AMPK (complex) phosphorylates ULK1 (complex)

Stable Identifier
R-HSA-5665868
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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In mammals, the ULK complex and the class III PI3 Kinase containing Beclin-1 complex jointly produce the phagophore membrane, the initial phase of autophagosome formation (Karanosis et al. 2013). It is not fully understood how ULK1 is modulated in response to environmental cues. Phosphorylation plays an essential role (Dunlop & Tee 2013), but it is not clear how phosphorylation of ULK1 (or ATG13) leads to regulation (Ravikumar et al. 2010). Nor is it clear what ULK1 kinase activity achieves, it is not required for formation of the core complex but may be important for the recruitment of other proteins or have a direct role in subsequent autophagosome formation. Exactly how the ULK1 complex transduces upstream signals to the downstream central autophagy pathway is unclear (Wong et al. 2013).

At least 30 phosphorylation sites have been identified on ULK1, although the majority of the responsible kinases and the functions of these phosphorylation events remain to be identified (Dorsey et al. 2009, Mack et al. 2012). During glucose starvation, several sites in human ULK1 (Ser-317 - Kim et al. 2011, S467, S556, T575, and S638 - Egan et al. 2011) are reported to be phosphorylated by AMPK and required for efficient autophagy (Kim et al. 2011, Egan et al. 2011). These five phosphorylations are annotated here.

ULK1 phosphorylation activates its kinase activity and leads to the inhibition of mTORC1, via phosphorylation of TSC2 and raptor (Kim et al. 2011). Two AMPK phosphorylation sites in ULK1 (S556 and T575) also appear to be 14-3-3 binding sites.

Literature References
PubMed ID Title Journal Year
21258367 AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

Kim, J, Kundu, M, Viollet, B, Guan, KL

Nat. Cell Biol. 2011
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Catalyst Activity
Title
protein serine/threonine kinase activity of p-AMPK heterotrimer:AMP:ULK1:ATG13:RB1CC1:ATG101 [cytosol]
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Activity
Orthologous Events
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