Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?

Shillingford, Shanelle R.; Bennett, Anton M.

doi:10.1146/annurev-pharmtox-051921-121923

Cited by 11 publications

(8 citation statements)

References 128 publications

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“…Until now, the role of DUSP8 in the progression of cancer has been largely neglected. By using a phosphokinase assay, we were able to identify potential new substrates GSK-3α/β, GSK-3β, Src, STAT5a/b, WNK1, PRAS40, RSK1/2, β-catenin, c-Jun and HSP60 known as drivers of cancer, whose relevant residues could be dephosphorylated by DUSP8 in addition to the reported DUSP8 relevant residues of JNK and p38 [ 21 , 22 ]. Our in silico analysis of genes associated with JNK signaling revealed that OS is decreased in lung cancer when downregulated.…”

Section: Discussionmentioning

confidence: 99%

miR-147b mediated suppression of DUSP8 promotes lung cancer progression

Turkowski,

Herzberg,

Günther

et al. 2024

Oncogene

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Dual-specificity phosphatase 8 (DUSP8) plays an important role as a selective c-Jun N-terminal kinase (JNK) phosphatase in mitogen-activated protein kinase (MAPK) signaling. In this study, we found that DUSP8 is silenced by miR-147b in patients with lung adenocarcinoma (LUAD), which correlates with poor overall survival. Overexpression of DUSP8 resulted in a tumor-suppressive phenotype in vitro and in vivo experimental models, whereas silencing DUSP8 with a siRNA approach abrogated the tumor-suppressive properties. We found that miR-147b is a posttranscriptional regulator of DUSP8 that is highly expressed in patients with LUAD and is associated with lower survival. NanoString analysis revealed that the MAPK signaling pathway is mainly affected by overexpression of miR-147b, leading to increased proliferation and migration and decreased apoptosis in vitro. Moreover, induction of miR-147b promotes tumor progression in vitro and in vivo experimental models. Knockdown of miR-147b restored DUSP8, decreased tumor progression in vitro, and increased apoptosis via JNK phosphorylation. These results suggest that miR-147b plays a key role in regulating MAPK signaling in LUAD. The link between DUSP8 and miR-147b may provide novel approaches for the treatment of lung cancer.

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Section: Discussionmentioning

confidence: 99%

miR-147b mediated suppression of DUSP8 promotes lung cancer progression

Turkowski,

Herzberg,

Günther

et al. 2024

Oncogene

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“…Future studies will need to address the question whether NMA1982 is indeed crucial for N. meningitidis survival and virulence, and thus may validate NMA1982 as a novel therapeutic target for the treatment of meningococcal diseases. Human PTPs have become attractive drug targets for many serious conditions, most notably cancer [49][50][51] . Compared to human PTPs, the shorter P-loop in NMA1982 results in a unique active site conformation, which may allow for the development of small molecule inhibitors with selectivity for the N. meningitidis protein.…”

Section: Discussionmentioning

confidence: 99%

Enzyme Mechanistic Studies of NMA1982, a Protein Tyrosine Phosphatase and Potential Virulence Factor in Neisseria meningitidis

Wu,

Coureuil,

Nassif

et al. 2023

Preprint

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Protein phosphorylation is an integral part of many cellular processes, not only in eukaryotes but also in bacteria. The discovery of both prokaryotic protein kinases and phosphatases has created interest in generating antibacterial therapeutics that target these enzymes. NMA1982 is a putative phosphatase from Neisseria meningitidis, the causative agent of meningitis and meningococcal septicemia. The overall fold of NMA1982 closely resembles that of protein tyrosine phosphatases (PTPs). However, the hallmark C(X)5R PTP signature motif, containing the catalytic cysteine and invariant arginine, is shorter by one amino acid in NMA1982. This has cast doubt about the catalytic mechanism of NMA1982 and its assignment to the PTP superfamily. Here, we demonstrate that NMA1982 indeed employs a catalytic mechanism that is specific to PTPs. Mutagenesis experiments, transition state inhibition, pH-dependence activity, and oxidative inactivation experiments all support that NMA1982 is a genuine PTP. Importantly, we show that NMA1982 is secreted by N. meningitidis, suggesting that this protein is a potential virulence factor. Future studies will need to address whether NMA1982 is indeed essential for N. meningitidis survival and virulence. Based on its unique active site conformation, NMA1982 may become a suitable target for developing selective antibacterial drugs.

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“…While activation of the signaling cascade is corroborated by phosphorylation, dephosphorylation catalyzed by a phosphatase is needed to terminate the signaling to avoid excessive proliferation [ 129 ]. Most protein phosphatases are either specific to phospho-Ser/-Thr, designated as PPT, or phospho-Tyr, designated as PTP, while phosphatase and tensin homologs (PTEN) are specific to phosphatidylinositides [ 90 , 126 , 130 ]. The reaction mechanisms for PPT and PTP during dephosphorylation are completely different, while there is a similarity between PTP and PTEN in that they both employ Cys as the catalytic amino acid.…”

Section: Cellular Responses To 1 Omentioning

confidence: 99%

Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death

2023

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Energy transfer to ground state triplet molecular oxygen results in the generation of singlet molecular oxygen (1O2), which has potent oxidizing ability. Irradiation of light, notably ultraviolet A, to a photosensitizing molecule results in the generation of 1O2, which is thought to play a role in causing skin damage and aging. It should also be noted that 1O2 is a dominant tumoricidal component that is generated during the photodynamic therapy (PDT). While type II photodynamic action generates not only 1O2 but also other reactive species, endoperoxides release pure 1O2 upon mild exposure to heat and, hence, are considered to be beneficial compounds for research purposes. Concerning target molecules, 1O2 preferentially reacts with unsaturated fatty acids to produce lipid peroxidation. Enzymes that contain a reactive cysteine group at the catalytic center are vulnerable to 1O2 exposure. Guanine base in nucleic acids is also susceptible to oxidative modification, and cells carrying DNA with oxidized guanine units may experience mutations. Since 1O2 is produced in various physiological reactions in addition to photodynamic reactions, overcoming technical challenges related to its detection and methods used for its generation would allow its potential functions in biological systems to be better understood.

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Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?

Cited by 11 publications

References 128 publications

miR-147b mediated suppression of DUSP8 promotes lung cancer progression

miR-147b mediated suppression of DUSP8 promotes lung cancer progression

Enzyme Mechanistic Studies of NMA1982, a Protein Tyrosine Phosphatase and Potential Virulence Factor in Neisseria meningitidis

Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death

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