CDK1 substitutes for mTOR kinase to activate mitotic cap-dependent protein translation

Shuda, Masahiro; Velásquez, Celestino; Cheng, Erdong; Cordek, Daniel G.; Kwun, Hyun Jin; Chang, Yuan

doi:10.1073/pnas.1505787112

Cited by 118 publications

(179 citation statements)

References 52 publications

(69 reference statements)

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“…1A). λ Phosphatase treatment collapses all 4E-BP1 isoforms to the unphosphorylated form (24). These data are consistent with the δ-isoform having a unique phosphorylation site in addition to phosphorylations at other known sites.…”

Section: δ-4e-bp1 Hyperphosphorylation Is a Feature Of Mitosis Acrosssupporting

confidence: 74%

“…Several serine/threonine kinases have been shown to phosphorylate 4E-BP1, such as p38 MAPK, ERK, PIM2, ATM, CDK1, PLK1, LRRK2, GSK3β, and CK1e (15)(16)(17)(18)(19)(20)(21)(22)(23). We recently demonstrated that cyclin-dependent kinase 1 (CDK1) phosphorylates 4E-BP1 at canonical sites T37, T46, S65, and T70 during mitosis and generates a high-molecularweight phospho-isoform called δ-4E-BP1, even in the absence of mTOR activity (24). Although we have observed active capdependent translation during mitosis, the function of hyperphosphorylated δ-4E-BP1 and its contribution to tumorigenesis remain unknown.…”

Section: Merkel Cell Polyomavirusmentioning

confidence: 99%

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Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Velásquez

Cheng

Shuda

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonical sites (T37, T46, S65, and T70) and the noncanonical S83 site, resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. Although S83 phosphorylation of 4E-BP1 does not affect general cap-dependent translation, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus small T antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

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Section: δ-4e-bp1 Hyperphosphorylation Is a Feature Of Mitosis Acrosssupporting

confidence: 74%

Section: Merkel Cell Polyomavirusmentioning

confidence: 99%

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Velásquez

Cheng

Shuda

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Although CDK1 can substitute for mTOR in phosphorylating 4E-BP1 at canonical sites, resulting in release of eIF4E, it also phosphorylates 4E-BP1 at novel sites to form the mitosis-specific d-4E-BP1 isoform. 4 This is not an insignificant activity. As cells enter mitosis, levels of 4E-BP1 phosphorylation are higher than in any other part of the cell cycle (Fig.…”

Section: Mitosis-associated Capdependent Translation (Mact)mentioning

confidence: 92%

“…3,4 Coldwell et al recently showed, using alternative cell synchronization methods, that cap-dependent translation actually continues or even increases during mitosis. 3 During interphase, cap-dependent protein translation is initiated by the eIF4F cap initiation complex composed of the cap (m 7 GpppN)-binding protein eIF4E, the RNA helicase eIF4A, and a scaffolding protein eIF4G.…”

Section: Cap-dependent Translation and The Cell Cyclementioning

confidence: 99%

“…6 The MCV small T (sT) oncoprotein targets cellular E3 ligases, including cdc20, promoting mitotic entry and activation of mitotic kinases such as CDK1/CYCB1. 4 In addition to its other typical mitotic targets, CDK1 phosphorylates and inactivates 4E-BP1. Although CDK1 can substitute for mTOR in phosphorylating 4E-BP1 at canonical sites, resulting in release of eIF4E, it also phosphorylates 4E-BP1 at novel sites to form the mitosis-specific d-4E-BP1 isoform.…”

Section: Mitosis-associated Capdependent Translation (Mact)mentioning

confidence: 99%

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Mitotic 4E-BP1 hyperphosphorylation and cap-dependent translation

Shuda¹,

Chang

Moore

2015

Cell Cycle

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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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CDK1 substitutes for mTOR kinase to activate mitotic cap-dependent protein translation

Cited by 118 publications

References 52 publications

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Mitotic 4E-BP1 hyperphosphorylation and cap-dependent translation

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

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