|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
|
Fig. 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 Bcl2, leading to increased autophagic activity of beclin 1 protein
(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.
|
