CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability

Choi, Seung Hyuk; Martínez, Thomas F.; Kim, Seongjae; Donaldson, Cynthia J.; Shokhirev, Maxim N.; Saghatelian, Alan; Jones, Katherine A.

doi:10.1101/gad.322339.118

Cited by 51 publications

(58 citation statements)

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“…In conclusion, using a chemoproteomic approach, we have discovered that CDK4 phosphorylates 4E-BP1 during the M-to-G 1 transition, thereby maintaining capdependent translation. These findings shed further light on the cell cycle-dependent phosphorylation of 4E-BP1, the regulation of which was previously reported to be mediated by CDK1 and CDK12 in mitotic cells [29,61,62], and PLK1 and CDK1 in cells undergoing meiosis [22,32,[63][64][65]. Given this newly discovered role of CDK4, it is likely that inhibition of mitotic 4E-BP1 phosphorylation is a previously unknown function of CDK4/6 inhibitors such as palbociclib, and may explain the synergy between these drugs and mTOR inhibitors [66][67][68][69][70][71][72].…”

Section: Discussionsupporting

confidence: 71%

“…While our report is the first to directly connect CDK4 to 4E-BP1 regulation, this is not the only CDK linked to phosphorylation of this translational repressor. CDK12, via phosphorylation of 4E-BP1 at S65 and T70, cooperates with mTORC1 to drive selective translation of proteins involved in maintenance of the mitotic genome [29]. Additionally, CDK1, the master regulator of the G 2 /M transition, can substitute for mTORC1 to phosphorylate 4E-BP1 at the putative mTORC1 sites to activate cap-dependent translation during mitosis [30,31] and meiosis [32].…”

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confidence: 99%

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Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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Phosphorylation of translational repressor eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) controls the initiation of capdependent translation, a type of protein synthesis that is frequently upregulated in human diseases such as cancer. Because of its critical cellular function, it is not surprising that multiple kinases can post-translationally modify 4E-BP1 to drive aberrant cap-dependent translation. We recently reported a site-selective chemoproteomic method for uncovering kinase-substrate interactions, and using this approach, we discovered the cyclin-dependent kinase (CDK)4 as a new 4E-BP1 kinase. Herein, we describe our extension of this work and reveal the role of CDK4 in modulating 4E-BP1 activity in the transition from mitosis to G1, thereby demonstrating a novel role for this kinase in cell cycle regulation.Cap-dependent translation is an important cellular process that controls the translation of select mRNAs typically encoding for growth factors and oncogenes [1][2][3][4]. The initiation of cap-dependent mRNA translation is governed by the availability of eIF4E, the m 7 GpppX-cap-binding translation initiation factor [5,6]. This protein is highly regulated, primarily through the work of the 4E-BPs, which sequester eIF4E from eIF4G and the eIF4F translation initiation complex [7][8][9][10][11][12][13]. The activity of 4E-binding protein 1 (4E-BP1) is in turn regulated by phosphorylation, where hypophosphorylated 4E-BP1 binds strongly to eIF4E to inhibit translation, while hyperphosphorylated 4E-BP1 releases eIF4E to initiate capdependent translation [13][14][15][16]. For many years, the only validated kinase known to affect 4E-BP1 phosphorylation has been mechanistic target of rapamycin complex 1 (mTORC1), which was shown to hierarchically phosphorylate 4E-BP1 at T37 and T46 followed by T70 and S65 [14,15,17,18]. However, several findings have called into question the exclusivity of mTORC1 for each of these phosphorylation sites [19], namely reports demonstrating that other unknown kinases can also phosphorylate 4E-BP1 to stimulate cap-dependent translation [20][21][22], particularly in cases of mTOR inhibitor drug resistance [23][24][25][26].Recently, our laboratory has developed a chemoproteomic pipeline by which to identify site-specific kinase-substrate interactions, Phosphosite-Accurate kinase-substrate cross(X)linking Assay or PhAXA [27]. Using this methodology, we discovered that cyclin-dependent kinase 4 (CDK4), which is primarily responsible for controlling the cell cycle checkpoint at the G 1 /S transition through phosphorylation of the retinoblastoma tumor suppressor protein (Rb) Abbreviations 4E-BP1, 4E-binding protein 1; CDK, cyclin-dependent kinase; FDR, false discovery rate; mTORC1, mechanistic target of rapamycin complex 1; PSMs, peptide-spectrum matches; WT, wild-type.

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Section: Discussionsupporting

confidence: 71%

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confidence: 99%

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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“…Phosphorylation of 4EBP promotes 5 cap-dependent mRNA translation by dissociation of 4EBP from eIF4E, thus allowing assembly of the eIF4F complex. 4EBP is also phosphorylated by other kinases to regulate its function in an mTORC1-dependent or -independent manner [62,63]. In addition to regulating key effectors of protein synthesis, mTOR also regulates synthesis of amino acids, the building blocks for protein synthesis.…”

Section: Protein Synthesismentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

156

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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Section: Cdk12 In Translationmentioning

confidence: 99%

“…Besides the regulatory role in mRNA biosynthesis, CDK12 also regulates the translation of mRNA [14]. Choi et al found that CDK12 promoted translation of mRNAs via phosphorylating 4E-binding Protein 1 (4E-BP1), the mRNA 5 cap-binding repressor [14]. More specifically, CDK12 cooperates with the mechanistic target of rapamycin (mTORC1) to affect the translation of mRNAs encoding DNA repair factors, ribosome and translation factors via phosphorylating 4E-BP1 at two Ser-Pro sites (S65, T70) that control the exchange of 4E-BP1, with eukaryotic initiation factor 4G (eIF4G) at the 5 cap of target mRNAs.…”

Section: Cdk12 In Translationmentioning

confidence: 99%

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Liang

et al. 2020

Cells

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Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK12′s biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy.

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CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability

Cited by 51 publications

References 72 publications

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

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