Dynamic switch of negative feedback regulation in Drosophila Akt-TOR signaling

Area of Science:

• Cell Biology
• Molecular Biology
• Developmental Biology

Background:

• Akt signaling is crucial for cell proliferation, size, and metabolism, acting as a central node between Insulin receptor and TOR signaling.
• Dysregulated Akt activity is implicated in cancer and metabolic diseases like diabetes mellitus.
• Understanding Akt regulatory circuitries is vital for comprehending normal development and disease pathogenesis.

Purpose of the Study:

• To investigate the regulatory mechanisms governing dAkt (Drosophila Akt) activation during normal development.
• To elucidate the role of negative feedback loops in controlling dAkt activity in vivo and in cell culture.
• To determine how the Akt-TOR pathway adapts its feedback routing in response to varying signaling loads.

Main Methods:

• Genome-wide RNA interference (RNAi) screen in Drosophila cells.
• In vivo analyses using the third instar larval wing imaginal disc in Drosophila.
• Phosphorylation-based assays to assess dAkt activation and feedback mechanisms.

Main Results:

• Negative feedback regulation of dAkt occurs during normal Drosophila development in vivo.
• S6 Kinase (S6K)-dependent negative feedback is significant in cell culture but plays a minor role in vivo.
• Under wild-type conditions, dAkt activation is primarily regulated by S6K-independent feedback from TOR Complex 1 (TORC1).
• Feedback inhibition switches from TORC1 to S6K in the context of elevated TORC1 activity, such as in tsc2 mutants.

Conclusions:

• The Akt-TOR pathway exhibits dynamic adaptation of negative feedback routing in vivo.
• The specific feedback regulators (TORC1 vs. S6K) depend on the overall activity load of the signaling circuit.
• These findings provide insights into how developmental signaling pathways maintain balance and respond to perturbations.