Family-wide Characterization of the DENN Domain Rab GDP-GTP Exchange Factors

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2010 Oct 13

PMID 20937701

Citations 173

Authors

Shin-Ichiro Yoshimura

Andreas Gerondopoulos

Andrea Linford

Daniel J Rigden

Francis A Barr

Affiliations

Soon will be listed here.

Abstract

A key requirement for Rab function in membrane trafficking is site-specific activation by GDP-GTP exchange factors (GEFs), but the majority of the 63 human Rabs have no known GEF. We have performed a systematic characterization of the 17 human DENN domain proteins and demonstrated that they are specific GEFs for 10 Rabs. DENND1A/1B localize to clathrin patches at the plasma membrane and activate Rab35 in an endocytic pathway trafficking Shiga toxin to the trans-Golgi network. DENND2 GEFs target to actin filaments and control Rab9-dependent trafficking of mannose-6-phosphate receptor to lysosomes. DENND4 GEFs target to a tubular membrane compartment adjacent to the Golgi, where they activate Rab10, which suggests a function in basolateral polarized sorting in epithelial cells that compliments the non-DENN GEF Sec2 acting on Rab8 in apical sorting. DENND1C, DENND3, DENND5A/5B, MTMR5/13, and MADD activate Rab13, Rab12, Rab39, Rab28, and Rab27A/27B, respectively. Together, these findings provide a basis for future studies on Rab regulation and function.

Citing Articles

RAB-10 cooperates with EHBP-1 to capture vesicular carriers during post-Golgi exocytic trafficking.

Liu S, Wei J, Zhong L, Hai S, Song S, Xie C J Cell Biol. 2025; 224(4).

PMID: 39982707 PMC: 11844438. DOI: 10.1083/jcb.202410003.

Split-Small GTPase Reassembly as a Method to Control Cellular Signaling with User-Defined Inputs.

He Y, Faulkner B, Hyun E, Stains C bioRxiv. 2025; .

PMID: 39975372 PMC: 11838316. DOI: 10.1101/2025.01.28.635345.

Variations in rumen microbiota and host genome impacted feed efficiency in goat breeds.

Rabee A, Abou-Souliman I, Yousif A, Lamara M, El-Sherbieny M, Elwakeel E Front Microbiol. 2025; 16:1492742.

PMID: 39944650 PMC: 11813914. DOI: 10.3389/fmicb.2025.1492742.

Unlocking Opportunities and Overcoming Challenges in Genetically Engineered Biofortification.

Shohael A, Kelly J, Venkataraman S, Hefferon K Nutrients. 2025; 17(3).

PMID: 39940376 PMC: 11821181. DOI: 10.3390/nu17030518.

Rab10-associated tubulation as an early marker for biogenesis of the assembly compartment in cytomegalovirus-infected cells.

Mahmutefendic Lucin H, Stimac I, Marcelic M, Skocaj M, Lisnic B, Omerovic A Front Cell Dev Biol. 2025; 12:1517236.

PMID: 39866842 PMC: 11760598. DOI: 10.3389/fcell.2024.1517236.

References

Sato T, Mushiake S, Kato Y, Sato K, Sato M, Takeda N . The Rab8 GTPase regulates apical protein localization in intestinal cells. Nature. 2007; 448(7151):366-9. DOI: 10.1038/nature05929. View

Espinosa E, Calero M, Sridevi K, Pfeffer S . RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport. Cell. 2009; 137(5):938-48. PMC: 2801561. DOI: 10.1016/j.cell.2009.03.043. View

Siniossoglou S, Pelham H . Ric1p and Rgp1p form a complex that catalyses nucleotide exchange on Ypt6p. EMBO J. 2000; 19(18):4885-94. PMC: 314221. DOI: 10.1093/emboj/19.18.4885. View

Wang W, Sacher M . TRAPP stimulates guanine nucleotide exchange on Ypt1p. J Cell Biol. 2000; 151(2):289-96. PMC: 2192651. DOI: 10.1083/jcb.151.2.289. View

Fuchs E, Haas A, Spooner R, Yoshimura S, Lord J, Barr F . Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways. J Cell Biol. 2007; 177(6):1133-43. PMC: 2064371. DOI: 10.1083/jcb.200612068. View

Lombardi D, Soldati T, Riederer M, Goda Y, Zerial M, Pfeffer S . Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J. 1993; 12(2):677-82. PMC: 413253. DOI: 10.1002/j.1460-2075.1993.tb05701.x. View

Barr F, Lambright D . Rab GEFs and GAPs. Curr Opin Cell Biol. 2010; 22(4):461-70. PMC: 2929657. DOI: 10.1016/j.ceb.2010.04.007. View

Delprato A, Lambright D . Structural basis for Rab GTPase activation by VPS9 domain exchange factors. Nat Struct Mol Biol. 2007; 14(5):406-12. PMC: 2254184. DOI: 10.1038/nsmb1232. View

Harsay E, Schekman R . Avl9p, a member of a novel protein superfamily, functions in the late secretory pathway. Mol Biol Cell. 2007; 18(4):1203-19. PMC: 1838974. DOI: 10.1091/mbc.e06-11-1035. View

10.

Pan X, Eathiraj S, Munson M, Lambright D . TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism. Nature. 2006; 442(7100):303-6. DOI: 10.1038/nature04847. View

11.

Wada M, Nakanishi H, Satoh A, Hirano H, Obaishi H, Matsuura Y . Isolation and characterization of a GDP/GTP exchange protein specific for the Rab3 subfamily small G proteins. J Biol Chem. 1997; 272(7):3875-8. DOI: 10.1074/jbc.272.7.3875. View

12.

Dong G, Medkova M, Novick P, Reinisch K . A catalytic coiled coil: structural insights into the activation of the Rab GTPase Sec4p by Sec2p. Mol Cell. 2007; 25(3):455-62. PMC: 1847580. DOI: 10.1016/j.molcel.2007.01.013. View

13.

Coppola T, Perret-Menoud V, Gattesco S, Magnin S, Pombo I, Blank U . The death domain of Rab3 guanine nucleotide exchange protein in GDP/GTP exchange activity in living cells. Biochem J. 2002; 362(Pt 2):273-9. PMC: 1222386. DOI: 10.1042/0264-6021:3620273. View

14.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

15.

Fritz-Laylin L, Prochnik S, Ginger M, Dacks J, Carpenter M, Field M . The genome of Naegleria gruberi illuminates early eukaryotic versatility. Cell. 2010; 140(5):631-42. DOI: 10.1016/j.cell.2010.01.032. View

16.

Peranen J, Auvinen P, Virta H, Wepf R, Simons K . Rab8 promotes polarized membrane transport through reorganization of actin and microtubules in fibroblasts. J Cell Biol. 1996; 135(1):153-67. PMC: 2121014. DOI: 10.1083/jcb.135.1.153. View

17.

Robinson F, Niesman I, Beiswenger K, Dixon J . Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice. Proc Natl Acad Sci U S A. 2008; 105(12):4916-21. PMC: 2290800. DOI: 10.1073/pnas.0800742105. View

18.

Sato Y, Fukai S, Ishitani R, Nureki O . Crystal structure of the Sec4p.Sec2p complex in the nucleotide exchanging intermediate state. Proc Natl Acad Sci U S A. 2007; 104(20):8305-10. PMC: 1895945. DOI: 10.1073/pnas.0701550104. View

19.

Nachury M, Loktev A, Zhang Q, Westlake C, Peranen J, Merdes A . A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007; 129(6):1201-13. DOI: 10.1016/j.cell.2007.03.053. View

20.

Haas A, Yoshimura S, Stephens D, Preisinger C, Fuchs E, Barr F . Analysis of GTPase-activating proteins: Rab1 and Rab43 are key Rabs required to maintain a functional Golgi complex in human cells. J Cell Sci. 2007; 120(Pt 17):2997-3010. DOI: 10.1242/jcs.014225. View