Full text data of RABGEF1
RABGEF1
(RABEX5)
[Confidence: low (only semi-automatic identification from reviews)]
Rab5 GDP/GTP exchange factor (RAP1; Rabaptin-5-associated exchange factor for Rab5; Rabex-5)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Rab5 GDP/GTP exchange factor (RAP1; Rabaptin-5-associated exchange factor for Rab5; Rabex-5)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9UJ41
ID RABX5_HUMAN Reviewed; 708 AA.
AC Q9UJ41; Q3HKR2; Q3HKR3; Q53FG0;
DT 05-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 2.
DT 22-JAN-2014, entry version 114.
DE RecName: Full=Rab5 GDP/GTP exchange factor;
DE AltName: Full=RAP1;
DE AltName: Full=Rabaptin-5-associated exchange factor for Rab5;
DE AltName: Full=Rabex-5;
GN Name=RABGEF1; Synonyms=RABEX5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=11098082; DOI=10.1016/S0304-3835(00)00553-X;
RA Nimmrich I., Erdmann S., Melchers U., Finke U., Hentsch S.,
RA Moyer M.P., Hoffmann I., Mueller O.;
RT "Seven genes that are differentially transcribed in colorectal tumor
RT cell lines.";
RL Cancer Lett. 160:37-43(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Cervix carcinoma;
RA Barbieri M.A., Hunker C.M.;
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, AND INTERACTION WITH RABEP1.
RX PubMed=9323142; DOI=10.1016/S0092-8674(00)80380-3;
RA Horiuchi H., Lippe R., McBride H.M., Rubino M., Woodman P.,
RA Stenmark H., Rybin V., Wilm M., Ashman K., Mann M., Zerial M.;
RT "A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links
RT nucleotide exchange to effector recruitment and function.";
RL Cell 90:1149-1159(1997).
RN [9]
RP FUNCTION, AND INTERACTION WITH RABEP1.
RX PubMed=11452015; DOI=10.1091/mbc.12.7.2219;
RA Lippe R., Miaczynska M., Rybin V., Runge A., Zerial M.;
RT "Functional synergy between Rab5 effector Rabaptin-5 and exchange
RT factor Rabex-5 when physically associated in a complex.";
RL Mol. Biol. Cell 12:2219-2228(2001).
RN [10]
RP INTERACTION WITH GGA1; GGA2; GGA3; AP1G1 AND AP1G2, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12505986; DOI=10.1093/emboj/cdg015;
RA Mattera R., Arighi C.N., Lodge R., Zerial M., Bonifacino J.S.;
RT "Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5
RT complex.";
RL EMBO J. 22:78-88(2003).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 310-611, FUNCTION,
RP INTERACTION WITH RAB5; RAB21 AND RAB22, AND MUTAGENESIS OF ASP-530;
RP PRO-534; TYR-571 AND THR-574.
RX PubMed=15339665; DOI=10.1016/j.cell.2004.08.009;
RA Delprato A., Merithew E., Lambright D.G.;
RT "Structure, exchange determinants, and family-wide rab specificity of
RT the tandem helical bundle and Vps9 domains of Rabex-5.";
RL Cell 118:607-617(2004).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 139-252 IN COMPLEX WITH
RP UBIQUITIN, UBIQUITINATION, AND MUTAGENESIS OF ALA-196.
RX PubMed=16499958; DOI=10.1016/j.cell.2006.02.020;
RA Penengo L., Mapelli M., Murachelli A.G., Confalonieri S., Magri L.,
RA Musacchio A., Di Fiore P.P., Polo S., Schneider T.R.;
RT "Crystal structure of the ubiquitin binding domains of rabex-5 reveals
RT two modes of interaction with ubiquitin.";
RL Cell 124:1183-1195(2006).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 310-614 IN COMPLEX WITH
RP RAB21.
RX PubMed=17450153; DOI=10.1038/nsmb1232;
RA Delprato A., Lambright D.G.;
RT "Structural basis for Rab GTPase activation by VPS9 domain exchange
RT factors.";
RL Nat. Struct. Mol. Biol. 14:406-412(2007).
CC -!- FUNCTION: Rab effector protein acting as linker between gamma-
CC adaptin, RAB4A or RAB5A. Involved in endocytic membrane fusion and
CC membrane trafficking of recycling endosomes. Stimulates nucleotide
CC exchange on RAB5A. Can act as a ubiquitin ligase (By similarity).
CC -!- SUBUNIT: Interacts with RGS14; the interaction is GTP-dependent
CC (By similarity). Heterodimer with RABEP1. The heterodimer binds
CC RAB4A and RAB5A that have been activated by GTP-binding. Interacts
CC with RAB21, and with 100-fold lower affinity also with RAB22.
CC Binds TSC2, GGA1, GGA2, GGA3, AP1G1 and AP1G2. Interacts with
CC ubiquitinated EGFR.
CC -!- INTERACTION:
CC P00533:EGFR; NbExp=4; IntAct=EBI-913954, EBI-297353;
CC Q9BQD3:KXD1; NbExp=2; IntAct=EBI-913954, EBI-739657;
CC P0CG47:UBB; NbExp=6; IntAct=EBI-913954, EBI-413034;
CC P62990:UBC (xeno); NbExp=2; IntAct=EBI-913954, EBI-413053;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Early endosome. Recycling
CC endosome.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9UJ41-1; Sequence=Displayed;
CC Note=No experimental confirmation available;
CC Name=2;
CC IsoId=Q9UJ41-2; Sequence=VSP_010690, VSP_010691, VSP_010692;
CC Name=3; Synonyms=Long;
CC IsoId=Q9UJ41-3; Sequence=VSP_010690, VSP_010692;
CC -!- PTM: Monoubiquitinated.
CC -!- SIMILARITY: Contains 1 A20-type zinc finger.
CC -!- SIMILARITY: Contains 1 VPS9 domain.
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DR EMBL; AJ250042; CAB57359.1; -; mRNA.
DR EMBL; DQ230533; ABA64473.1; -; mRNA.
DR EMBL; DQ230534; ABA64474.1; -; mRNA.
DR EMBL; AK127790; BAC87138.1; -; mRNA.
DR EMBL; BT007107; AAP35771.1; -; mRNA.
DR EMBL; AK223329; BAD97049.1; -; mRNA.
DR EMBL; AC027644; AAQ93362.1; -; Genomic_DNA.
DR EMBL; BC015330; AAH15330.1; -; mRNA.
DR RefSeq; NP_055319.1; NM_014504.2.
DR RefSeq; XP_005250336.1; XM_005250279.1.
DR UniGene; Hs.530053; -.
DR PDB; 1TXU; X-ray; 2.35 A; A=310-611.
DR PDB; 2C7M; X-ray; 2.40 A; A=139-252.
DR PDB; 2C7N; X-ray; 2.10 A; A/C/E/G/I/K=139-252.
DR PDB; 2OT3; X-ray; 2.10 A; A=310-614.
DR PDBsum; 1TXU; -.
DR PDBsum; 2C7M; -.
DR PDBsum; 2C7N; -.
DR PDBsum; 2OT3; -.
DR ProteinModelPortal; Q9UJ41; -.
DR SMR; Q9UJ41; 155-252, 312-604.
DR DIP; DIP-29348N; -.
DR IntAct; Q9UJ41; 11.
DR MINT; MINT-1189235; -.
DR STRING; 9606.ENSP00000284957; -.
DR PhosphoSite; Q9UJ41; -.
DR DMDM; 56405102; -.
DR PaxDb; Q9UJ41; -.
DR PRIDE; Q9UJ41; -.
DR DNASU; 27342; -.
DR Ensembl; ENST00000284957; ENSP00000284957; ENSG00000154710.
DR Ensembl; ENST00000450873; ENSP00000415815; ENSG00000154710.
DR GeneID; 27342; -.
DR KEGG; hsa:27342; -.
DR UCSC; uc003tvf.3; human.
DR CTD; 27342; -.
DR GeneCards; GC07P066205; -.
DR HGNC; HGNC:17676; RABGEF1.
DR HPA; HPA001407; -.
DR MIM; 609700; gene.
DR neXtProt; NX_Q9UJ41; -.
DR PharmGKB; PA134946532; -.
DR eggNOG; NOG301606; -.
DR HOGENOM; HOG000070180; -.
DR HOVERGEN; HBG062584; -.
DR ChiTaRS; RABGEF1; human.
DR EvolutionaryTrace; Q9UJ41; -.
DR GeneWiki; RABGEF1; -.
DR GenomeRNAi; 27342; -.
DR NextBio; 50418; -.
DR PRO; PR:Q9UJ41; -.
DR ArrayExpress; Q9UJ41; -.
DR CleanEx; HS_RABGEF1; -.
DR Genevestigator; Q9UJ41; -.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0017112; F:Rab guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR InterPro; IPR003123; VPS9.
DR InterPro; IPR013995; VPS9_subgr.
DR InterPro; IPR002653; Znf_A20.
DR Pfam; PF02204; VPS9; 1.
DR Pfam; PF01754; zf-A20; 1.
DR SMART; SM00167; VPS9; 1.
DR SMART; SM00259; ZnF_A20; 1.
DR PROSITE; PS51205; VPS9; 1.
DR PROSITE; PS51036; ZF_A20; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Coiled coil; Complete proteome;
KW Cytoplasm; Endocytosis; Endosome; Metal-binding; Protein transport;
KW Reference proteome; Transport; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1 708 Rab5 GDP/GTP exchange factor.
FT /FTId=PRO_0000191315.
FT DOMAIN 449 592 VPS9.
FT ZN_FING 151 185 A20-type.
FT REGION 139 252 Interaction with ubiquitinated proteins.
FT COILED 624 665 Potential.
FT VAR_SEQ 1 138 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_010690.
FT VAR_SEQ 199 238 Missing (in isoform 2).
FT /FTId=VSP_010691.
FT VAR_SEQ 377 415 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_010692.
FT MUTAGEN 196 196 A->G: Reduces affinity for ubiquitin 3-
FT fold.
FT MUTAGEN 530 530 D->A: Strongly reduced activity.
FT MUTAGEN 534 534 P->A: Strongly reduced activity.
FT MUTAGEN 571 571 Y->A: Strongly reduced activity.
FT MUTAGEN 574 574 T->A: Strongly reduced activity.
FT CONFLICT 199 199 V -> A (in Ref. 2; ABA64474).
FT CONFLICT 203 203 C -> Y (in Ref. 2; ABA64474).
FT CONFLICT 476 476 E -> D (in Ref. 3; BAC87138).
FT CONFLICT 487 487 K -> R (in Ref. 5; BAD97049).
FT STRAND 161 163
FT HELIX 167 169
FT HELIX 174 198
FT HELIX 239 248
FT HELIX 318 325
FT HELIX 328 346
FT TURN 347 350
FT HELIX 353 372
FT HELIX 418 440
FT HELIX 448 461
FT TURN 462 464
FT TURN 467 471
FT HELIX 479 494
FT HELIX 495 497
FT HELIX 501 523
FT HELIX 529 543
FT HELIX 548 558
FT TURN 561 565
FT HELIX 568 585
FT HELIX 589 591
FT HELIX 595 602
SQ SEQUENCE 708 AA; 79371 MW; 007E404F13AC91D8 CRC64;
MVVVTGREPD SRRQDGAMSS SDAEDDFLEP ATPTATQAGH ALPLLPQERC AEFPALRGPP
TQGACSSCVQ RGPVLCHRAP PGAAGEHAAT EGREGAPSVS GTHALLQRPL GADCGDRPAA
CGPAEGPLCQ AQVVSRKKMS LKSERRGIHV DQSDLLCKKG CGYYGNPAWQ GFCSKCWREE
YHKARQKQIQ EDWELAERVL LCCPGWSAMV QFQLTATSAS WAQVILLLQP PKWLGLQKLQ
REEEEAFASS QSSQGAQSLT FSKFEEKKTN EKTRKVTTVK KFFSASSRVG SKKEIQEAKA
PSPSINRQTS IETDRVSKEF IEFLKTFHKT GQEIYKQTKL FLEGMHYKRD LSIEEQSECA
QDFYHNVAER MQTRGKERRF HHVGQAGLEL LTSGDPPASA SQSAGNTGVE PPHPAVPPER
VEKIMDQIEK YIMTRLYKYV FCPETTDDEK KDLAIQKRIR ALRWVTPQML CVPVNEDIPE
VSDMVVKAIT DIIEMDSKRV PRDKLACITK CSKHIFNAIK ITKNEPASAD DFLPTLIYIV
LKGNPPRLQS NIQYITRFCN PSRLMTGEDG YYFTNLCCAV AFIEKLDAQS LNLSQEDFDR
YMSGQTSPRK QEAESWSPDA CLGVKQMYKN LDLLSQLNER QERIMNEAKK LEKDLIDWTD
GIAREVQDIV EKYPLEIKPP NQPLAAIDSE NVENDKLPPP LQPQVYAG
//
ID RABX5_HUMAN Reviewed; 708 AA.
AC Q9UJ41; Q3HKR2; Q3HKR3; Q53FG0;
DT 05-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 2.
DT 22-JAN-2014, entry version 114.
DE RecName: Full=Rab5 GDP/GTP exchange factor;
DE AltName: Full=RAP1;
DE AltName: Full=Rabaptin-5-associated exchange factor for Rab5;
DE AltName: Full=Rabex-5;
GN Name=RABGEF1; Synonyms=RABEX5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=11098082; DOI=10.1016/S0304-3835(00)00553-X;
RA Nimmrich I., Erdmann S., Melchers U., Finke U., Hentsch S.,
RA Moyer M.P., Hoffmann I., Mueller O.;
RT "Seven genes that are differentially transcribed in colorectal tumor
RT cell lines.";
RL Cancer Lett. 160:37-43(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Cervix carcinoma;
RA Barbieri M.A., Hunker C.M.;
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, AND INTERACTION WITH RABEP1.
RX PubMed=9323142; DOI=10.1016/S0092-8674(00)80380-3;
RA Horiuchi H., Lippe R., McBride H.M., Rubino M., Woodman P.,
RA Stenmark H., Rybin V., Wilm M., Ashman K., Mann M., Zerial M.;
RT "A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links
RT nucleotide exchange to effector recruitment and function.";
RL Cell 90:1149-1159(1997).
RN [9]
RP FUNCTION, AND INTERACTION WITH RABEP1.
RX PubMed=11452015; DOI=10.1091/mbc.12.7.2219;
RA Lippe R., Miaczynska M., Rybin V., Runge A., Zerial M.;
RT "Functional synergy between Rab5 effector Rabaptin-5 and exchange
RT factor Rabex-5 when physically associated in a complex.";
RL Mol. Biol. Cell 12:2219-2228(2001).
RN [10]
RP INTERACTION WITH GGA1; GGA2; GGA3; AP1G1 AND AP1G2, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12505986; DOI=10.1093/emboj/cdg015;
RA Mattera R., Arighi C.N., Lodge R., Zerial M., Bonifacino J.S.;
RT "Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5
RT complex.";
RL EMBO J. 22:78-88(2003).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 310-611, FUNCTION,
RP INTERACTION WITH RAB5; RAB21 AND RAB22, AND MUTAGENESIS OF ASP-530;
RP PRO-534; TYR-571 AND THR-574.
RX PubMed=15339665; DOI=10.1016/j.cell.2004.08.009;
RA Delprato A., Merithew E., Lambright D.G.;
RT "Structure, exchange determinants, and family-wide rab specificity of
RT the tandem helical bundle and Vps9 domains of Rabex-5.";
RL Cell 118:607-617(2004).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 139-252 IN COMPLEX WITH
RP UBIQUITIN, UBIQUITINATION, AND MUTAGENESIS OF ALA-196.
RX PubMed=16499958; DOI=10.1016/j.cell.2006.02.020;
RA Penengo L., Mapelli M., Murachelli A.G., Confalonieri S., Magri L.,
RA Musacchio A., Di Fiore P.P., Polo S., Schneider T.R.;
RT "Crystal structure of the ubiquitin binding domains of rabex-5 reveals
RT two modes of interaction with ubiquitin.";
RL Cell 124:1183-1195(2006).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 310-614 IN COMPLEX WITH
RP RAB21.
RX PubMed=17450153; DOI=10.1038/nsmb1232;
RA Delprato A., Lambright D.G.;
RT "Structural basis for Rab GTPase activation by VPS9 domain exchange
RT factors.";
RL Nat. Struct. Mol. Biol. 14:406-412(2007).
CC -!- FUNCTION: Rab effector protein acting as linker between gamma-
CC adaptin, RAB4A or RAB5A. Involved in endocytic membrane fusion and
CC membrane trafficking of recycling endosomes. Stimulates nucleotide
CC exchange on RAB5A. Can act as a ubiquitin ligase (By similarity).
CC -!- SUBUNIT: Interacts with RGS14; the interaction is GTP-dependent
CC (By similarity). Heterodimer with RABEP1. The heterodimer binds
CC RAB4A and RAB5A that have been activated by GTP-binding. Interacts
CC with RAB21, and with 100-fold lower affinity also with RAB22.
CC Binds TSC2, GGA1, GGA2, GGA3, AP1G1 and AP1G2. Interacts with
CC ubiquitinated EGFR.
CC -!- INTERACTION:
CC P00533:EGFR; NbExp=4; IntAct=EBI-913954, EBI-297353;
CC Q9BQD3:KXD1; NbExp=2; IntAct=EBI-913954, EBI-739657;
CC P0CG47:UBB; NbExp=6; IntAct=EBI-913954, EBI-413034;
CC P62990:UBC (xeno); NbExp=2; IntAct=EBI-913954, EBI-413053;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Early endosome. Recycling
CC endosome.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9UJ41-1; Sequence=Displayed;
CC Note=No experimental confirmation available;
CC Name=2;
CC IsoId=Q9UJ41-2; Sequence=VSP_010690, VSP_010691, VSP_010692;
CC Name=3; Synonyms=Long;
CC IsoId=Q9UJ41-3; Sequence=VSP_010690, VSP_010692;
CC -!- PTM: Monoubiquitinated.
CC -!- SIMILARITY: Contains 1 A20-type zinc finger.
CC -!- SIMILARITY: Contains 1 VPS9 domain.
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; AJ250042; CAB57359.1; -; mRNA.
DR EMBL; DQ230533; ABA64473.1; -; mRNA.
DR EMBL; DQ230534; ABA64474.1; -; mRNA.
DR EMBL; AK127790; BAC87138.1; -; mRNA.
DR EMBL; BT007107; AAP35771.1; -; mRNA.
DR EMBL; AK223329; BAD97049.1; -; mRNA.
DR EMBL; AC027644; AAQ93362.1; -; Genomic_DNA.
DR EMBL; BC015330; AAH15330.1; -; mRNA.
DR RefSeq; NP_055319.1; NM_014504.2.
DR RefSeq; XP_005250336.1; XM_005250279.1.
DR UniGene; Hs.530053; -.
DR PDB; 1TXU; X-ray; 2.35 A; A=310-611.
DR PDB; 2C7M; X-ray; 2.40 A; A=139-252.
DR PDB; 2C7N; X-ray; 2.10 A; A/C/E/G/I/K=139-252.
DR PDB; 2OT3; X-ray; 2.10 A; A=310-614.
DR PDBsum; 1TXU; -.
DR PDBsum; 2C7M; -.
DR PDBsum; 2C7N; -.
DR PDBsum; 2OT3; -.
DR ProteinModelPortal; Q9UJ41; -.
DR SMR; Q9UJ41; 155-252, 312-604.
DR DIP; DIP-29348N; -.
DR IntAct; Q9UJ41; 11.
DR MINT; MINT-1189235; -.
DR STRING; 9606.ENSP00000284957; -.
DR PhosphoSite; Q9UJ41; -.
DR DMDM; 56405102; -.
DR PaxDb; Q9UJ41; -.
DR PRIDE; Q9UJ41; -.
DR DNASU; 27342; -.
DR Ensembl; ENST00000284957; ENSP00000284957; ENSG00000154710.
DR Ensembl; ENST00000450873; ENSP00000415815; ENSG00000154710.
DR GeneID; 27342; -.
DR KEGG; hsa:27342; -.
DR UCSC; uc003tvf.3; human.
DR CTD; 27342; -.
DR GeneCards; GC07P066205; -.
DR HGNC; HGNC:17676; RABGEF1.
DR HPA; HPA001407; -.
DR MIM; 609700; gene.
DR neXtProt; NX_Q9UJ41; -.
DR PharmGKB; PA134946532; -.
DR eggNOG; NOG301606; -.
DR HOGENOM; HOG000070180; -.
DR HOVERGEN; HBG062584; -.
DR ChiTaRS; RABGEF1; human.
DR EvolutionaryTrace; Q9UJ41; -.
DR GeneWiki; RABGEF1; -.
DR GenomeRNAi; 27342; -.
DR NextBio; 50418; -.
DR PRO; PR:Q9UJ41; -.
DR ArrayExpress; Q9UJ41; -.
DR CleanEx; HS_RABGEF1; -.
DR Genevestigator; Q9UJ41; -.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0017112; F:Rab guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR InterPro; IPR003123; VPS9.
DR InterPro; IPR013995; VPS9_subgr.
DR InterPro; IPR002653; Znf_A20.
DR Pfam; PF02204; VPS9; 1.
DR Pfam; PF01754; zf-A20; 1.
DR SMART; SM00167; VPS9; 1.
DR SMART; SM00259; ZnF_A20; 1.
DR PROSITE; PS51205; VPS9; 1.
DR PROSITE; PS51036; ZF_A20; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Coiled coil; Complete proteome;
KW Cytoplasm; Endocytosis; Endosome; Metal-binding; Protein transport;
KW Reference proteome; Transport; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1 708 Rab5 GDP/GTP exchange factor.
FT /FTId=PRO_0000191315.
FT DOMAIN 449 592 VPS9.
FT ZN_FING 151 185 A20-type.
FT REGION 139 252 Interaction with ubiquitinated proteins.
FT COILED 624 665 Potential.
FT VAR_SEQ 1 138 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_010690.
FT VAR_SEQ 199 238 Missing (in isoform 2).
FT /FTId=VSP_010691.
FT VAR_SEQ 377 415 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_010692.
FT MUTAGEN 196 196 A->G: Reduces affinity for ubiquitin 3-
FT fold.
FT MUTAGEN 530 530 D->A: Strongly reduced activity.
FT MUTAGEN 534 534 P->A: Strongly reduced activity.
FT MUTAGEN 571 571 Y->A: Strongly reduced activity.
FT MUTAGEN 574 574 T->A: Strongly reduced activity.
FT CONFLICT 199 199 V -> A (in Ref. 2; ABA64474).
FT CONFLICT 203 203 C -> Y (in Ref. 2; ABA64474).
FT CONFLICT 476 476 E -> D (in Ref. 3; BAC87138).
FT CONFLICT 487 487 K -> R (in Ref. 5; BAD97049).
FT STRAND 161 163
FT HELIX 167 169
FT HELIX 174 198
FT HELIX 239 248
FT HELIX 318 325
FT HELIX 328 346
FT TURN 347 350
FT HELIX 353 372
FT HELIX 418 440
FT HELIX 448 461
FT TURN 462 464
FT TURN 467 471
FT HELIX 479 494
FT HELIX 495 497
FT HELIX 501 523
FT HELIX 529 543
FT HELIX 548 558
FT TURN 561 565
FT HELIX 568 585
FT HELIX 589 591
FT HELIX 595 602
SQ SEQUENCE 708 AA; 79371 MW; 007E404F13AC91D8 CRC64;
MVVVTGREPD SRRQDGAMSS SDAEDDFLEP ATPTATQAGH ALPLLPQERC AEFPALRGPP
TQGACSSCVQ RGPVLCHRAP PGAAGEHAAT EGREGAPSVS GTHALLQRPL GADCGDRPAA
CGPAEGPLCQ AQVVSRKKMS LKSERRGIHV DQSDLLCKKG CGYYGNPAWQ GFCSKCWREE
YHKARQKQIQ EDWELAERVL LCCPGWSAMV QFQLTATSAS WAQVILLLQP PKWLGLQKLQ
REEEEAFASS QSSQGAQSLT FSKFEEKKTN EKTRKVTTVK KFFSASSRVG SKKEIQEAKA
PSPSINRQTS IETDRVSKEF IEFLKTFHKT GQEIYKQTKL FLEGMHYKRD LSIEEQSECA
QDFYHNVAER MQTRGKERRF HHVGQAGLEL LTSGDPPASA SQSAGNTGVE PPHPAVPPER
VEKIMDQIEK YIMTRLYKYV FCPETTDDEK KDLAIQKRIR ALRWVTPQML CVPVNEDIPE
VSDMVVKAIT DIIEMDSKRV PRDKLACITK CSKHIFNAIK ITKNEPASAD DFLPTLIYIV
LKGNPPRLQS NIQYITRFCN PSRLMTGEDG YYFTNLCCAV AFIEKLDAQS LNLSQEDFDR
YMSGQTSPRK QEAESWSPDA CLGVKQMYKN LDLLSQLNER QERIMNEAKK LEKDLIDWTD
GIAREVQDIV EKYPLEIKPP NQPLAAIDSE NVENDKLPPP LQPQVYAG
//
MIM
609700
*RECORD*
*FIELD* NO
609700
*FIELD* TI
*609700 RAB GUANINE NUCLEOTIDE EXCHANGE FACTOR 1; RABGEF1
;;RABAPTIN 5-ASSOCIATED EXCHANGE FACTOR FOR RAB5; RABEX5
read more*FIELD* TX
DESCRIPTION
RABGEF1 forms a complex with rabaptin-5 (RABPT5; 603616) that is
required for endocytic membrane fusion, and it serves as a specific
guanine nucleotide exchange factor (GEF) for RAB5 (RAB5A; 179512)
(Horiuchi et al., 1997).
CLONING
Using an overlay assay on HeLa cell and bovine brain cytosol to identify
RAB5-interacting proteins, followed by mass spectrometry, EST database
analysis, and screening a bovine brain cDNA library, Horiuchi et al.
(1997) cloned bovine Rabgef1, which they termed Rabex5. The deduced
492-amino acid protein has a calculated molecular mass of 57.1 kD and
shares significant homology with yeast Vps9, a protein implicated in
endocytic traffic. A 60-kD RABGEF1 protein was detected in HeLa cells,
bovine brain, and all mouse tissues examined, suggesting that it is
ubiquitously expressed.
Penengo et al. (2006) determined that the 491-amino acid human RABEX5
protein has 2 adjacent N-terminal ubiquitin (see 191339)-binding
domains, which they called the RUZ (RABEX5 ubiquitin-binding zinc
finger) and MIU (motif interacting with ubiquitin) domains, and a
central Vps9 domain, which contains RAB5-GEF catalytic activity.
GENE FUNCTION
Using immunodepletion experiments, Horiuchi et al. (1997) found that the
RABGEF1-RABPT5 complex was essential for both homotypic and heterotypic
endosome fusions. Both RABGEF1 and RABPT5 bound RAB5 preferentially in
the presence of GTP rather than GDP. RABGEF1 displayed specific GDP/GTP
exchange activity on RAB5 upon delivery of RAB5 to the membrane.
Mattera et al. (2003) found that the GGAs (e.g., GGA1; 606004), a family
of ARF (see 103180)-dependent clathrin adaptors involved in selection of
trans-Golgi network cargo, interacted with the RABGEF1-RABPT5 complex in
vitro and in vivo.
Tam et al. (2004) found that activated mouse mast cells showed a rapid
upregulation of Rabgef1 mRNA expression, followed by a precipitous
decline in protein expression. Immunoprecipitation analysis indicated
that Rabgef1 interacted with activated Ras (HRAS; 190020)-GTP and
inhibited Ras-mediated responses. Antisense Rabgef1 negatively regulated
release of cytokines and lipid mediators from activated mast cells. Tam
et al. (2004) concluded that RABGEF1 binds to RAS and suppresses RAS
activation and RAS-mediated functional responses.
Using in vitro pull-down assays, Penengo et al. (2006) found that the
RUZ and MIU domains of human RABEX5 bound ubiquitin independently.
Mutation analysis showed that the MIU domain, but not the RUZ domain,
sustained coupled monoubiquitination of RABEX5 in transfected HeLa
cells. Coimmunoprecipitation analysis revealed that both FLAG-tagged and
endogenous RABEX5, via its RUZ and MIU domains, bound to endogenous
ubiquitinated EGFR (131550). Confocal microscopy showed that GFP-tagged
RABEX5 was recruited to the plasma membrane upon EGF (131530) treatment
and remained colocalized with EGFR at several stations of the endocytic
pathway. Structural and biochemical analyses revealed that the RUZ and
MIU domains of RABEX5 interacted simultaneously with distinct surfaces
on ubiquitin that were centered on asp58 and ile44, respectively.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RABGEF1
gene to chromosome 7 (TMAP RH75235).
ANIMAL MODEL
Tam et al. (2004) generated Rabgef1 -/- mice, most of which died shortly
after birth. ELISA analysis detected significantly enhanced release of
Hexb (606873), proinflammatory cytokines, and lipid mediators in
Rabgef1-deficient activated mast cells. All mutant mice that survived to
adulthood developed severe skin inflammation with epidermal hyperplasia,
dermal inflammation, abundant mast cells, and increased vascularity, but
no detectable skin pathogens. Serum IgE and histamine were also
increased in Rabgef1 -/- mice.
*FIELD* RF
1. Horiuchi, H.; Lippe, R.; McBride, H. M.; Rubino, M.; Woodman, P.;
Stenmark, H.; Rybin, V.; Wilm, M.; Ashman, K.; Mann, M.; Zerial, M.
: A novel Rab5 GDP/GTP exchange factor complexed to rabaptin-5 links
nucleotide exchange to effector recruitment and function. Cell 90:
1149-1159, 1997.
2. Mattera, R.; Arighi, C. N.; Lodge, R.; Zerial, M.; Bonifacino,
J. S.: Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5
complex. EMBO J. 22: 78-88, 2003.
3. Penengo, L.; Mapelli, M.; Murachelli, A. G.; Confalonieri, S.;
Magri, L.; Musacchio, A.; Di Fiore, P. P.; Polo, S.; Schneider, T.
R.: Crystal structure of the ubiquitin binding domains of Rabex-5
reveals two modes of interaction with ubiquitin. Cell 124: 1183-1195,
2006.
4. Tam, S.-Y.; Tsai, M.; Snouwaert, J. N.; Kalesnikoff, J.; Scherrer,
D.; Nakae, S.; Chatterjea, D.; Bouley, D. M.; Galli, S. J.: RabGEF1
is a negative regulator of mast cell activation and skin inflammation. Nature
Immun. 5: 844-852, 2004.
*FIELD* CN
Matthew B. Gross - updated: 3/3/2010
*FIELD* CD
Paul J. Converse: 11/7/2005
*FIELD* ED
wwang: 03/04/2010
mgross: 3/3/2010
mgross: 11/7/2005
*RECORD*
*FIELD* NO
609700
*FIELD* TI
*609700 RAB GUANINE NUCLEOTIDE EXCHANGE FACTOR 1; RABGEF1
;;RABAPTIN 5-ASSOCIATED EXCHANGE FACTOR FOR RAB5; RABEX5
read more*FIELD* TX
DESCRIPTION
RABGEF1 forms a complex with rabaptin-5 (RABPT5; 603616) that is
required for endocytic membrane fusion, and it serves as a specific
guanine nucleotide exchange factor (GEF) for RAB5 (RAB5A; 179512)
(Horiuchi et al., 1997).
CLONING
Using an overlay assay on HeLa cell and bovine brain cytosol to identify
RAB5-interacting proteins, followed by mass spectrometry, EST database
analysis, and screening a bovine brain cDNA library, Horiuchi et al.
(1997) cloned bovine Rabgef1, which they termed Rabex5. The deduced
492-amino acid protein has a calculated molecular mass of 57.1 kD and
shares significant homology with yeast Vps9, a protein implicated in
endocytic traffic. A 60-kD RABGEF1 protein was detected in HeLa cells,
bovine brain, and all mouse tissues examined, suggesting that it is
ubiquitously expressed.
Penengo et al. (2006) determined that the 491-amino acid human RABEX5
protein has 2 adjacent N-terminal ubiquitin (see 191339)-binding
domains, which they called the RUZ (RABEX5 ubiquitin-binding zinc
finger) and MIU (motif interacting with ubiquitin) domains, and a
central Vps9 domain, which contains RAB5-GEF catalytic activity.
GENE FUNCTION
Using immunodepletion experiments, Horiuchi et al. (1997) found that the
RABGEF1-RABPT5 complex was essential for both homotypic and heterotypic
endosome fusions. Both RABGEF1 and RABPT5 bound RAB5 preferentially in
the presence of GTP rather than GDP. RABGEF1 displayed specific GDP/GTP
exchange activity on RAB5 upon delivery of RAB5 to the membrane.
Mattera et al. (2003) found that the GGAs (e.g., GGA1; 606004), a family
of ARF (see 103180)-dependent clathrin adaptors involved in selection of
trans-Golgi network cargo, interacted with the RABGEF1-RABPT5 complex in
vitro and in vivo.
Tam et al. (2004) found that activated mouse mast cells showed a rapid
upregulation of Rabgef1 mRNA expression, followed by a precipitous
decline in protein expression. Immunoprecipitation analysis indicated
that Rabgef1 interacted with activated Ras (HRAS; 190020)-GTP and
inhibited Ras-mediated responses. Antisense Rabgef1 negatively regulated
release of cytokines and lipid mediators from activated mast cells. Tam
et al. (2004) concluded that RABGEF1 binds to RAS and suppresses RAS
activation and RAS-mediated functional responses.
Using in vitro pull-down assays, Penengo et al. (2006) found that the
RUZ and MIU domains of human RABEX5 bound ubiquitin independently.
Mutation analysis showed that the MIU domain, but not the RUZ domain,
sustained coupled monoubiquitination of RABEX5 in transfected HeLa
cells. Coimmunoprecipitation analysis revealed that both FLAG-tagged and
endogenous RABEX5, via its RUZ and MIU domains, bound to endogenous
ubiquitinated EGFR (131550). Confocal microscopy showed that GFP-tagged
RABEX5 was recruited to the plasma membrane upon EGF (131530) treatment
and remained colocalized with EGFR at several stations of the endocytic
pathway. Structural and biochemical analyses revealed that the RUZ and
MIU domains of RABEX5 interacted simultaneously with distinct surfaces
on ubiquitin that were centered on asp58 and ile44, respectively.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RABGEF1
gene to chromosome 7 (TMAP RH75235).
ANIMAL MODEL
Tam et al. (2004) generated Rabgef1 -/- mice, most of which died shortly
after birth. ELISA analysis detected significantly enhanced release of
Hexb (606873), proinflammatory cytokines, and lipid mediators in
Rabgef1-deficient activated mast cells. All mutant mice that survived to
adulthood developed severe skin inflammation with epidermal hyperplasia,
dermal inflammation, abundant mast cells, and increased vascularity, but
no detectable skin pathogens. Serum IgE and histamine were also
increased in Rabgef1 -/- mice.
*FIELD* RF
1. Horiuchi, H.; Lippe, R.; McBride, H. M.; Rubino, M.; Woodman, P.;
Stenmark, H.; Rybin, V.; Wilm, M.; Ashman, K.; Mann, M.; Zerial, M.
: A novel Rab5 GDP/GTP exchange factor complexed to rabaptin-5 links
nucleotide exchange to effector recruitment and function. Cell 90:
1149-1159, 1997.
2. Mattera, R.; Arighi, C. N.; Lodge, R.; Zerial, M.; Bonifacino,
J. S.: Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5
complex. EMBO J. 22: 78-88, 2003.
3. Penengo, L.; Mapelli, M.; Murachelli, A. G.; Confalonieri, S.;
Magri, L.; Musacchio, A.; Di Fiore, P. P.; Polo, S.; Schneider, T.
R.: Crystal structure of the ubiquitin binding domains of Rabex-5
reveals two modes of interaction with ubiquitin. Cell 124: 1183-1195,
2006.
4. Tam, S.-Y.; Tsai, M.; Snouwaert, J. N.; Kalesnikoff, J.; Scherrer,
D.; Nakae, S.; Chatterjea, D.; Bouley, D. M.; Galli, S. J.: RabGEF1
is a negative regulator of mast cell activation and skin inflammation. Nature
Immun. 5: 844-852, 2004.
*FIELD* CN
Matthew B. Gross - updated: 3/3/2010
*FIELD* CD
Paul J. Converse: 11/7/2005
*FIELD* ED
wwang: 03/04/2010
mgross: 3/3/2010
mgross: 11/7/2005