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PMID: 20937701 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors.

The Journal of cell biology ·Vol. 191 ·No. 2 ·2010-10-18 ·Pages 367-81

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

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.

MeSH Terms
Biological Transport Guanine Nucleotide Exchange Factors/analysis,chemistry,physiology HeLa Cells Humans Lysosomes/metabolism Protein Structure, Tertiary Shiga Toxin/metabolism rab GTP-Binding Proteins/analysis,chemistry,physiology trans-Golgi Network/metabolism
Chemicals
Guanine Nucleotide Exchange Factors Shiga Toxin rab GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yoshimura Shin-ichiro
Cancer Research Centre and 2 Institute of Integrative Biology, University of Liverpool, Liverpool L3 9TA, England, UK.
Gerondopoulos Andreas
Linford Andrea
Rigden Daniel J
Barr Francis A
References (68)
68 references, click to expand
  1. The Rab8 GTPase regulates apical protein localization in intestinal cells.
    Nature. 2007 Jul 19;448(7151):366-9 PMID: 17597763
  2. RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport.
    Cell. 2009 May 29;137(5):938-48 PMID: 19490898
  3. Ric1p and Rgp1p form a complex that catalyses nucleotide exchange on Ypt6p.
    EMBO J. 2000 Sep 15;19(18):4885-94 PMID: 10990452
  4. TRAPP stimulates guanine nucleotide exchange on Ypt1p.
    J Cell Biol. 2000 Oct 16;151(2):289-96 PMID: 11038176
  5. Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways.
    J Cell Biol. 2007 Jun 18;177(6):1133-43 PMID: 17562788
  6. Rab9 functions in transport between late endosomes and the trans Golgi network.
    EMBO J. 1993 Feb;12(2):677-82 PMID: 8440258
  7. Rab GEFs and GAPs.
    Curr Opin Cell Biol. 2010 Aug;22(4):461-70 PMID: 20466531
  8. Structural basis for Rab GTPase activation by VPS9 domain exchange factors.
    Nat Struct Mol Biol. 2007 May;14(5):406-12 PMID: 17450153
  9. Avl9p, a member of a novel protein superfamily, functions in the late secretory pathway.
    Mol Biol Cell. 2007 Apr;18(4):1203-19 PMID: 17229886
  10. TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism.
    Nature. 2006 Jul 20;442(7100):303-6 PMID: 16855591
  11. Isolation and characterization of a GDP/GTP exchange protein specific for the Rab3 subfamily small G proteins.
    J Biol Chem. 1997 Feb 14;272(7):3875-8 PMID: 9020086
  12. A catalytic coiled coil: structural insights into the activation of the Rab GTPase Sec4p by Sec2p.
    Mol Cell. 2007 Feb 9;25(3):455-62 PMID: 17289591
  13. The death domain of Rab3 guanine nucleotide exchange protein in GDP/GTP exchange activity in living cells.
    Biochem J. 2002 Mar 1;362(Pt 2):273-9 PMID: 11853534
  14. Clustal W and Clustal X version 2.0.
    Bioinformatics. 2007 Nov 1;23(21):2947-8 PMID: 17846036
  15. The genome of Naegleria gruberi illuminates early eukaryotic versatility.
    Cell. 2010 Mar 5;140(5):631-42 PMID: 20211133
  16. Rab8 promotes polarized membrane transport through reorganization of actin and microtubules in fibroblasts.
    J Cell Biol. 1996 Oct;135(1):153-67 PMID: 8858170
  17. 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 Mar 25;105(12):4916-21 PMID: 18349142
  18. Crystal structure of the Sec4p.Sec2p complex in the nucleotide exchanging intermediate state.
    Proc Natl Acad Sci U S A. 2007 May 15;104(20):8305-10 PMID: 17488829
  19. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.
    Cell. 2007 Jun 15;129(6):1201-13 PMID: 17574030
  20. 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 Sep 1;120(Pt 17):2997-3010 PMID: 17684057
  21. aex-3 encodes a novel regulator of presynaptic activity in C. elegans.
    Neuron. 1997 Apr;18(4):613-22 PMID: 9136770
  22. Lysosome biogenesis requires Rab9 function and receptor recycling from endosomes to the trans-Golgi network.
    J Cell Biol. 1994 May;125(3):573-82 PMID: 7909812
  23. Targeting Rab GTPases to distinct membrane compartments.
    Nat Rev Mol Cell Biol. 2004 Nov;5(11):886-96 PMID: 15520808
  24. The Mon1-Ccz1 complex is the GEF of the late endosomal Rab7 homolog Ypt7.
    Curr Biol. 2010 Sep 28;20(18):1654-9 PMID: 20797862
  25. Rab3GEP is the non-redundant guanine nucleotide exchange factor for Rab27a in melanocytes.
    J Biol Chem. 2008 Aug 22;283(34):23209-16 PMID: 18559336
  26. Sec2 is a highly efficient exchange factor for the Rab protein Sec4.
    J Mol Biol. 2007 Feb 2;365(5):1359-67 PMID: 17134721
  27. The Connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes.
    Mol Cell. 2010 Feb 12;37(3):370-82 PMID: 20159556
  28. Disruption of ST5 is associated with mental retardation and multiple congenital anomalies.
    J Med Genet. 2010 Feb;47(2):91-8 PMID: 19843505
  29. Multiple sequence alignment with the Clustal series of programs.
    Nucleic Acids Res. 2003 Jul 1;31(13):3497-500 PMID: 12824352
  30. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.
    Am J Hum Genet. 2003 May;72(5):1141-53 PMID: 12687498
  31. Regulation of synaptic transmission by RAB-3 and RAB-27 in Caenorhabditis elegans.
    Mol Biol Cell. 2006 Jun;17(6):2617-25 PMID: 16571673
  32. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly.
    Am J Hum Genet. 2010 Feb 12;86(2):185-95 PMID: 20159109
  33. Prediction of protein binding regions in disordered proteins.
    PLoS Comput Biol. 2009 May;5(5):e1000376 PMID: 19412530
  34. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.
    Nat Biotechnol. 2008 Dec;26(12):1367-72 PMID: 19029910
  35. Assay and properties of rab6 interaction with dynein-dynactin complexes.
    Methods Enzymol. 2005;403:607-18 PMID: 16473624
  36. A novel Rab9 effector required for endosome-to-TGN transport.
    J Cell Biol. 1997 Jul 28;138(2):283-90 PMID: 9230071
  37. Prediction of disordered regions in proteins based on the meta approach.
    Bioinformatics. 2008 Jun 1;24(11):1344-8 PMID: 18426805
  38. Organelle identity and the signposts for membrane traffic.
    Nature. 2005 Dec 1;438(7068):597-604 PMID: 16319879
  39. Functional dissection of Rab GTPases involved in primary cilium formation.
    J Cell Biol. 2007 Jul 30;178(3):363-9 PMID: 17646400
  40. Assembly of the biogenesis of lysosome-related organelles complex-3 (BLOC-3) and its interaction with Rab9.
    J Biol Chem. 2010 Mar 5;285(10):7794-804 PMID: 20048159
  41. The structural basis for activation of the Rab Ypt1p by the TRAPP membrane-tethering complexes.
    Cell. 2008 Jun 27;133(7):1202-13 PMID: 18585354
  42. uDENN, DENN, and dDENN: indissociable domains in Rab and MAP kinases signaling pathways.
    Biochem Biophys Res Commun. 2001 Sep 28;287(3):688-95 PMID: 11563850
  43. Femtomole sequencing of proteins from polyacrylamide gels by nano-electrospray mass spectrometry.
    Nature. 1996 Feb 1;379(6564):466-9 PMID: 8559255
  44. Rab10 is involved in basolateral transport in polarized Madin-Darby canine kidney cells.
    Traffic. 2007 Jan;8(1):47-60 PMID: 17132146
  45. Crag regulates epithelial architecture and polarized deposition of basement membrane proteins in Drosophila.
    Dev Cell. 2008 Mar;14(3):354-64 PMID: 18331716
  46. Sec2p mediates nucleotide exchange on Sec4p and is involved in polarized delivery of post-Golgi vesicles.
    J Cell Biol. 1997 Jun 30;137(7):1495-509 PMID: 9199166
  47. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules.
    J Biol Chem. 2002 Aug 2;277(31):28191-9 PMID: 12019270
  48. Structure, exchange determinants, and family-wide rab specificity of the tandem helical bundle and Vps9 domains of Rabex-5.
    Cell. 2004 Sep 3;118(5):607-17 PMID: 15339665
  49. Jalview Version 2--a multiple sequence alignment editor and analysis workbench.
    Bioinformatics. 2009 May 1;25(9):1189-91 PMID: 19151095
  50. A GTPase-activating protein controls Rab5 function in endocytic trafficking.
    Nat Cell Biol. 2005 Sep;7(9):887-93 PMID: 16086013
  51. Assay and functional properties of Rabkinesin-6/Rab6-KIFL/MKlp2 in cytokinesis.
    Methods Enzymol. 2005;403:618-28 PMID: 16473625
  52. The retromer complex and clathrin define an early endosomal retrograde exit site.
    J Cell Sci. 2007 Jun 15;120(Pt 12):2022-31 PMID: 17550971
  53. A Rab8-specific GDP/GTP exchange factor is involved in actin remodeling and polarized membrane transport.
    Mol Biol Cell. 2002 Sep;13(9):3268-80 PMID: 12221131
  54. Rab proteins as membrane organizers.
    Nat Rev Mol Cell Biol. 2001 Feb;2(2):107-17 PMID: 11252952
  55. Caenorhabditis elegans RME-6 is a novel regulator of RAB-5 at the clathrin-coated pit.
    Nat Cell Biol. 2005 Jun;7(6):559-69 PMID: 15895077
  56. Molecular cloning and characterization of the noncatalytic subunit of the Rab3 subfamily-specific GTPase-activating protein.
    J Biol Chem. 1998 Sep 18;273(38):24781-5 PMID: 9733780
  57. A chemical genetic screen for modulators of exocytic transport identifies inhibitors of a transport mechanism linked to GTR2 function.
    Eukaryot Cell. 2010 Jan;9(1):116-26 PMID: 19897736
  58. Coordination of Rab8 and Rab11 in primary ciliogenesis.
    Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6346-51 PMID: 20308558
  59. Lightoid and Claret: a rab GTPase and its putative guanine nucleotide exchange factor in biogenesis of Drosophila eye pigment granules.
    Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11652-7 PMID: 15289618
  60. SNX-BAR proteins in phosphoinositide-mediated, tubular-based endosomal sorting.
    Semin Cell Dev Biol. 2010 Jun;21(4):371-80 PMID: 19914387
  61. Rab13 regulates membrane trafficking between TGN and recycling endosomes in polarized epithelial cells.
    J Cell Biol. 2008 Sep 8;182(5):845-53 PMID: 18779367
  62. Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins.
    J Biol Chem. 1997 Feb 21;272(8):4655-8 PMID: 9030515
  63. The connecdenn family, Rab35 guanine nucleotide exchange factors interfacing with the clathrin machinery.
    J Biol Chem. 2010 Apr 2;285(14):10627-37 PMID: 20154091
  64. MUSCLE: multiple sequence alignment with high accuracy and high throughput.
    Nucleic Acids Res. 2004 Mar 19;32(5):1792-7 PMID: 15034147
  65. ELM: the status of the 2010 eukaryotic linear motif resource.
    Nucleic Acids Res. 2010 Jan;38(Database issue):D167-80 PMID: 19920119
  66. Regulation of endocytic recycling by C. elegans Rab35 and its regulator RME-4, a coated-pit protein.
    EMBO J. 2008 Apr 23;27(8):1183-96 PMID: 18354496
  67. Purification and properties of Rab3 GEP (DENN/MADD).
    Methods Enzymol. 2005;403:254-61 PMID: 16473592
  68. Rab10 regulates membrane transport through early endosomes of polarized Madin-Darby canine kidney cells.
    Mol Biol Cell. 2006 Jul;17(7):3156-75 PMID: 16641372
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.201008051
Published
2010-10-18
Epub
2010-00-11
Pages
367-81
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2958468
Subset
IM
Grants
Wellcome Trust · United Kingdom
Wellcome Trust · 08246/Z/07/Z · United Kingdom
External Links
PubMed source DOI: 10.1083/jcb.201008051 PMC Full Text View journal details
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