Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase

Ballard, Darby J; Peng, Hao-Yun; Das, Jugal Kishore; Kumar, Anil; Wang, Liqing; Ren, Yijie; Xiong, Xiaofang; Ren, Xingcong; Yang, Jin‐Ming; Song, Jianxun

doi:10.3389/fmolb.2021.727863

Cited by 21 publications

(18 citation statements)

References 128 publications

(152 reference statements)

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“…eEF2K activity is regulated by several upstream signalling pathways, as well as factors such as calcium ion and oxygen levels ( Ballard et al, 2021 ). Given that the Rpl24 Bst mutation increases phosphorylation of P-eEF2, we assessed what effect the mutation had on multiple kinases upstream of eEF2K in Apc fl/fl Kras G12D/+ and Apc fl/fl Kras G12D/+ Rpl24 Bst/+ small intestinal tissue and organoids.…”

Section: Resultsmentioning

confidence: 99%

Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Knight

Vlahov

Gay

et al. 2021

eLife

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Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models.

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Section: Resultsmentioning

confidence: 99%

Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Knight

Vlahov

Gay

et al. 2021

eLife

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“…We also observed a significant phosphorylation increase of T59 on EEF2. Since EEF2K acts as a negative regulator of protein synthesis by phosphorylating EEF2 on T59, its phosphorylation by mTORC1 switches off its kinase activity, resulting in EEF2 activation and facilitating translational elongation . Interestingly, EIF4B, one substrate of RPS6KB1 and an indispensable factor in translational initiation, displayed increased and decreased phosphorylation on different sites, suggesting at least two distinct kinases regulate its activity.…”

Section: Resultsmentioning

confidence: 99%

Temporal Proteomic and Phosphoproteomic Analysis of EV-A71-Infected Human Cells

Zhao

Wang

et al. 2022

J. Proteome Res.

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Human enterovirus A71 (EV-A71), a member of the Picornaviridae family, is one of the main etiological viruses that lead to hand, foot, and mouth disease (HFMD). We utilized a multiplex tandem mass tag-based quantitative proteomic technique to monitor the alternation of the whole cell proteome and phosphoproteome of human rhabdomyosarcoma cells over the course of EV-A71 infection. We successfully quantified more than 7000 host proteins and 17,000 phosphosites, of which 80 proteins and nearly 1700 phosphosites were significantly regulated upon viral infection. We found that Myc proto-oncogene protein level decreased significantly, benefiting EV-A71 replication. Multiple signaling pathways were regulated in phosphorylation events that converge for protein translation, cell cycle control, and cell survival. Numerous host factors targeted by virus proteins are phosphoproteins. These factors are involved in host translational initiation, unfolded protein response, endoplasmic reticulum stress, and stress granule formation, and their phosphorylation may play key roles in the virus life cycle. Notably, we identified three conserved phosphorylation sites on viral polyproteins that have not been previously reported. Our study provides valuable resources for a systematic understanding of the interaction between the host cells and the EV-A71 at the protein and the post-translational level.

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“…eEF2K is able to influence synaptic plasticity, memory, and regulate protein translation in dendrites. Increased eEF2K expression is observed in AD, PD and epilepsy, and its phosphorylation is reduced as a key downstream effector of mTOR ( Ballard et al, 2021 ). In conclusion, targeting PI3K/Akt is of great value for studying the pathogenesis of neurological diseases and new drug development.…”

Section: Pi3k/akt Signal Pathway and The Nervous Systemmentioning

confidence: 99%

Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases

et al. 2022

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Neurological diseases impose a tremendous and increasing burden on global health, and there is currently no curative agent. Puerarin, a natural isoflavone extracted from the dried root of Pueraria montana var. Lobata (Willd.) Sanjappa and Predeep, is an active ingredient with anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-regulating effects. It has great potential in the treatment of neurological and other diseases. Phosphatidylinositol 3-kinases/protein kinase B (PI3K/Akt) signal pathway is a crucial signal transduction mechanism that regulates biological processes such as cell regeneration, apoptosis, and cognitive memory in the central nervous system, and is closely related to the pathogenesis of nervous system diseases. Accumulating evidence suggests that the excellent neuroprotective effect of puerarin may be related to the regulation of the PI3K/Akt signal pathway. Here, we summarized the main biological functions and neuroprotective effects of puerarin via activating PI3K/Akt signal pathway in neurological diseases. This paper illustrates that puerarin, as a neuroprotective agent, can protect nerve cells and delay the progression of neurological diseases through the PI3K/Akt signal pathway.

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Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase

Cited by 21 publications

References 128 publications

Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Temporal Proteomic and Phosphoproteomic Analysis of EV-A71-Infected Human Cells

Protective effects and mechanism of puerarin targeting PI3K/Akt signal pathway on neurological diseases

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