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Dynamic Switch of Negative Feedback Regulation in Drosophila Akt–TOR Signaling
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Dynamic Switch of Negative Feedback Regulation in Drosophila Akt–TOR Signaling
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Dynamic Switch of Negative Feedback Regulation in Drosophila Akt–TOR Signaling
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Journal Article
Dynamic Switch of Negative Feedback Regulation in Drosophila Akt–TOR Signaling
2010
Overview
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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Cellular signal transduction
/ Drosophila melanogaster - genetics
/ Drosophila melanogaster - metabolism
/ Drosophila Proteins - genetics
/ Drosophila Proteins - metabolism
/ Genome-Wide Association Study
/ Kinases
/ Protein Kinases - metabolism
/ Proteins
/ Proto-Oncogene Proteins c-akt - genetics
/ Proto-Oncogene Proteins c-akt - metabolism
/ Ribosomal Protein S6 Kinases, 70-kDa - genetics
