p-ULK1 phosphorylates DENND3

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R-HSA-8876446
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Reaction [transition]
Species
Homo sapiens
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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
23147242 Endocytosis and autophagy: Shared machinery for degradation

Lamb, CA, Dooley, HC, Tooze, SA

Bioessays 2013
26177209 DENND3: a signaling/trafficking interface in autophagy

Xu, J, McPherson, PS

Cell Cycle 2015
25925668 Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy

Xu, J, Fotouhi, M, McPherson, PS

EMBO Rep. 2015
21718402 Small GTPase Rab12 regulates constitutive degradation of transferrin receptor

Matsui, T, Itoh, T, Fukuda, M

Traffic 2011
23478338 Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4

Matsui, T, Fukuda, M

EMBO Rep. 2013
20937701 Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors

Yoshimura, S, Gerondopoulos, A, Linford, A, Rigden, DJ, Barr, FA

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

Fan, SJ, Snell, C, Turley, H, Li, JL, McCormick, R, Perera, SM, Heublein, S, Kazi, S, Azad, A, Wilson, C, Harris, AL, Goberdhan, DC

Oncogene 2016
24719330 Dennd3 functions as a guanine nucleotide exchange factor for small GTPase Rab12 in mouse embryonic fibroblasts

Matsui, T, Noguchi, K, Fukuda, M

J. Biol. Chem. 2014
23295650 The ULK1 complex: sensing nutrient signals for autophagy activation

Wong, PM, Puente, C, Ganley, IG, Jiang, X

Autophagy 2013
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Title
protein serine/threonine kinase activity of p-T180,S317,S467,S556,S638,T575-ULK1 [cytosol]
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