigations demonstrated that TPPII inhibition decreases activity of pERK1/2, which belong to the MAP kinases family [31]. Activation of the MAP kinase signaling pathway is one of the most potent prosurvival signals in cancer cells.…”