RBCC

Full text data of RAB5A

RAB5A (RAB5) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ras-related protein Rab-5A

UniProt P20339
ID RAB5A_HUMAN Reviewed; 215 AA.
AC P20339; Q6FI44;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Ras-related protein Rab-5A;
GN Name=RAB5A; Synonyms=RAB5;
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].
RX PubMed=2501306;
RA Zahraoui A., Touchot N., Chardin P., Tavitian A.;
RT "The human Rab genes encode a family of GTP-binding proteins related
RT to yeast YPT1 and SEC4 products involved in secretion.";
RL J. Biol. Chem. 264:12394-12401(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], ISOPRENYLATION AT CYS-212 AND CYS-213, AND
RP MASS SPECTROMETRY.
RX PubMed=7991565; DOI=10.1073/pnas.91.25.11963;
RA Farnsworth C.C., Seabra M.C., Ericsson L.H., Gelb M.H., Glomset J.A.;
RT "Rab geranylgeranyl transferase catalyzes the geranylgeranylation of
RT adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:11963-11967(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kim J.W.;
RT "Identification of a new oncogene in human cancers.";
RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cervix, and Placenta;
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 [9]
RP INTERACTION WITH EEA1.
RX PubMed=10491193; DOI=10.1046/j.1432-1327.1999.00743.x;
RA Callaghan J.M., Nixon S., Bucci C., Toh B.-H., Stenmark H.;
RT "Direct interaction of EEA1 with Rab5b.";
RL Eur. J. Biochem. 265:361-366(1999).
RN [10]
RP INTERACTION WITH SUN2.
RX PubMed=10818110; DOI=10.1074/jbc.M909600199;
RA Hoffenberg S., Liu X., Nikolova L., Hall H.S., Dai W., Baughn R.E.,
RA Dickey B.F., Barbieri M.A., Aballay A., Stahl P.D., Knoll B.J.;
RT "A novel membrane-anchored Rab5 interacting protein required for
RT homotypic endosome fusion.";
RL J. Biol. Chem. 275:24661-24669(2000).
RN [11]
RP INTERACTION WITH ZFYVE20.
RC TISSUE=Cervix carcinoma;
RX PubMed=11062261; DOI=10.1083/jcb.151.3.601;
RA Nielsen E., Christoforidis S., Uttenweiler-Joseph S., Miaczynska M.,
RA Dewitte F., Wilm M., Hoflack B., Zerial M.;
RT "Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and
RT recruited to endosomes through a FYVE finger domain.";
RL J. Cell Biol. 151:601-612(2000).
RN [12]
RP ACTIVATION BY RIN1.
RX PubMed=11703925; DOI=10.1016/S1534-5807(01)00008-9;
RA Tall G.G., Barbieri M.A., Stahl P.D., Horazdovsky B.F.;
RT "Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide
RT exchange activity of RIN1.";
RL Dev. Cell 1:73-82(2001).
RN [13]
RP INTERACTION WITH ALS2CL.
RX PubMed=15388334; DOI=10.1016/j.febslet.2004.07.092;
RA Hadano S., Otomo A., Suzuki-Utsunomiya K., Kunita R., Yanagisawa Y.,
RA Showguchi-Miyata J., Mizumura H., Ikeda J.-E.;
RT "ALS2CL, the novel protein highly homologous to the carboxy-terminal
RT half of ALS2, binds to Rab5 and modulates endosome dynamics.";
RL FEBS Lett. 575:64-70(2004).
RN [14]
RP INTERACTION WITH RUFY1.
RX PubMed=14617813; DOI=10.1091/mbc.E03-05-0343;
RA Fouraux M.A., Deneka M., Ivan V., van der Heijden A., Raymackers J.,
RA van Suylekom D., van Venrooij W.J., van der Sluijs P., Pruijn G.J.M.;
RT "Rabip4' is an effector of rab5 and rab4 and regulates transport
RT through early endosomes.";
RL Mol. Biol. Cell 15:611-624(2004).
RN [15]
RP FUNCTION, AND MUTAGENESIS OF GLN-79.
RX PubMed=14978216; DOI=10.1091/mbc.E03-07-0493;
RA Gauthier-Campbell C., Bredt D.S., Murphy T.H., El-Husseini A.;
RT "Regulation of dendritic branching and filopodia formation in
RT hippocampal neurons by specific acylated protein motifs.";
RL Mol. Biol. Cell 15:2205-2217(2004).
RN [16]
RP INTERACTION WITH ZFYVE20, AND MUTAGENESIS OF GLY-54; ALA-56 AND
RP PHE-57.
RX PubMed=16034420; DOI=10.1038/nature03798;
RA Eathiraj S., Pan X., Ritacco C., Lambright D.G.;
RT "Structural basis of family-wide Rab GTPase recognition by rabenosyn-
RT 5.";
RL Nature 436:415-419(2005).
RN [17]
RP INTERACTION WITH GAPVD1.
RX PubMed=16410077; DOI=10.1016/j.bbrc.2005.12.099;
RA Hunker C.M., Galvis A., Kruk I., Giambini H., Veisaga M.L.,
RA Barbieri M.A.;
RT "Rab5-activating protein 6, a novel endosomal protein with a role in
RT endocytosis.";
RL Biochem. Biophys. Res. Commun. 340:967-975(2006).
RN [18]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS).
RX PubMed=12433916; DOI=10.1074/jbc.M211042200;
RA Zhu G., Liu J., Terzyan S., Zhai P., Li G., Zhang X.C.;
RT "High resolution crystal structures of human Rab5a and five mutants
RT with substitutions in the catalytically important phosphate-binding
RT loop.";
RL J. Biol. Chem. 278:2452-2460(2003).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 15-184 IN COMPLEX WITH GTP
RP ANALOG; GDP AND RABEP1, AND MUTAGENESIS OF PHE-57; TRP-74; GLN-79;
RP TYR-82; TYR-89; LYS-116 AND ARG-120.
RX PubMed=15378032; DOI=10.1038/nsmb832;
RA Zhu G., Zhai P., Liu J., Terzyan S., Li G., Zhang X.C.;
RT "Structural basis of Rab5-Rabaptin5 interaction in endocytosis.";
RL Nat. Struct. Mol. Biol. 11:975-983(2004).
CC -!- FUNCTION: Required for the fusion of plasma membranes and early
CC endosomes. Contributes to the regulation of filopodia extension.
CC -!- ENZYME REGULATION: Regulated by guanine nucleotide exchange
CC factors (GEFs) which promote the exchange of bound GDP for free
CC GTP.
CC -!- SUBUNIT: Binds EEA1. Interacts with RIN1 and GAPVD1, which
CC regulate its pathway, probably by acting as a GEF. Interacts with
CC RINL. Interacts with ALS2CL, RABEP1, SUN2, ZFYVE20 and RUFY1.
CC Interacts with SGSM1 and SGSM3 (By similarity). Interacts with
CC PIK3CB (By similarity).
CC -!- INTERACTION:
CC Q96Q42:ALS2; NbExp=2; IntAct=EBI-399437, EBI-1044902;
CC Q9UKG1:APPL1; NbExp=17; IntAct=EBI-399437, EBI-741243;
CC Q15075:EEA1; NbExp=4; IntAct=EBI-399437, EBI-298113;
CC Q01968:OCRL; NbExp=10; IntAct=EBI-399437, EBI-6148898;
CC P23727:PIK3R1 (xeno); NbExp=5; IntAct=EBI-399437, EBI-520244;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side (By similarity). Early endosome membrane; Lipid-anchor (By
CC similarity). Melanosome. Cytoplasmic vesicle (By similarity). Cell
CC projection, ruffle (By similarity). Note=Enriched in stage I
CC melanosomes.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rab family.
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DR EMBL; M28215; AAA60245.1; -; mRNA.
DR EMBL; AF464088; AAO15677.1; -; mRNA.
DR EMBL; AF498936; AAM21084.1; -; mRNA.
DR EMBL; AK312618; BAG35504.1; -; mRNA.
DR EMBL; CR536492; CAG38731.1; -; mRNA.
DR EMBL; CH471055; EAW64301.1; -; Genomic_DNA.
DR EMBL; BC001267; AAH01267.1; -; mRNA.
DR EMBL; BC018288; AAH18288.1; -; mRNA.
DR PIR; F34323; F34323.
DR RefSeq; NP_004153.2; NM_004162.4.
DR UniGene; Hs.475663; -.
DR PDB; 1N6H; X-ray; 1.51 A; A=15-184.
DR PDB; 1N6I; X-ray; 1.60 A; A=15-184.
DR PDB; 1N6K; X-ray; 1.55 A; A=15-184.
DR PDB; 1N6L; X-ray; 1.60 A; A=15-184.
DR PDB; 1N6N; X-ray; 1.60 A; A=15-184.
DR PDB; 1N6O; X-ray; 1.80 A; A=15-184.
DR PDB; 1N6P; X-ray; 1.54 A; A=15-184.
DR PDB; 1N6R; X-ray; 1.55 A; A=15-184.
DR PDB; 1R2Q; X-ray; 1.05 A; A=15-184.
DR PDB; 1TU3; X-ray; 2.31 A; A/B/C/D/E=15-184.
DR PDB; 1TU4; X-ray; 2.20 A; A/B/C/D=15-184.
DR PDB; 3MJH; X-ray; 2.03 A; A/C=16-183.
DR PDBsum; 1N6H; -.
DR PDBsum; 1N6I; -.
DR PDBsum; 1N6K; -.
DR PDBsum; 1N6L; -.
DR PDBsum; 1N6N; -.
DR PDBsum; 1N6O; -.
DR PDBsum; 1N6P; -.
DR PDBsum; 1N6R; -.
DR PDBsum; 1R2Q; -.
DR PDBsum; 1TU3; -.
DR PDBsum; 1TU4; -.
DR PDBsum; 3MJH; -.
DR ProteinModelPortal; P20339; -.
DR SMR; P20339; 15-184.
DR DIP; DIP-380N; -.
DR IntAct; P20339; 20.
DR MINT; MINT-209361; -.
DR STRING; 9606.ENSP00000273047; -.
DR PhosphoSite; P20339; -.
DR DMDM; 1346958; -.
DR PaxDb; P20339; -.
DR PRIDE; P20339; -.
DR DNASU; 5868; -.
DR Ensembl; ENST00000273047; ENSP00000273047; ENSG00000144566.
DR GeneID; 5868; -.
DR KEGG; hsa:5868; -.
DR UCSC; uc003cbn.3; human.
DR CTD; 5868; -.
DR GeneCards; GC03P019963; -.
DR HGNC; HGNC:9783; RAB5A.
DR HPA; CAB004567; -.
DR MIM; 179512; gene.
DR neXtProt; NX_P20339; -.
DR PharmGKB; PA34143; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233968; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P20339; -.
DR KO; K07887; -.
DR OMA; RYWIREL; -.
DR OrthoDB; EOG77DJ7M; -.
DR PhylomeDB; P20339; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; RAB5A; human.
DR EvolutionaryTrace; P20339; -.
DR GeneWiki; RAB5A; -.
DR GenomeRNAi; 5868; -.
DR NextBio; 22790; -.
DR PRO; PR:P20339; -.
DR ArrayExpress; P20339; -.
DR Bgee; P20339; -.
DR CleanEx; HS_RAB5A; -.
DR Genevestigator; P20339; -.
DR GO; GO:0015629; C:actin cytoskeleton; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030139; C:endocytic vesicle; IEA:Ensembl.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0019003; F:GDP binding; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR GO; GO:0045921; P:positive regulation of exocytosis; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:2000286; P:receptor internalization involved in canonical Wnt receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0051489; P:regulation of filopodium assembly; IDA:UniProtKB.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:InterPro.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR003579; Small_GTPase_Rab_type.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00175; RAB; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51419; RAB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cell projection; Complete proteome;
KW Cytoplasmic vesicle; Differentiation; Endosome; GTP-binding;
KW Lipoprotein; Membrane; Neurogenesis; Nucleotide-binding; Prenylation;
KW Protein transport; Reference proteome; Transport.
FT CHAIN 1 215 Ras-related protein Rab-5A.
FT /FTId=PRO_0000121104.
FT NP_BIND 27 35 GTP.
FT NP_BIND 75 79 GTP.
FT NP_BIND 133 136 GTP.
FT NP_BIND 163 165 GTP.
FT MOTIF 49 57 Effector region (By similarity).
FT LIPID 212 212 S-geranylgeranyl cysteine.
FT LIPID 213 213 S-geranylgeranyl cysteine.
FT MUTAGEN 54 54 G->Q: Strongly decreases ZFYVE20 binding
FT affinity.
FT MUTAGEN 56 56 A->E: Strongly decreases ZFYVE20 binding
FT affinity.
FT MUTAGEN 57 57 F->A: Strongly decreases RABEP1 and
FT ZFYVE20 binding affinity.
FT MUTAGEN 74 74 W->A: Strongly decreases RABEP1 binding
FT affinity.
FT MUTAGEN 79 79 Q->L: Loss of GTPase activity. Does not
FT inhibit filopodia formation.
FT MUTAGEN 82 82 Y->A: Strongly decreases RABEP1 binding
FT affinity.
FT MUTAGEN 89 89 Y->A: Strongly decreases RABEP1 binding
FT affinity.
FT MUTAGEN 116 116 K->E: No effect on RABEP1 binding
FT affinity.
FT MUTAGEN 120 120 R->E: No effect on RABEP1 binding
FT affinity.
FT CONFLICT 81 81 R -> G (in Ref. 1; AAA60245).
FT CONFLICT 197 197 R -> G (in Ref. 1; AAA60245).
FT STRAND 17 26
FT STRAND 28 32
FT HELIX 33 42
FT STRAND 53 64
FT STRAND 67 76
FT HELIX 80 85
FT HELIX 86 90
FT STRAND 94 101
FT HELIX 105 121
FT STRAND 127 133
FT HELIX 135 140
FT HELIX 145 154
FT STRAND 158 161
FT TURN 164 166
FT HELIX 170 179
SQ SEQUENCE 215 AA; 23659 MW; EC03DDF96BBEF821 CRC64;
MASRGATRPN GPNTGNKICQ FKLVLLGESA VGKSSLVLRF VKGQFHEFQE STIGAAFLTQ
TVCLDDTTVK FEIWDTAGQE RYHSLAPMYY RGAQAAIVVY DITNEESFAR AKNWVKELQR
QASPNIVIAL SGNKADLANK RAVDFQEAQS YADDNSLLFM ETSAKTSMNV NEIFMAIAKK
LPKNEPQNPG ANSARGRGVD LTEPTQPTRN QCCSN
//

MIM 179512
*RECORD*
*FIELD* NO
179512
*FIELD* TI
*179512 RAS-ASSOCIATED PROTEIN RAB5A; RAB5A
;;RAB5
*FIELD* TX

CLONING

The S. cerevisiae YPT1 and SEC4 genes encode Ras-related GTP-binding
read moreproteins involved in the regulation of secretion. Mammalian cells
express a large number of RAB proteins, GTP-binding proteins closely
related to YPT1 and SEC4. By screening a human pheochromocytoma library
with probes derived from the SEC4 gene and from various rat and human
RAB cDNAs, Zahraoui et al. (1989) isolated cDNAs encoding RAB1 (179508),
RAB2 (179509), RAB3A (179490), RAB3B (179510), RAB4 (179511), RAB5, and
RAB6 (179513). Except for the closely related RAB3A and RAB3B, the
deduced human RAB proteins share 32 to 50% homology. The predicted
214-amino acid RAB5 protein is 31% and 38% identical to SEC4 and YPT1,
respectively. All 6 human RAB proteins tested bound GTP and exhibited
GTPase activities in vitro. Northern blot analysis revealed that RAB5
was expressed as 2.7- and 2.8-kb mRNAs in a human fibroblast cell line.

GENE FUNCTION

Bucci et al. (1992) demonstrated that RAB5 is a rate-limiting component
of the machinery regulating the kinetics of membrane traffic in the
early endocytic pathway.

Stenmark et al. (1995) reported that rabaptin-5 (603616) is an effector
of RAB5 that transmits the signal of the active GTP-bound RAB5
conformation to the membrane docking and/or fusion apparatus. Xiao et
al. (1997) found that tuberin (191092) exhibits substantial
GTPase-activating protein (GAP) activity towards RAB5, and that
rabaptin-5 mediates the tuberin association with RAB5. The authors
suggested that tuberin functions as a RAB5GAP in vivo to negatively
regulate RAB5-GTP activity in endocytosis.

Epidermal growth factor receptor (EGFR; 131550) signaling involves small
GTPases of the Rho family, and EGFR trafficking involves small GTPases
of the Rab family. Lanzetti et al. (2000) reported that the EPS8
(600206) protein connects these signaling pathways. EPS8 is a substrate
of EGFR that is held in a complex with SOS1 (182530) by the adaptor
protein E3B1 (603050), thereby mediating activation of RAC (602048).
Through its SH3 domain, EPS8 interacts with RNTRE (605405). Lanzetti et
al. (2000) showed that RNTRE is a RAB5 GTPase-activating protein whose
activity is regulated by EGFR. By entering in a complex with EPS8, RNTRE
acts on RAB5 and inhibits internalization of the EGFR. Furthermore,
RNTRE diverts EPS8 from its RAC-activating function, resulting in the
attenuation of RAC signaling. Thus, depending on its state of
association with E3B1 or RNTRE, EPS8 participates in both EGFR signaling
through RAC and EGFR trafficking through RAB5.

Otomo et al. (2003) showed that the ALS2 protein (ALSIN; 606352)
specifically binds to small GTPase RAB5 and functions as a guanine
nucleotide exchange factor (GEF) for RAB5. Ectopically expressed ALS2
localized with RAB5 and early endosome antigen-1 (EEA1; 605070) onto
early endosomal compartments and stimulated the enlargement of endosomes
in cultured cortical neurons. The C terminus of ALS2 carrying a VPS9
domain mediated not only the activation of RAB5 via a guanine-nucleotide
exchanging reaction but also the endosomal localization of ALS2, whereas
the N-terminal half containing the RCC1 (179710)-like domain acted
suppressive in its membranous localization. The DH/PH domain in the
middle portion of ALS2 enhanced the VPS9 domain-mediated endosome
fusions. Otomo et al. (2003) hypothesized that a perturbation of
endosomal dynamics caused by loss of the ALS2 functional domain that
confers RAB5 GEF activity might underlie neuronal dysfunction and
degeneration in a number of motor neuron diseases.

Miaczynska et al. (2004) identified a pathway directly linking the small
GTPase RAB5, a key regulator of endocytosis, to signal transduction and
mitogenesis. This pathway operated via APPL1 (604299) and APPL2
(606231), 2 RAB5 effectors that reside on a subpopulation of endosomes.
In response to extracellular stimuli such as EGF (131530) and oxidative
stress, APPL1 translocated from the membranes to the nucleus, where it
interacted with the nucleosome remodeling and histone deacetylase (NURD)
multiprotein complex, a regulator of chromatin structure and gene
expression. Both APPL1 and APPL2 were essential for cell proliferation,
and their function required RAB5 binding. These findings identified an
endosomal compartment bearing RAB5 and APPL proteins as an intermediate
in signaling between the plasma membrane and the nucleus.

Lanzetti et al. (2004) demonstrated that RAB5 is indispensable for a
form of receptor tyrosine kinase-induced actin remodeling called
circular ruffling. Three independent signals, originating from RAB5,
phosphatidylinositol-3-hydroxykinase, and RAC (see 602048),
respectively, are simultaneously required for the induction of circular
ruffles. RAB5 signals to the actin cytoskeleton through RNTRE, a
RAB5-specific GTPase-activating protein (GAP). Lanzetti et al. (2004)
demonstrated that RNTRE has the dual function of RAB5-GAP and RAB5
effector. They also showed that RNTRE is critical for macropinocytosis,
a process connected to the formation of circular ruffles. Finally, RNTRE
interacts with both F-actin and actinin-4 (604638), an F-actin bundling
protein. Lanzetti et al. (2004) proposed that RNTRE establishes a
3-pronged connection with RAB5, F-actin, and actinin-4. This may aid
crosslinking of actin fibers into actin networks at the plasma membrane.
Lanzetti et al. (2004) concluded that they showed that RAB5 is a
signaling GTPase and elucidated the major molecular elements of its
downstream pathway.

Using a genetically encoded fluorescence resonance energy transfer
(FRET) biosensor, Kitano et al. (2008) described a change in RAB5
activity during the engulfment of apoptotic thymocytes. RAB5 activity on
phagosome membranes began to increase on disassembly of the actin coat
encapsulating phagosomes. RAB5 activation was either continuous or
repetitive for up to 10 minutes, but it ended before the collapse of
engulfed apoptotic cells. Expression of a dominant-negative mutant of
RAB5 delayed this collapse of apoptotic thymocytes, showing a role for
RAB5 in phagosome maturation. Disruption of microtubules with nocodazole
inhibited RAB5 activation on the phagosome membrane without perturbing
the engulfment of apoptotic cells. Furthermore, Kitano et al. (2008)
found that GAPEX5 (611714) is the guanine nucleotide exchange factor
essential for RAB5 activation during the engulfment of apoptotic cells.
GAPEX5 was bound to a microtubule tip-associating protein, EB1 (603108),
whose depletion inhibited RAB5 activation during phagocytosis. Kitano et
al. (2008) therefore proposed a mechanistic model in which the
recruitment of GAPEX5 to phagosomes through the microtubule network
induces the transient RAB5 activation.

Ohya et al. (2009) reported the reconstitution of early endosomal canine
Rab5 GTPase, its key regulators, and effectors together with SNAREs into
proteoliposomes using a set of 17 recombinant human proteins. These
vesicles behave like minimal synthetic endosomes, fusing with purified
early endosomes or with each other in vitro. Membrane fusion measured by
content-mixing and morphologic assays requires the cooperativity between
Rab5 effectors and cognate SNAREs which, together, form a more efficient
core machinery than SNAREs alone. Ohya et al. (2009) concluded that in
reconstituting a fusion mechanism dependent on both a Rab GTPase and
SNAREs, their work showed that the 2 machineries act coordinately to
increase the specificity and efficiency of the membrane tethering and
fusion process.

Kinchen and Ravichandran (2010) used genetic, cell biologic, and
molecular studies in C. elegans and mammalian cells to identify SAND1
and its partner CCZ1 as factors in corpse removal. In worms deficient in
either sand1 or ccz1, apoptotic cells were internalized and the
phagosomes recruited the small GTPase Rab5 but failed to progress to the
subsequent Rab7 (602298)-positive stage. The mammalian orthologs of
SAND1, namely MON1A (611464) and MON1B (608954), were similarly required
for phagosome maturation. Mechanistically, Mon1 interacts with GTP-bound
Rab5, identifying Mon1 as a previously unrecognized Rab5 effector.
Moreover, a Mon1-Ccz1 complex (but neither protein alone) could bind
Rab7 and could also influence Rab7 activation, suggesting Mon1-Ccz1 as
an important link in progression from the Rab5-positive stage to the
Rab7-positive stage of phagosome maturation. Taken together, Kinchen and
Ravichandran (2010) concluded that these data identified SAND1 and CCZ1
as critical and evolutionarily conserved components regulating the
processing of ingested apoptotic cell corpses.

To test the hypothesis that Rab5 is a master regulator of endosome
biogenesis, Zeigerer et al. (2012) developed a mathematical model of
endosome dependency on Rab5 and validated it by titrating down all 3
Rab5 isoforms in adult mouse liver using state-of-the-art RNA
interference technology. Unexpectedly, the endocytic system was
resilient to depletion of Rab5 and collapsed only when Rab5 decreased to
a critical level. Loss of Rab5 below this threshold caused a marked
reduction in the number of early endosomes, late endosomes, and
lysosomes, associated with a block of low-density lipoprotein
endocytosis. Loss of endosomes caused failure to deliver apical proteins
to the bile canaliculi, suggesting a requirement for polarized cargo
sorting. Zeigerer et al. (2012) concluded that their results
demonstrated for the first time the role of Rab5 as an endosome
organizer in vivo and revealed the resilience mechanisms of the
endocytic system.

MAPPING

By in situ hybridization, Rousseau-Merck et al. (1991) mapped the RAB5
gene to 3p24-p22. This gene was designated RAB5A after the
identification and naming of RAB5B (179514).

*FIELD* RF
1. Bucci, C.; Parton, R. G.; Mather, I. H.; Stunnenberg, H.; Simons,
K.; Hoflack, B.; Zerial, M.: The small GTPase rab5 functions as a
regulatory factor in the early endocytic pathway. Cell 70: 715-728,
1992.

2. Kinchen, J. M.; Ravichandran, K. S.: Identification of two evolutionarily
conserved genes regulating processing of engulfed apoptotic cells. Nature 464:
778-782, 2010.

3. Kitano, M.; Nakaya, M.; Nakamura, T.; Nagata, S.; Matsuda, M.:
Imaging of Rab5 activity identifies essential regulators for phagosome
maturation. Nature 453: 241-245, 2008.

4. Lanzetti, L.; Palamidessi, A.; Areces, L.; Scita, G.; Di Fiore,
P. P.: Rab5 is a signalling GTPase involved in actin remodelling
by receptor tyrosine kinases. Nature 429: 309-314, 2004.

5. Lanzetti, L.; Rybin, V.; Malabarba, M. G.; Christoforidis, S.;
Scita, G.; Zerial, M.; Di Fiore, P. P.: The Eps8 protein coordinates
EGF receptor signalling through Rac and trafficking through Rab5. Nature 408:
374-377, 2000.

6. Miaczynska, M.; Christoforidis, S.; Giner, A.; Shevchenko, A.;
Uttenweiler-Joseph, S.; Habermann, B.; Wilm, M.; Parton, R. G.; Zerial,
M.: APPL proteins link Rab5 to nuclear signal transduction via an
endosomal compartment. Cell 116: 445-456, 2004.

7. Ohya, T.; Miaczynska, M.; Coskun, U.; Lommer, B.; Runge, A.; Drechsel,
D.; Kalaidzidis, Y.; Zerial, M.: Reconstitution of Rab- and SNARE-dependent
membrane fusion by synthetic endosomes. Nature 459: 1091-1097, 2009.

8. Otomo, A.; Hadano, S.; Okada, T.; Mizumura, H.; Kunita, R.; Nishijima,
H.; Showguchi-Miyata, J.; Yanagisawa, Y.; Kohiki, E.; Suga, E.; Yasuda,
M.; Osuga, H.; Nishimoto, T.; Narumiya, S.; Ikeda, J.-E.: ALS2, a
novel guanine nucleotide exchange factor for the small GTPase Rab5,
is implicated in endosomal dynamics. Hum. Molec. Genet. 12: 1671-1687,
2003.

9. Rousseau-Merck, M. F.; Zahraoui, A.; Touchot, N.; Tavitian, A.;
Berger, R.: Chromosome assignment of four RAS-related RAB genes. Hum.
Genet. 86: 350-354, 1991.

10. Stenmark, H.; Vitale, G.; Ullrich, O.; Zerial, M.: Rabaptin-5
is a direct effector of the small GTPase Rab5 in endocytic membrane
fusion. Cell 83: 423-432, 1995.

11. Xiao, G.-H.; Shoarinejad, F.; Jin, F.; Golemis, E. A.; Yeung,
R. S.: The tuberous sclerosis 2 gene product, tuberin, functions
as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J.
Biol. Chem. 272: 6097-6100, 1997.

12. Zahraoui, A.; Touchot, N.; Chardin, P.; Tavitian, A.: The human
rab genes encode a family of GTP-binding proteins related to yeast
YPT1 and SEC4 products involved in secretion. J. Biol. Chem. 264:
12394-12401, 1989.

13. Zeigerer, A.; Gilleron, J.; Bogorad, R. L.; Marsico, G.; Nonaka,
H.; Seifert, S.; Epstein-Barash, H.; Kuchimanchi, S.; Peng, C. G.;
Ruda, V. M.; Del Conte-Zerial, P.; Hengstler, J. G.; Kalaidzidis,
Y.; Koteliansky, V.; Zerial, M.: Rab5 is necessary for the biogenesis
of the endolysosomal system in vivo. Nature 485: 465-470, 2012.

*FIELD* CN
Ada Hamosh - updated: 6/5/2012
Ada Hamosh - updated: 4/28/2010
Ada Hamosh - updated: 7/9/2009
Ada Hamosh - updated: 6/12/2008
George E. Tiller - updated: 5/5/2005
Ada Hamosh - updated: 7/8/2004
Stylianos E. Antonarakis - updated: 5/3/2004
Ada Hamosh - updated: 11/15/2000
Rebekah S. Rasooly - updated: 3/9/1999

*FIELD* CD
Victor A. McKusick: 7/9/1990

*FIELD* ED
alopez: 06/07/2012
terry: 6/5/2012
alopez: 4/29/2010
terry: 4/28/2010
alopez: 7/15/2009
terry: 7/9/2009
alopez: 6/17/2008
terry: 6/12/2008
tkritzer: 5/5/2005
alopez: 7/12/2004
terry: 7/8/2004
mgross: 5/3/2004
mgross: 11/15/2000
mgross: 3/10/1999
mgross: 3/9/1999
carol: 8/18/1998
carol: 5/4/1992
supermim: 3/16/1992
carol: 3/22/1991
carol: 7/9/1990

RBCC Red Blood Cell Collection

Full text data of RAB5A