Mnk2 and Mnk1 Are Essential for Constitutive and Inducible Phosphorylation of Eukaryotic Initiation Factor 4E but Not for Cell Growth or Development

Ueda, Takeshi; Watanabe-Fukunaga, Rie; Fukuyama, Hidehiro; Nagata, Shigekazu; Fukunaga, Rikiro

doi:10.1128/mcb.24.15.6539-6549.2004

Cited by 507RNA and protein synthesis mechanismsPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

Mnk2 and Mnk1 Are Essential for Constitutive and Inducible Phosphorylation of Eukaryotic Initiation Factor 4E but Not for Cell Growth or Development

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Ueda, Takeshi, Watanabe-Fukunaga, Rie, Fukuyama, Hidehiro, Nagata, Shigekazu, Fukunaga, Rikiro·2004·Molecular and Cellular Biology

DOI 10.1128/mcb.24.15.6539-6549.2004PMC PMC444855

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Abstract

Mnk1 and Mnk2 are protein kinases that are directly phosphorylated and activated by extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases and implicated in the regulation of protein synthesis through their phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) at Ser209. To investigate their physiological functions, we generated mice lacking the Mnk1 or Mnk2 gene or both; the resulting KO mice were viable, fertile, and developed normally. In embryonic fibroblasts prepared from Mnk1-Mnk2 DKO mice, eIF4E was not detectably phosphorylated at Ser209, even when the ERK and/or p38 MAP kinases were activated. Analysis of embryonic fibroblasts from single KO mice revealed that Mnk1 is responsible for the inducible phosphorylation of eIF4E in response to MAP kinase activation, whereas Mnk2 mainly contributes to eIF4E's basal, constitutive phosphorylation. Lipopolysaccharide (LPS)- or insulin-induced upregulation of eIF4E phosphorylation in the spleen, liver, or skeletal muscle was abolished in Mnk1(-/-) mice, whereas the basal eIF4E phosphorylation levels were decreased in Mnk2(-/-) mice. In Mnk1-Mnk2 DKO mice, no phosphorylated eIF4E was detected in any tissue studied, even after LPS or insulin injection. However, neither general protein synthesis nor cap-dependent translation, as assayed by a bicistronic reporter assay system, was affected in Mnk-deficient embryonic fibroblasts, despite the absence of phosphorylated eIF4E. Thus, Mnk1 and Mnk2 are exclusive eIF4E kinases both in cultured fibroblasts and adult tissues, and they regulate inducible and constitutive eIF4E phosphorylation, respectively. These results strongly suggest that eIF4E phosphorylation at Ser209 is not essential for cell growth during development.

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MNK1 and MNK2 are substrates of both p38 and ERK.
“The two MNKs are substrates both for p38 and for ERK (27).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [27]

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Authors: Ueda, T., Watanabe-Fukunaga, R., Fukuyama, H., Nagata, S., & Fukunaga, R.
Affiliations: Department of Genetics, Graduate School of Medicine
The University of Osaka (JP)
Japan Science and Technology Agency (JP)
Corresponding author: Fukunaga, Rikiro
ORCID: Ueda, Takeshi
Fukuyama, Hidehiro
Nagata, Shigekazu
Fukunaga, Rikiro
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2004-08-01
Volume: 24
Issue: 15
Pages: 6539-6549
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.24.15.6539-6549.2004
PMC: PMC444855
OpenAlex: W2102889876
Cited by: 507
References: 68
Citations by year: 2026: 12 · 2025: 15 · 2024: 21 · 2023: 28 · 2022: 19 · 2021: 27 · 2020: 37 · 2019: 20 · 2018: 32 · 2017: 26 · 2016: 26 · 2015: 23 · 2014: 28 · 2013: 16 · 2012: 30
FWCI: 7.22
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: MNK1, MNK2, eIF4E phosphorylation, ERK signaling, p38 MAPK, cap-dependent translation, protein synthesis regulation, embryonic fibroblasts, lipopolysaccharide response, insulin response, cell growth and development
MeSH terms: Animals, Cell Division, Cells, Cultured, Embryo, Mammalian, Fibroblasts, Genotype, Lipopolysaccharides, Liver, Models, Genetic, Phosphorylation, Serine, Spleen, Time Factors, Tissue Distribution, Transfection, Protein Biosynthesis, Blotting, Southern, Immunoblotting, Polymerase Chain Reaction, Protein Serine-Threonine Kinases, Genes, Reporter, Mice, Knockout, Muscle, Skeletal, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Eukaryotic Initiation Factor-4E, p38 Mitogen-Activated Protein Kinases, Mice

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Mnk2 and Mnk1 Are Essential for Constitutive and Inducible Phosphorylation of Eukaryotic Initiation Factor 4E but Not for Cell Growth or Development

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