Diet-dependent effects of the Drosophila Mnk1/Mnk2 homolog Lk6 on growth via eIF4E.
The control of cellular growth is tightly linked to the regulation of protein synthesis. A key function in translation initiation is fulfilled by the 5' cap binding eukaryotic initiation factor 4E (eIF4E), and dysregulation of eIF4E is associated with malignant transformation and tumorigenesis . In mammals, the activity of eIF4E is modulated by phosphorylation at Ser209 by mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1 and Mnk2) , which themselves are activated by ERK and p38 MAPK in response to mitogens, cytokines or cellular stress . Whether phosphorylation of eIF4E at Ser209 exerts a positive or inhibitory effect on translation efficiency has remained controversial. Here we provide a genetic characterization of the Drosophila homolog of Mnk1/2, Lk6. Lk6 function is dispensable under a high protein diet, consistent with the recent finding that mice lacking both Mnk1 and Mnk2 are not growth-impaired . Interestingly, loss of Lk6 function causes a significant growth reduction when the amino acid content in the diet is reduced. Overexpression of Lk6 also results in growth inhibition in an eIF4E-dependent manner. We propose a model of eIF4E regulation that may reconcile the contradictory findings with regard to the role of phosphorylation by Mnk1/2.
Reiling
Jan H
JH
Zoologisches Institut, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Doepfner
Kathrin T
KT
Hafen
Ernst
E
Stocker
Hugo
H
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001837:Body Weights and Measures; D004032:Diet; D004330:Drosophila / Q000254:growth & development* / Q000378:metabolism; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D016415:Sequence Alignment; D014921:Wings, Animal / Q000254:growth & development
D000596:Amino Acids; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; C500415:Lk6 protein, Drosophila; D020929:Mitogen-Activated Protein Kinase Kinases