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

Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 11/2010; 30(21):5160-7. DOI: 10.1128/MCB.00448-10
Source: PubMed

ABSTRACT The m(7)G 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.

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    • "MNKs binds to eIF4G and phosphorylate eIF4E (Pyronnet et al., 1999; Scheper et al., 2002; Shveygert et al., 2010). In cap pull-down assays performed in DG lysates, TrkB-Fc and CGP57380 inhibited HFS-evoked Ser 209 eIF4E phosphorylation at both early and late time points (Figures 3 and 5A–5C). "
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    • "MNKs binds to eIF4G and phosphorylate eIF4E (Pyronnet et al., 1999; Scheper et al., 2002; Shveygert et al., 2010). In cap pull-down assays performed in DG lysates, TrkB-Fc and CGP57380 inhibited HFS-evoked Ser 209 eIF4E phosphorylation at both early and late time points (Figures 3 and 5A–5C). "
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