Reactome | p-AMPK:AMP binds the ULK complex

p-AMPK:AMP binds the ULK complex

Stable Identifier

R-HSA-5672011

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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The heterotrimeric AMPK kinase complex, when bound to AMP, binds strongly to the ULK1 kinase complex. Rapamycin increases the co-immunoprecipitation of AMPK and ULK1, suggesting that mTORC1 activity may regulate their association. mTORC1 phosphorylates ULK1 on S758 and this phosphorylation disrupts the interaction between ULK1 and AMPK (Kim et al. 2011, Egan et al. 2011), suggesting that under nutrient-rich conditions, active mTORC1 phosphorylates ULK1 to disrupt ULK1-AMPK interaction, which keeps ULK1 inactive.

When cellular energy is depleted, AMPK is activated and inhibits mTORC1 via phosphorylation of TSC2 and raptor, thereby, reducing S758 phosphorylation on ULK1. The S758 unphosphorylated ULK1 is able to associate with, and be activated by, AMPK (Egan et al. 2011). This coordinated phosphorylation of ULK1 by mTORC1 and AMPK may provide a mechanism by which cells can properly respond to a wide range of stimuli.

ULK1 was identified as the mammalian homologue of yeast Atg1 (Kuroyanagi et al. 1998, Chan et al. 2007). It functions in a complex with ATG13 (KIAA0652) and RB1CC1 (FIP200), this considered to be the core ULK complex, which associates with ATG101 (Hosokawa et al. 2009, Jung et al. 2009, Ganley et al. 2009, Mercer et al. 2009). ATG13 binds ULK1 (and ULK2), mediating the interaction with RB1CC1. All four components of this complex are essential for autophagy induction and predominantly localized to the cytosol, associating with the isolation membrane upon autophagy induction (Mizushima 2011). RB1CC1 in this complex can interact with many other proteins including Pyk2, FAK, TSC1, p53, ASK1, and TRAF2 (Gan & Guan 2008).

Literature References

PubMed ID	Title	Journal	Year
21205641	Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy Joshi, A, Dillin, A, Mair, W, Shaw, RJ, Taylor, R, Gwinn, DM, Fitzpatrick, J, Vasquez, DS, Viollet, B, Kohnz, RA, Egan, DF, Mihaylova, MM, Kundu, M, Shackelford, DB, Hansen, M, Gelino, S, Asara, JM	Science	2011