Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction

Mayya Shveygert, Constanze Kaiser, Shelton Bradrick, Matthias Gromeier

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The m7G cap binding protein eukaryotic initiation factor 4E (eIF4E) is a rate-limiting determinant of protein synthesis. Elevated eIF4E levels, commonly associated with neoplasia, promote oncogenesis, and phosphorylation of eIF4E at Ser209 is critical for its tumorigenic potential. eIF4E phosphorylation is catalyzed by mitogen-activated protein kinase (MAPK)-interacting serine/threonine kinase (Mnk), a substrate of Erk1/2 and p38 MAPKs. Interaction with the scaffolding protein eIF4G, which also binds eIF4E, brings Mnk and its substrate into physical proximity. Thus, Mnk-eIF4G interaction is important for eIF4E phosphorylation. Through coimmunoprecipitation assays, we showed that MAPK-mediated phosphorylation of the Mnk1 active site controls eIF4G binding. Utilizing a naturally occurring splice variant, we demonstrated that the C-terminal domain of Mnk1 restricts its interaction with eIF4G, preventing eIF4E phosphorylation in the absence of MAPK signaling. Furthermore, using a small-molecule Mnk1 inhibitor and kinase-dead mutant, we established that Mnk1 autoregulates its interaction with eIF4G, releasing itself from the scaffold after phosphorylation of its substrate. Our findings indicate tight control of eIF4E phosphorylation through modulation of Mnk1-eIF4G interaction.

Original languageEnglish (US)
Pages (from-to)5160-5167
Number of pages8
JournalMolecular and Cellular Biology
Volume30
Issue number21
DOIs
StatePublished - 2010
Externally publishedYes

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Eukaryotic Initiation Factor-4E
Mitogen-Activated Protein Kinases
Phosphorylation
RNA Cap-Binding Proteins
Protein-Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
Catalytic Domain
Carcinogenesis
Proteins
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

Cite this

Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. / Shveygert, Mayya; Kaiser, Constanze; Bradrick, Shelton; Gromeier, Matthias.

In: Molecular and Cellular Biology, Vol. 30, No. 21, 2010, p. 5160-5167.

Research output: Contribution to journalArticle

Shveygert, Mayya ; Kaiser, Constanze ; Bradrick, Shelton ; Gromeier, Matthias. / Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. In: Molecular and Cellular Biology. 2010 ; Vol. 30, No. 21. pp. 5160-5167.
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