scholarly journals Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2967
Author(s):  
Celia Pinto-Díez ◽  
Raquel Ferreras-Martín ◽  
Rebeca Carrión-Marchante ◽  
Víctor M. González ◽  
María Elena Martín
Keyword(s):  
Map Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Polypyrimidine Tract Binding Protein ◽  
Hematological Cancers ◽  
Mitogen Activated Protein ◽  
Specific Proteins ◽  
Nuclear Ribonucleoprotein

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.

Mnk inhibitors: a patent review

2021 ◽  
Vol 10 (1) ◽  
pp. 25-35
Author(s):  
Ahmed M Abdelaziz ◽  
Mingfeng Yu ◽  
Shudong Wang
Keyword(s):  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Research Articles ◽  
Eukaryotic Initiation Factor 4E ◽  
Current State ◽  
Patent Review ◽  
Hematological Cancers ◽  
Mitogen Activated Protein ◽  
Patent Applications

The alteration of mRNA translation has a crucial role in defining the changes in cellular proteome. The phosphorylation of eukaryotic initiation factor 4E by mitogen-activated protein kinase-interacting kinases (Mnks) leads to the release and translation of mRNAs of specific oncogenic proteins. In recent years, the efforts made by the pharmaceutical industry to develop novel chemical skeletons to create potent and selective Mnk inhibitors have been fruitful. The pyridone-aminal scaffold has been utilized to generate several series of Mnk inhibitors presented in multiple patent applications and research articles. Tomivosertib (eFT508) is one of the molecules with such scaffold. It is one of the first two Mnk inhibitors that entered clinical trials, and has displayed momentous activity against several solid and hematological cancers. The present compilation provides a succinct review of the current state of development of pyridone-aminal-derived Mnk inhibitors through the analysis of relevant patent applications filed in the last 5 years.

scholarly journals The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

2018 ◽  
Author(s):  
Senthilmurugan Ramalingam ◽  
Vidya P. Ramamurthy ◽  
Lalji K. Gediya ◽  
Francis N. Murigi ◽  
Puranik Purushottamachar ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mesenchymal Transition ◽  
Eukaryotic Initiation Factor 4E ◽  
Mtorc1 Signaling ◽  
Mitogen Activated Protein ◽  
Orally Bioavailable ◽  
Tumor Growth And Metastasis

ABSTRACTCurrently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

scholarly journals The Mitogen-Activated Protein Kinase Signal-Integrating Kinase Mnk2 Is a Eukaryotic Initiation Factor 4E Kinase with High Levels of Basal Activity in Mammalian Cells

2001 ◽  
Vol 21 (3) ◽  
pp. 743-754 ◽  
Author(s):  
Gert C. Scheper ◽  
Nick A. Morrice ◽  
Miranda Kleijn ◽  
Christopher G. Proud
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
3T3 Cells ◽  
Mapk Pathways ◽  
Eukaryotic Initiation Factor 4E ◽  
Mitogen Activated Protein ◽  
Swiss 3T3

ABSTRACT The cap-binding translation initiation factor eukaryotic initiation factor 4E (eIF4E) is phosphorylated in vivo at Ser209 in response to a variety of stimuli. In this paper, we show that the mitogen-activated protein kinase (MAPK) signal-integrating kinase Mnk2 phosphorylates eIF4E at this residue. Mnk2 binds to the scaffolding protein eIF4G, and overexpression of Mnk2 results in increased phosphorylation of endogenous eIF4E, showing that it can act as an eIF4E kinase in vivo. We have identified eight phosphorylation sites in Mnk2, of which at least three potential MAPK sites are likely to be essential for Mnk2 activity. In contrast to that of Mnk1, the activity of overexpressed Mnk2 is high under control conditions and could only be reduced substantially by a combination of PD98059 and SB203580, while the activity of endogenous Mnk2 in Swiss 3T3 cells was hardly affected upon treatment with these inhibitors. These compounds did not abolish phosphorylation of eIF4E, implying that Mnk2 may mediate phosphorylation of eIF4E in Swiss 3T3 cells. In vitro phosphorylation studies show that Mnk2 is a significantly better substrate than Mnk1 for extracellular signal-regulated kinase 2 (ERK2), p38MAPKα, and p38MAPKβ. Therefore, the high levels of activity of Mnk2 under several conditions may be explained by efficient activation of Mnk2 by low levels of activity of the upstream kinases. Interestingly, we found that the association of both Mnk1 and Mnk2 with eIF4G increased upon inhibition of the MAPK pathways while activation of ERK resulted in decreased binding to eIF4G. This might reflect a mechanism to ensure rapid, but transient, phosphorylation of eIF4E upon stimulation of the MAPK pathways.

scholarly journals The N and C Termini of the Splice Variants of the Human Mitogen-Activated Protein Kinase-Interacting Kinase Mnk2 Determine Activity and Localization

2003 ◽  
Vol 23 (16) ◽  
pp. 5692-5705 ◽  
Author(s):  
Gert C. Scheper ◽  
Josep L. Parra ◽  
Mary Wilson ◽  
Barbara van Kollenburg ◽  
Alfred C. O. Vertegaal ◽  
...  
Keyword(s):  
Map Kinase ◽  
Binding Site ◽  
Mammalian Cells ◽  
Map Kinases ◽  
Splice Variants ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mitogen Activated Protein

ABSTRACT The cap-binding eukaryotic initiation factor eIF4E is phosphorylated by the mitogen-activated protein (MAP) kinase-interacting kinases (Mnk's). Three forms of the Mnk's exist in human cells: Mnk1, Mnk2a, and Mnk2b. These last two are derived from the same gene by alternative splicing and differ only at their C termini. While Mnk2a contains a MAP kinase-binding site in this region, Mnk2b lacks such a sequence and is much less readily activated by MAP kinases in vitro. Expression of Mnk2b in mammalian cells leads to increased phosphorylation of eIF4E, showing that it acts as an eIF4E kinase in vivo. While Mnk2a is cytoplasmic, a substantial amount of Mnk2b is found in the nucleus. Both enzymes contain a stretch of basic residues in their N termini that plays a role in binding to eIF4G and functions as a nuclear localization signal. Binding of eIF4G or nuclear import appears to be regulated by the C terminus of Mnk2a. Furthermore, the MAP kinase-binding site of Mnk2a regulates nuclear entry. Within the nucleus, Mnk2b and certain variants of Mnk2a that are present in the nucleus colocalize with the promyelocytic leukemia protein PML, which also binds to eIF4E.

scholarly journals Regulation of Eukaryotic Initiation Factor 4E (eIF4E) Phosphorylation by Mitogen-Activated Protein Kinase Occurs through Modulation of Mnk1-eIF4G Interaction

2010 ◽  
Vol 30 (21) ◽  
pp. 5160-5167 ◽  
Author(s):  
Mayya Shveygert ◽  
Constanze Kaiser ◽  
Shelton S. Bradrick ◽  
Matthias Gromeier
Keyword(s):  
Protein Kinase ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Serine Threonine Kinase ◽  
Eukaryotic Initiation Factor 4E ◽  
Tumorigenic Potential ◽  
Mitogen Activated Protein

ABSTRACT The m7G cap binding protein eukaryotic initiation factor 4E (eIF4E) is a rate-limiting determinant of protein synthesis. Elevated eIF4E levels, commonly associated with neoplasia, promote oncogenesis, and phosphorylation of eIF4E at Ser209 is critical for its tumorigenic potential. eIF4E phosphorylation is catalyzed by mitogen-activated protein kinase (MAPK)-interacting serine/threonine kinase (Mnk), a substrate of Erk1/2 and p38 MAPKs. Interaction with the scaffolding protein eIF4G, which also binds eIF4E, brings Mnk and its substrate into physical proximity. Thus, Mnk-eIF4G interaction is important for eIF4E phosphorylation. Through coimmunoprecipitation assays, we showed that MAPK-mediated phosphorylation of the Mnk1 active site controls eIF4G binding. Utilizing a naturally occurring splice variant, we demonstrated that the C-terminal domain of Mnk1 restricts its interaction with eIF4G, preventing eIF4E phosphorylation in the absence of MAPK signaling. Furthermore, using a small-molecule Mnk1 inhibitor and kinase-dead mutant, we established that Mnk1 autoregulates its interaction with eIF4G, releasing itself from the scaffold after phosphorylation of its substrate. Our findings indicate tight control of eIF4E phosphorylation through modulation of Mnk1-eIF4G interaction.

scholarly journals Role of Mitogen Activated Protein Kinase Signaling in Parkinson’s Disease

2018 ◽  
Vol 19 (10) ◽  
pp. 2973 ◽  
Author(s):  
Anastasiia Bohush ◽  
Grazyna Niewiadomska ◽  
Anna Filipek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Map Kinases ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Important Player

Parkinson’s disease (PD) is a neurodegenerative disorder caused by insufficient dopamine production due to the loss of 50% to 70% of dopaminergic neurons. A shortage of dopamine, which is predominantly produced by the dopaminergic neurons within the substantia nigra, causes clinical symptoms such as reduction of muscle mass, impaired body balance, akinesia, bradykinesia, tremors, postural instability, etc. Lastly, this can lead to a total loss of physical movement and death. Since no cure for PD has been developed up to now, researchers using cell cultures and animal models focus their work on searching for potential therapeutic targets in order to develop effective treatments. In recent years, genetic studies have prominently advocated for the role of improper protein phosphorylation caused by a dysfunction in kinases and/or phosphatases as an important player in progression and pathogenesis of PD. Thus, in this review, we focus on the role of selected MAP kinases such as JNKs, ERK1/2, and p38 MAP kinases in PD pathology.

scholarly journals Filarial Lymphatic Pathology Reflects Augmented Toll-Like Receptor-Mediated, Mitogen-Activated Protein Kinase-Mediated Proinflammatory Cytokine Production

2011 ◽  
Vol 79 (11) ◽  
pp. 4600-4608 ◽  
Author(s):  
Subash Babu ◽  
R. Anuradha ◽  
N. Pavan Kumar ◽  
P. Jovvian George ◽  
V. Kumaraswami ◽  
...  
Keyword(s):  
Lymphatic Filariasis ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Map Kinases ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Map Kinase Pathways

ABSTRACTLymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined cytokine responses to different Toll ligands in patients with chronic lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic-normal (EN) individuals. TLR2, -7, and -9 ligands induced significantly elevated production of Th1 and other proinflammatory cytokines in CP patients in comparison to both INF and EN patients. TLR adaptor expression was not significantly different among the groups; however, both TLR2 and TLR9 ligands induced significantly higher levels of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinases (MAPK) as well as increased activation of NF-κB in CP individuals. Pharmacologic inhibition of both ERK1/2 and p38 MAP kinase pathways resulted in significantly diminished production of proinflammatory cytokines in CP individuals. Our data, therefore, strongly suggest an important role for TLR2- and TLR9-mediated proinflammatory cytokine induction and activation of both the MAPK and NF-κB pathways in the development of pathology in human lymphatic filariasis.

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