6b3y

Structural highlights

Function

DEND3_MOUSE Guanine nucleotide exchange factor (GEF) activating Rab12. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab12 into its active GTP-bound form. Regulates autophagy in response to starvation through Rab12 activation (PubMed:24719330, PubMed:25925668, PubMed:28249939). Starvation leads to ULK1/2-dependent phosphorylation of Ser-554 and Ser-572, which in turn allows recruitment of 14-3-3 adapter proteins and leads to up-regulation of GEF activity towards Rab12 (PubMed:25925668). Also plays a role in protein transport from recycling endosomes to lysosomes, regulating, for instance, the degradation of the transferrin receptor and of the amino acid transporter PAT4 (PubMed:21718402, PubMed:24719330). Starvation also induces phosphorylation at Tyr-940, which leads to up-regulated GEF activity and initiates autophagy (PubMed:28249939).^{[1] [2] [3] [4]}

References

1. ↑ Matsui T, Itoh T, Fukuda M. Small GTPase Rab12 regulates constitutive degradation of transferrin receptor. Traffic. 2011 Oct;12(10):1432-43. doi: 10.1111/j.1600-0854.2011.01240.x. Epub, 2011 Jul 29. PMID:21718402 doi:http://dx.doi.org/10.1111/j.1600-0854.2011.01240.x
2. ↑ Matsui T, Noguchi K, Fukuda M. Dennd3 functions as a guanine nucleotide exchange factor for small GTPase Rab12 in mouse embryonic fibroblasts. J Biol Chem. 2014 May 16;289(20):13986-95. doi: 10.1074/jbc.M113.546689. Epub, 2014 Apr 9. PMID:24719330 doi:http://dx.doi.org/10.1074/jbc.M113.546689
3. ↑ Xu J, Fotouhi M, McPherson PS. Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy. EMBO Rep. 2015 Jun;16(6):709-18. doi: 10.15252/embr.201440006. Epub 2015 Apr 29. PMID:25925668 doi:http://dx.doi.org/10.15252/embr.201440006
4. ↑ Xu J, McPherson PS. Regulation of DENND3, the exchange factor for the small GTPase Rab12 through an intramolecular interaction. J Biol Chem. 2017 Apr 28;292(17):7274-7282. doi: 10.1074/jbc.M116.772434. Epub, 2017 Mar 1. PMID:28249939 doi:http://dx.doi.org/10.1074/jbc.M116.772434