Phosphorylation of the mRNA cap-binding protein eIF4E and cancer

doi:10.1016/j.cellsig.2020.109689

Cellular Signalling

Volume 73, September 2020, 109689

https://doi.org/10.1016/j.cellsig.2020.109689 Get rights and content

Highlights

•
Phosphorylation of eIF4E is involved in a number of key biological processes in tumorigenesis and progression.
•
Hyperphosphorylation of eIF4E is associated with poor prognosis of patients with several cancer types.
•
MNK inhibitors and eIF4E Ser209 mutation can significantly suppress tumor proliferation and metastasis.

Abstract

Dysregulated protein synthesis is frequently involved in oncogenesis and cancer progression. Translation initiation is thought to be the rate-limiting step in protein synthesis, and the mRNA 5′ cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) is a pivotal factor that initiates translation. The activities of eIF4E are regulated at multiple levels, one of which is through its phosphorylation at Serine 209 by the mitogen-activated protein kinase-interacting kinases (MNKs, including MNK1 and MNK2). Benefiting from novel mouse genetic tools and pharmacological MNK inhibitors, our understanding of a role for eIF4E phosphorylation in tumor biology and cancer therapy has greatly evolved in recent years. Importantly, recent studies have found that the level of eIF4E phosphorylation is frequently upregulated in a wide variety of human cancer types, and phosphorylation of eIF4E drives a number of important processes in cancer biology, including cell transformation, proliferation, apoptosis, metastasis and angiogenesis. The MNK-eIF4E axis is being assessed as a therapeutic target either alone or in combination with other therapies in different cancer models. As novel MNK inhibitors are being developed, experimental studies bring new hope to cure human cancers that are not responsive to traditional therapies. Herein we review recent progress on our understanding of a mechanistic role for phosphorylation of eIF4E in cancer biology and therapy.

Section snippets

The cap-binding protein eIF4E and translational control

mRNA translation (protein synthesis) is the most energy-consuming step in gene expression and is highly regulated [1]. Translational control provides a fast adaptive response to environmental cues and is essential for maintaining protein homeostasis in cells [2]. mRNA translation in eukaryotes can includes three steps: initiation, elongation and termination [2,3]. Protein synthesis is controlled primarily at the step of mRNA translation initiation [2]. Most eukaryotic mRNAs are translated by a

The MAPK-MNK signaling pathway

The activity of eIF4E is regulated through its phosphorylation by two MAP kinase-interacting kinases (MNKs, i.e. MNK1 and MNK2) at a single residue Ser²⁰⁹ [18,19]. MNK1 and MNK2 belong to the serine/threonine protein kinase family and are activated by extracellular signal-regulated kinases (ERKs) or p38 MAPK under the stimulation of extracellular factors, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines [20]. Extracellular signal–regulated kinases (ERKs, including ERK

eIF4E phosphorylation in tumor biology

The regulation of cell proliferation and survival by eIF4E phosphorylation has only been observed in cancer but not in normal tissues, and aberrant levels of eIF4E phosphorylation are found in a variety of human cancers, such as nasopharyngeal carcinoma, astrocytoma and melanoma. Increasing evidence supports that eIF4E phosphorylation is involved in a number of key processes in tumor biology including cell proliferation, transformation, apoptosis, tumor metastasis and angiogenesis (Fig. 2).

Targeting eIF4E phosphorylation in experimental cancer therapy

As phosphorylation of eIF4E plays an important role in many fundamental processes of tumor biology, repressing eIF4E phosphorylation can be used as a potential strategy to treat cancer patients. One strategy is to pharmacologically inhibit MNKs, since they are the only kinases that can phosphorylate eIF4E. The candidate compounds are CGP57380, cercosporamide and 5-(2-(phenylamino) pyrimidin-4-yl) thiazole-2(3H)-one derivatives. CGP57380 is a potent MNK1 inhibitor with an IC50 of 2.2 μM in vitro

Clinical studies on eIF4E phosphorylation and MNKs in human cancer

High levels of eIF4E phosphorylation are correlated with poor clinical prognosis in human cancers. Clinical studies have found that eIF4E was significantly over-phosphorylated in a wide variety of human cancer tissues compared with the adjacent normal tissues [112]. Elevated levels of p-MNK1, p-eIF4E and p-p70S6K proteins are associated with tumor recurrence and poor prognosis in astrocytoma [110]. Overexpression of p-eIF4E and co-expression of p-MNK1, p-eIF4E and p-p70S6K proteins are

Conclusions

In conclusion, phosphorylation of the cap-binding protein eIF4E is involved in a number of key biological processes in tumorigenesis and progression, including cell proliferation, transformation, apoptosis, tumor metastasis and angiogenesis. Clinical evidence supports that hyperphosphorylation of eIF4E is associated with poor prognosis of patients with several cancer types. MNK inhibitors and eIF4E Ser209 mutation can significantly suppress tumor proliferation and metastasis in vivo and in vitro

Disclosure statement

The content of this review article represents the collective contributions of the listed authors. None of the authors have commercial interests of any kind to declare that are of relevance to the contents of the article.

Acknowledgements

We thank Dr. Robert Cormier for his critical reading of the manuscript. This study was supported by a National Institutes of Health Grant NS118026, a Faculty Start-Up Grant from the University of Minnesota Medical School, a Grant from University of Minnesota Foundation and a Grant from Whiteside Institute for Clinical Research to R.C., a Chinese National Science and Technology Major Project Grant (No. 2018ZX09711003) to W.Z.

References (117)

N. Sonenberg et al.
Regulation of translation initiation in eukaryotes: mechanisms and biological targets
Cell
(2009)
A.J. Shatkin
mRNA cap binding proteins: essential factors for initiating translation
Cell
(1985)
J. Marcotrigiano
Cocrystal structure of the messenger RNA 5′ cap-binding protein (eIF4E) bound to 7-methyl-GDP
Cell
(1997)
R. Groppo et al.
Translational control from head to tail
Curr. Opin. Cell Biol.
(2009)
R.J. Kaufman
Control of gene expression at the level of translation initiation
Curr. Opin. Biotechnol.
(1994)
B. Raught et al.
eIF4E activity is regulated at multiple levels
Int. J. Biochem. Cell Biol.
(1999)
C.G. Proud
Mnks, eIF4E phosphorylation and cancer
Biochim. Biophys. Acta
(2015)
C.R. Bramham et al.
Tuning specific translation in cancer metastasis and synaptic memory: control at the MNK-eIF4E Axis
Trends Biochem. Sci.
(2016)
R.A. Saxton et al.
mTOR signaling in growth, metabolism, and disease
Cell
(2017)
K. Hara
Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action
Cell
(2002)

D.H. Kim

mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery

Cell

(2002)

M.C. Brown et al.

MNK controls mTORC1:substrate association through regulation of TELO2 binding with mTORC1

Cell Rep.

(2017)

G.C. Scheper

Phosphorylation of eukaryotic initiation factor 4E markedly reduces its affinity for capped mRNA

J. Biol. Chem.

(2002)

J.K. Moy

eIF4E phosphorylation regulates ongoing pain, independently of inflammation, and hyperalgesic priming in the mouse CFA model

Neurobiol. Pain

(2018)

V.A. Polunovsky

Translational control of the antiapoptotic function of Ras

J. Biol. Chem.

(2000)

Y. Yu

eIF4E-phosphorylation-mediated Sox2 upregulation promotes pancreatic tumor cell repopulation after irradiation

Cancer Lett.

(2016)

Y. Liu

Inhibition of eukaryotic initiation factor 4E phosphorylation by cercosporamide selectively suppresses angiogenesis, growth and survival of human hepatocellular carcinoma

Biomed. Pharmacother.

(2016)

X. Feng

Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism

Cancer Lett.

(2017)

C.A. Chrestensen

MNK1 and MNK2 regulation in HER2-overexpressing breast cancer lines

J. Biol. Chem.

(2007)

X. Jin

Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold

Eur. J. Med. Chem.

(2019)

W. Zhang

Inhibiting MNK selectively targets cervical Cancer via suppressing eIF4E-mediated beta-catenin activation

Am J Med Sci

(2019)

J.K. Altman

Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors

Blood

(2013)

E.M. Kosciuczuk

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

Blood

(2016)

Z. Liu

Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway

Biochem. Biophys. Res. Commun.

(2016)

J. Li

Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-beta-catenin axis

Biochem. Biophys. Res. Commun.

(2016)

M. Grzmil

Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy

Cell. Signal.

(2016)

N. Lane et al.

The energetics of genome complexity

Nature

(2010)

N. Siddiqui et al.

Signalling to eIF4E in cancer

Biochem. Soc. Trans.

(2015)

Y.V. Svitkin

Sonenberg, [translational control by the poly(a) binding protein: a check for mRNA integrity]

Mol. Biol. (Mosk)

(2006)

A. Kahvejian

Mammalian poly(a)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms

Genes Dev.

(2005)

A.G. Hinnebusch

The scanning mechanism of eukaryotic translation initiation

Annu. Rev. Biochem.

(2014)

N. Sonenberg

eIF4E, the mRNA cap-binding protein: from basic discovery to translational research

Biochem. Cell Biol.

(2008)

A. Pause

Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function

Nature

(1994)

A.C. Gingras et al.

eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation

Annu. Rev. Biochem.

(1999)

P.P. Roux et al.

Signaling pathways involved in the regulation of mRNA translation

Mol. Cell. Biol.

(2018)

A.J. Waskiewicz

Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo

Mol. Cell. Biol.

(1999)

R. Fukunaga et al.

MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates

EMBO J.

(1997)

A.J. Waskiewicz

Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2

EMBO J.

(1997)

S. Pyronnet

Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E

EMBO J.

(1999)

T. Ueda

Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development

Mol. Cell. Biol.

(2004)

M. Marzec

Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells

PLoS One

(2011)

J. Zuberek

Phosphorylation of eIF4E attenuates its interaction with mRNA 5′ cap analogs by electrostatic repulsion: intein-mediated protein ligation strategy to obtain phosphorylated protein

RNA

(2003)

L. Furic

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

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

(2010)

N. Robichaud

Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3

Oncogene

(2015)

N. Robichaud

Translational control in the tumor microenvironment promotes lung metastasis: phosphorylation of eIF4E in neutrophils

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

(2018)

I. Topisirovic et al.

Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities

Cancer Res.

(2004)

A. Phillips et al.

MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA

Oncogene

(2008)

A. Aguilar-Valles

Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E

Nat. Commun.

(2018)

I.S. Amorim

Loss of eIF4E phosphorylation engenders depression-like behaviors via selective mRNA translation

J. Neurosci.

(2018)

J.K. Moy

The MNK-eIF4E signaling Axis contributes to injury-induced nociceptive plasticity and the development of chronic pain

J. Neurosci.

(2017)

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¹: Author contributions: X.Y., W.Z. and R.C. wrote the paper.

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ReviewPhosphorylation of the mRNA cap-binding protein eIF4E and cancer

Highlights

Abstract

Section snippets

The cap-binding protein eIF4E and translational control

The MAPK-MNK signaling pathway

eIF4E phosphorylation in tumor biology

Targeting eIF4E phosphorylation in experimental cancer therapy

Clinical studies on eIF4E phosphorylation and MNKs in human cancer

Conclusions

Disclosure statement

Acknowledgements

Cell

Cell

Cell

Curr. Opin. Cell Biol.

Curr. Opin. Biotechnol.

Int. J. Biochem. Cell Biol.

Biochim. Biophys. Acta

Trends Biochem. Sci.

Cell

Cell

Cell

Cell Rep.

J. Biol. Chem.

Neurobiol. Pain

J. Biol. Chem.

Cancer Lett.

Biomed. Pharmacother.

Cancer Lett.

J. Biol. Chem.

Eur. J. Med. Chem.

Am J Med Sci

Blood

Blood

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Cell. Signal.

The energetics of genome complexity

Nature

Signalling to eIF4E in cancer

Biochem. Soc. Trans.

Sonenberg, [translational control by the poly(a) binding protein: a check for mRNA integrity]

Mol. Biol. (Mosk)

Mammalian poly(a)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms

Genes Dev.

The scanning mechanism of eukaryotic translation initiation

Annu. Rev. Biochem.

eIF4E, the mRNA cap-binding protein: from basic discovery to translational research

Biochem. Cell Biol.

Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function

Nature

eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation

Annu. Rev. Biochem.

Signaling pathways involved in the regulation of mRNA translation

Mol. Cell. Biol.

Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo

Mol. Cell. Biol.

MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates

EMBO J.

Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2

EMBO J.

Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E

EMBO J.

Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development

Mol. Cell. Biol.

Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells

PLoS One

Phosphorylation of eIF4E attenuates its interaction with mRNA 5′ cap analogs by electrostatic repulsion: intein-mediated protein ligation strategy to obtain phosphorylated protein

RNA

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

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

Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3

Oncogene

Translational control in the tumor microenvironment promotes lung metastasis: phosphorylation of eIF4E in neutrophils

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

Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities

Cancer Res.

MNK1 and EIF4E are downstream effectors of MEKs in the regulation of the nuclear export of HDM2 mRNA

Oncogene

Review
Phosphorylation of the mRNA cap-binding protein eIF4E and cancer