Figure 2. Nutrient-dependent regulation of autophagy.

Autophagy proceeds constitutively at a low basal rate in most cells, and can be induced to high levels in response to starvation, loss of growth factor signaling, and other stressors. The TOR signaling pathway plays a central role in many of these responses. The kinase activity of TOR is inhibited by Tsc1 and Tsc2, which form a complex with GAP activity against the small GTPase Rheb, a direct activator of TOR (Wullschleger et al., 2006). The Tsc1/Tsc2 complex in turn is regulated by several upstream protein kinases, including Akt in response to insulin signaling and AMPK in response to AMP/ATP levels. Downstream of TOR, the protein kinases Atg1 and S6K have important roles in autophagy, but the relevant substrates of these kinases have not been determined (Kamada et al., 2000; Scott et al., 2004). In addition, both Atg1 and S6K inhibit TOR signaling through negative feedback loops (Lee et al., 2007; Scott et al., 2007). Signaling levels of reactive oxygen species (ROS) are generated in response to starvation and are required for activation of the autophagy-specific protease Atg4 (Scherz-Shouval et al., 2007). Starvation also inhibits the association of Beclin 1/Atg6 with Bcl-2, leading to increased autophagic activity of Beclin 1 (Pattingre et al., 2005). Abbreviations: AMP, adenosine monophosphate; ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase; GAP, GTPase activating protein; S6K, p70 S6 kinase; Tsc, tuberous sclerosis complex.