The MAP kinase-interacting kinases (MNKs) as targets in oncology

Xie, Jianling; Merrett, James E.; Jensen, Kirk B.; Proud, Christopher G.

doi:10.1080/14728222.2019.1571043

Cited by 33 publications

(30 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most other studies, which typically focus on the effect of MNK inhibition on levels of specific proteins on one or few candidates, are largely without any mechanistic rationale. Also, as they often use small molecule inhibitors of the MNKs which are now known to exert substantial offtarget effects (13), they too are difficult to contextualise in relation to our new data.…”

Section: Capclip Indicates That Phosphorylation Of Eif4e Generally Dementioning

confidence: 99%

“…The two mammalian MNKs, MNK1 and MNK2 (MKNK1 and MKNK2 are the human genes) each give rise to two splice forms, which in turn produce differing protein C-termini that affect the subcellular distribution of the corresponding MNK proteins and their association with upstream MAP kinases. Both mouse and human MNK2 are constitutively active and phosphorylate eIF4E under basal conditions, while MNK1 is strongly activated by upstream MAPK signalling and therefore plays a much greater role in inducible phosphorylation of eIF4E (reviewed in (13)). eIF4E is the only known substrate of the MNKs in vivo (13).…”

Section: Introductionmentioning

confidence: 99%

“…Both mouse and human MNK2 are constitutively active and phosphorylate eIF4E under basal conditions, while MNK1 is strongly activated by upstream MAPK signalling and therefore plays a much greater role in inducible phosphorylation of eIF4E (reviewed in (13)). eIF4E is the only known substrate of the MNKs in vivo (13).…”

Section: Introductionmentioning

confidence: 99%

“…While a number of studies have shown an association between elevated P-eIF4E levels and cancer (13), and while eIF4E S209A/S209A knock-in mice are greatly deficient for cellular transformation in a mouse PTEN KO model of high-grade prostate intraepithelial neoplasia (PIN), the translational consequences of eIF4E Ser209 phosphorylation remain unclear (14). While a small number of candidate mRNAs have been identified whose translation and/or polysomal association appears to increase with P-eIF4E, we understand neither the mechanistic basis for these selective translational differences nor the biological consequences of the changes in synthesis of specific proteins as they relate to upstream Ras/ERK signalling.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

capCLIP: a new tool to probe protein synthesis in human cells through capture and identification of the eIF4E-mRNA interactome

Jensen

Dredge

Toubia

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Translation initiation of eukaryotic mRNAs commences with recognition of the m 7 G cap by the capbinding protein eIF4E and the subsequent recruitment of additional translation initiation factors to the mRNA's 5′ end. eIF4E's essential role in translation suggests that the cellular eIF4E-mRNA interactome (or 'eIF4E cap-ome') may serve as a faithful proxy of cellular translational activity. Here we describe capCLIP, a novel method to systematically capture and quantify the eIF4E cap-ome. To validate capCLIP, we identified the eIF4E cap-omes in human cells ± the partial mTORC1 inhibitor rapamycin. TOP (terminal oligopyrimidine) mRNA representation is systematically reduced in rapamycin-treated cells, consistent with the well-known effect of mTORC1 inhibition on translation of these mRNAs. capCLIP tag data also permits the identification of a refined, 7-nucleotide consensus motif for TOP mRNAs (5′-CUYUYYC-3′). In addition, we apply capCLIP to probe the consequences of phosphorylation of eIF4E, a modification whose function had remained unclear. Phosphorylation of eIF4E drives an overall reduction in eIF4E-mRNA association, and strikingly, the mRNAs most sensitive to phosphorylation possess short 5′ UTRs. capCLIP provides a sensitive and comprehensive measure of cellular translational activity. We foresee its widespread use as a high-throughput means for assessing translation in contexts not amenable to existing methodologies.

show abstract

Section: Capclip Indicates That Phosphorylation Of Eif4e Generally Dementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

capCLIP: a new tool to probe protein synthesis in human cells through capture and identification of the eIF4E-mRNA interactome

Jensen

Dredge

Toubia

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, development of cancer cell protein synthesis inhibitory strategies is arousing growing interest in cancer research (Bhat et al, ). Such strategies include inhibition of specific targets in the translation machinery (Itoua Maïga et al, ) as well as inhibitors of upstream signaling pathways involved at different stages of cancer development (Bhat et al, ; Xie, Merrett, Jensen, & Proud, ).…”

Section: Introductionmentioning

confidence: 99%

A new potential anti‐cancer beta‐carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation

Carvalho

Viaene

Vandenbussche

et al. 2019

Drug Development Research

View full text Add to dashboard Cite

Gliomas remain highly fatal due to their high resistance to current therapies. Deregulation of protein synthesis contributes to cancer onset and progression and is a source of rising interest for new drugs. CM16, a harmine derivative with predicted high blood–brain barrier penetration, exerts antiproliferative effects partly through translation inhibition. We evaluated herein how CM16 alters the proteome of glioma cells. The analysis of the gel‐free LC/MS and auto‐MS/MS data showed that CM16 induces time‐ and concentration‐dependent significant changes in the total ion current chromatograms. In addition, we observed spontaneous clustering of the samples according to their treatment condition and their proper classification by unsupervised and supervised analyses, respectively. A two‐dimensional gel‐based approach analysis allowed us to identify that treatment with CM16 may downregulate four key proteins involved in glioma aggressiveness and associated with poor patient survival (HspB1, BTF3, PGAM1, and cofilin), while it may upregulate galectin‐1 and Ebp1. Consistently with the protein synthesis inhibition properties of CM16, HspB1, Ebp1, and BTF3 exert known roles in protein synthesis. In conclusion, the downregulation of HspB1, BTF3, PGAM1 and cofilin bring new insights in CM16 antiproliferative effects, further supporting CM16 as an interesting protein synthesis inhibitor to combat glioma.

show abstract

Eukaryotic initiation factor 4E (eIF4E): A recap of the cap‐binding protein

Batool

Aashaq

Andrabi

2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Eukaryotic initiation factor 4E (eIF4E), a fundamental effector and rate limiting element of protein synthesis, binds the 7‐methylguanosine cap at the 5′ end of eukaryotic messenger RNA (mRNA) specifically as a constituent of eIF4F translation initiation complex thus facilitating the recruitment of mRNA to the ribosomes. This review focusses on the engagement of signals contributing to growth factor originated maxim and their role in the activation of eIF4E to achieve a collective influence on cellular growth, with a key focus on conjuring vital processes like protein synthesis. The review invites considerable interest in elevating the appeal of eIF4E beyond its role in regulating translation viz a viz cancer genesis, attributed to its phosphorylation state that improves the prospect for the growth of the cancerous cell. This review highlights the latest studies that have envisioned to target these pathways and ultimately the translational machinery for therapeutic intervention. The review also brings forward the prospect of eIF4E to act as a converging juncture for signaling pathways like mTOR/PI3K and Mnk/MAPK to promote tumorigenesis.

show abstract

The MAP kinase-interacting kinases (MNKs) as targets in oncology

Cited by 33 publications

References 104 publications

capCLIP: a new tool to probe protein synthesis in human cells through capture and identification of the eIF4E-mRNA interactome

capCLIP: a new tool to probe protein synthesis in human cells through capture and identification of the eIF4E-mRNA interactome

A new potential anti‐cancer beta‐carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation

Eukaryotic initiation factor 4E (eIF4E): A recap of the cap‐binding protein

Contact Info

Product

Resources

About