Meta-Biol

• Pathways

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).