title: Dynamic switch of negative feedback regulation in Drosophila Akt-TOR signaling.
abstract: Akt represents a nodal point between the Insulin receptor and TOR signaling, and its activation by phosphorylation controls cell proliferation, cell size, and metabolism. The activity of Akt must be carefully balanced, as increased Akt signaling is frequently associated with cancer and as insufficient Akt signaling is linked to metabolic disease and diabetes mellitus. Using a genome-wide RNAi screen in Drosophila cells in culture, and in vivo analyses in the third instar wing imaginal disc, we studied the regulatory circuitries that define dAkt activation. We provide evidence that negative feedback regulation of dAkt occurs during normal Drosophila development in vivo. Whereas in cell culture dAkt is regulated by S6 Kinase (S6K)-dependent negative feedback, this feedback inhibition only plays a minor role in vivo. In contrast, dAkt activation under wild-type conditions is defined by feedback inhibition that depends on TOR Complex 1 (TORC1), but is S6K-independent. This feedback inhibition is switched from TORC1 to S6K only in the context of enhanced TORC1 activity, as triggered by mutations in tsc2. These results illustrate how the Akt-TOR pathway dynamically adapts the routing of negative feedback in response to the activity load of its signaling circuit in vivo.
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America. lutz.kockel@ucsf.edu
authors.forename: Lutz
authors.initials: L
authors.lastname: Kockel
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Kerr
authors.forename: Michael
authors.initials: M
authors.lastname: Melnick
authors.forename: Katja
authors.initials: K
authors.lastname: Brückner
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D055106:Genome-Wide Association Study; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D029721:Drosophila Proteins; D011494:Protein Kinases; C416303:target of rapamycin protein, Drosophila; C494917:Akt1 protein, Drosophila; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases