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J. Biol. Chem., Vol. 283, Issue 16, 10848-10857, April 18, 2008

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MEK Signaling Is Required for Phosphorylation of eIF2 following Amino Acid Limitation of HepG2 Human Hepatoma Cells^*

Michelle M. Thiaville, Yuan-Xiang Pan¹, Altin Gjymishka, Can Zhong, Randal J. Kaufman², and Michael S. Kilberg³

From the Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, Florida 32610 and the Departments of Biological Chemistry and Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0650

The mammalian amino acid response (AAR) pathway is up-regulated by protein or amino acid depletion. This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2 (eukaryotic initiation factor 2), and, through subsequent translational control, enhanced de novo synthesis of the transcription factor ATF4. The present studies demonstrate that inhibition of MEK activation in HepG2 human hepatoma cells by PD98059 or U0126 blocked the increased phosphorylation of eIF2 and ATF4 synthesis triggered by amino acid limitation, showing that the AAR requires activation of the MEK-ERK pathway. Inhibitors of the JNK or p38 MAPK pathways were ineffective. Consequently, inhibition of MEK activation blocked transcriptional induction of ATF4 target genes, but the induction was rescued by overexpression of ATF4 protein. Furthermore, the enhanced ERK phosphorylation following amino acid deprivation required GCN2 kinase activity and eIF2 phosphorylation. Inhibition of protein phosphatase 1 action on phospho-eIF2 by knockdown of GADD34 did not block the sensitivity to PD98059, suggesting that MEK functions to enhance GCN2-dependent eIF2 phosphorylation rather than suppressing dephosphorylation. Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway.

Received for publication, October 5, 2007 , and in revised form, February 20, 2008.

^* This work was supported by National Institutes of Health Grants DK-52064 and DK70647 (to M. S. K.) and DK-42394 and HL-52173 (to R. J. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL 61801.

² Investigator of the Howard Hughes Medical Institute.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Florida College of Medicine, Box 100245, Gainesville, FL 32610-0245. Tel.: 352-392-2711; Fax: 352-392-6511; E-mail: mkilberg{at}ufl.edu.

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