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Molecular and Cellular Biology, August 2004, p. 6539-6549, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6539-6549.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Takeshi Ueda,1,{dagger} Rie Watanabe-Fukunaga,1,2,{dagger} Hidehiro Fukuyama,1,3 Shigekazu Nagata,1,2,3 and Rikiro Fukunaga1,2,3*

Department of Genetics, Graduate School of Medicine,1 Graduate School of Frontier Biosciences, Osaka University,3 Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Suita, Osaka 565-0871, Japan2

Received 12 March 2004/ Returned for modification 24 April 2004/ Accepted 1 May 2004

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.

* Corresponding author. Mailing address: Graduate School of Frontier Biosciences, Department of Genetics, B-3, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3318. Fax: 81-6-6879-3319. E-mail: fukunaga{at}genetic.med.osaka-u.ac.jp.

{dagger} T.U. and R.W.-F. contributed equally to this work.

Molecular and Cellular Biology, August 2004, p. 6539-6549, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6539-6549.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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