DENND3 exchanges GTP for GDP on RAB12

Stable Identifier
Reaction [transition]
Homo sapiens
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DENND3 is a RAB12-specific GEF with roles in macroautophagy and the trafficking of proteins from the recycling endosome to the lysosome (Yoshimura et al, 2010; Matsui et al, 2014; Xu et al, 2015; reviewed in Xu and McPherson, 2015). DENND3 activity promotes the formation of active RAB12:GTP, required for the constitutive degradation of plasma membrane proteins such as the transferrin receptor and the amino acid transporter SLC36A4, also known as PAT4 (Matsui et al, 2011; Matsui and Fukuda, 2013; Matsui et al, 2014; Sirohi et al, 2013). Under starvation conditions, DENND3 is phosphorylated by the macroautophagy-promoting kinase ULK1. DENND3- and RAB12-dependent degradation of SLC36A4 contributes to the activation of the macroautophagy pathway by decreasing intracellular amino-acid levels and inhibiting mTORC1 (Matsui and Fukuda, 2013; Matsui et al, 2014; Xu et al, 2015; Fan et al, 2016; reviewed in Xu and McPherson, 2015).
Literature References
PubMed ID Title Journal Year
26177209 DENND3: a signaling/trafficking interface in autophagy

McPherson, PS, Xu, J

Cell Cycle 2015
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
23478338 Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4

Fukuda, M, Matsui, T

EMBO Rep. 2013
21718402 Small GTPase Rab12 regulates constitutive degradation of transferrin receptor

Fukuda, M, Itoh, T, Matsui, T

Traffic 2011
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
25341920 Rab proteins and the compartmentalization of the endosomal system

Wandinger-Ness, A, Zerial, M

Cold Spring Harb Perspect Biol 2014
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
27246931 Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

Oguchi, ME, Fukuda, M, Ishida, M

Cell Struct. Funct. 2016
23357852 M98K-OPTN induces transferrin receptor degradation and RAB12-mediated autophagic death in retinal ganglion cells

Chalasani, ML, Radha, V, Kumari, A, Swarup, G, Sudhakar, C, Sirohi, K

Autophagy 2013
Catalyst Activity

guanyl-nucleotide exchange factor activity of DENND3 [cytosol]

Orthologous Events
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