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.
Highlights
The development of multi-cellular organisms depends on the precise choreography of a diverse array of signal transduction pathways
Ectopic activation of the Akt–TOR pathway is frequently associated with tumor susceptibility and cancer and contributes to obesity-induced metabolic disease and type II diabetes
Our work shows that dAkt activity is regulated by two qualitatively different negative feedback mechanisms and that the activity level of the dAkt pathway dictates which feedback mechanism is utilized
Summary
The development of multi-cellular organisms depends on the precise choreography of a diverse array of signal transduction pathways. Besides the requirement of some signaling events to occur in a spatial or temporal on-off manner, other pathways need to stay homeostatically active within physiological boundaries. This requires balanced regulation by activating as well as repressing signals. The molecular component that executes the feedback-mediated inhibition is transcriptionally targeted by the very pathway that it regulates. This mechanism ensures an interdependence of signaling activity and feedback regulation and is often viewed as an inherent means to downregulate signaling pathways after stimulation
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