1. Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity
- Author
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Michael J. Pankratz, Michael Hoch, Martin A. Jünger, Torsten R. Bülow, and Margret H. Bülow
- Subjects
Cancer genetics ,Cancer models ,Cell growth ,Genetic interaction ,Indoles ,Transcription, Genetic ,Proto-Oncogene Proteins pp60(c-src) ,Biology ,Article ,Mice ,Transcription (biology) ,Peptide Initiation Factors ,medicine ,Animals ,Drosophila Proteins ,Src family kinase ,Transcription factor ,Cell Nucleus ,Sulfonamides ,Multidisciplinary ,Effector ,Forkhead Box Protein O3 ,Intracellular Signaling Peptides and Proteins ,Forkhead Transcription Factors ,Molecular biology ,Receptor, Insulin ,Cell biology ,Cell nucleus ,medicine.anatomical_structure ,Phenotype ,src-Family Kinases ,Larva ,NIH 3T3 Cells ,Drosophila ,Signal transduction ,Tyrosine kinase ,Proto-oncogene tyrosine-protein kinase Src ,Signal Transduction - Abstract
Biochemical experiments in mammalian cells have linked Src family kinase activity to the insulin signaling pathway. To explore the physiological link between Src and a central insulin pathway effector, we investigated the effect of different Src signaling levels on the Drosophila transcription factor dFOXO in vivo. Ectopic activation of Src42A in the starved larval fatbody was sufficient to drive dFOXO out of the nucleus. When Src signaling levels were lowered by means of loss-of-function mutations or pharmacological inhibition, dFOXO localization was shifted to the nucleus in growing animals, and transcription of the dFOXO target genes d4E-BP and dInR was induced. dFOXO loss-of-function mutations rescued the induction of dFOXO target gene expression and the body size reduction of Src42A mutant larvae, establishing dFOXO as a critical downstream effector of Src signaling. Furthermore, we provide evidence that the regulation of FOXO transcription factors by Src is evolutionarily conserved in mammalian cells., Scientific Reports, 4, ISSN:2045-2322 more...
- Published
- 2014