Reactome | p-ULK1 phosphorylates DENND3

p-ULK1 phosphorylates DENND3

Stable Identifier

R-HSA-8876446

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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ULK1 is a serine-threonine kinase with key roles in macroautophagy in response to starvation. Under high nutrient conditions, ULK1 is phosphorylated by mTORC1, inhibiting the autophagy pathway, while under nutrient-limited conditions, mTORC1 phosphorylation is replaced by AMPK-mediated phosphorylation, resulting in the activation of both ULK1 and the autophagy pathway (reviewed in Wong et al, 2013). How nutrient levels are sensed by mTORC1 and ULK1 is not fully established, but a number of recent papers have highlighted a role for RAB proteins and their regulators in autophagy (Matsui and Fukuda, 2013; Matsui et al, 2014; Xu et al, 2015; Fan et al, 2016; reviewed in Lamb et al, 2013; Xu and McPherson, 2015). Under starvation conditions, ULK1 phosphorylates DENND3, a RAB12 GEF, at serine residues 472 and 490, activating it and promoting the formation of GTP-bound RAB12 (Yoshimura et al, 2010; Xu et al, 2015). Active RAB12 promotes the constitutive recycling or degradation of a number of plasma membrane proteins including the amino acid transporter SLC36A4 (also known as PAT4). Degradation of SLC36A4 decreases the intracellular amino acid concentration, inactivating mTORC1 and promoting the macroautophagy pathway (Matsui et al, 2011; Matsui and Fukuda, 2013; Xu et al, 2015; Fan et al, 2016).

Literature References

PubMed ID	Title	Journal	Year
26177209	DENND3: a signaling/trafficking interface in autophagy McPherson, PS, Xu, J	Cell Cycle	2015
23147242	Endocytosis and autophagy: Shared machinery for degradation Tooze, SA, Dooley, HC, Lamb, CA	Bioessays	2013
25925668	Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy Fotouhi, M, McPherson, PS, Xu, J	EMBO Rep.	2015
21718402	Small GTPase Rab12 regulates constitutive degradation of transferrin receptor Fukuda, M, Itoh, T, Matsui, T	Traffic	2011
23478338	Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4 Fukuda, M, Matsui, T	EMBO Rep.	2013
20937701	Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors Linford, A, Rigden, DJ, Barr, FA, Gerondopoulos, A, Yoshimura, S	J. Cell Biol.	2010
26434594	PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer Snell, C, Perera, SM, Azad, A, Goberdhan, DC, Harris, AL, Li, JL, Turley, H, Fan, SJ, McCormick, R, Kazi, S, Wilson, C, Heublein, S	Oncogene	2016
24719330	Dennd3 functions as a guanine nucleotide exchange factor for small GTPase Rab12 in mouse embryonic fibroblasts Fukuda, M, Noguchi, K, Matsui, T	J. Biol. Chem.	2014
23295650	The ULK1 complex: sensing nutrient signals for autophagy activation Puente, C, Wong, PM, Jiang, X, Ganley, IG	Autophagy	2013