Full text data of RALBP1
RALBP1
(RLIP1, RLIP76)
[Confidence: low (only semi-automatic identification from reviews)]
RalA-binding protein 1; RalBP1 (76 kDa Ral-interacting protein; Dinitrophenyl S-glutathione ATPase; DNP-SG ATPase; Ral-interacting protein 1)
RalA-binding protein 1; RalBP1 (76 kDa Ral-interacting protein; Dinitrophenyl S-glutathione ATPase; DNP-SG ATPase; Ral-interacting protein 1)
UniProt
Q15311
ID RBP1_HUMAN Reviewed; 655 AA.
AC Q15311; D3DUI0;
DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=RalA-binding protein 1;
DE Short=RalBP1;
DE AltName: Full=76 kDa Ral-interacting protein;
DE AltName: Full=Dinitrophenyl S-glutathione ATPase;
DE Short=DNP-SG ATPase;
DE AltName: Full=Ral-interacting protein 1;
GN Name=RALBP1; Synonyms=RLIP1, RLIP76;
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], FUNCTION, AND INTERACTION WITH RALA.
RX PubMed=7673236; DOI=10.1074/jbc.270.38.22473;
RA Jullien-Flores V., Dorseuil O., Romero F., Letourneur F.,
RA Saragosti S., Berger R., Tavitian A., Gacon G., Camonis J.H.;
RT "Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with
RT CDC42/Rac GTPase-activating protein activity.";
RL J. Biol. Chem. 270:22473-22477(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, AND PROTEIN SEQUENCE OF
RP 2-15; 409-438 AND 472-486.
RC TISSUE=Bone marrow;
RX PubMed=10924126; DOI=10.1021/bi992964c;
RA Awasthi S., Cheng J., Singhal S.S., Saini M.K., Pandya U., Pikula S.,
RA Bandorowicz-Pikula J., Singh S.V., Zimniak P., Awasthi Y.C.;
RT "Novel function of human RLIP76: ATP-dependent transport of
RT glutathione conjugates and doxorubicin.";
RL Biochemistry 39:9327-9334(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [5]
RP INTERACTION WITH REPS2.
RC TISSUE=Brain;
RX PubMed=9422736; DOI=10.1074/jbc.273.2.814;
RA Ikeda M., Ishida O., Hinoi T., Kishida S., Kikuchi A.;
RT "Identification and characterization of a novel protein interacting
RT with Ral-binding protein 1, a putative effector protein of Ral.";
RL J. Biol. Chem. 273:814-821(1998).
RN [6]
RP FUNCTION, AND INTERACTION WITH CCNB1; CDK1; EPN1; NUMB AND TFAP2A.
RX PubMed=12775724; DOI=10.1074/jbc.M302191200;
RA Rosse C., L'Hoste S., Offner N., Picard A., Camonis J.;
RT "RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to
RT phosphorylate epsin during the switch off of endocytosis in mitosis.";
RL J. Biol. Chem. 278:30597-30604(2003).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=11437348; DOI=10.1006/abbi.2001.2395;
RA Sharma R., Singhal S.S., Cheng J., Yang Y., Sharma A., Zimniak P.,
RA Awasthi S., Awasthi Y.C.;
RT "RLIP76 is the major ATP-dependent transporter of glutathione-
RT conjugates and doxorubicin in human erythrocytes.";
RL Arch. Biochem. Biophys. 391:171-179(2001).
RN [8]
RP INTERACTION WITH DAB2IP.
RX PubMed=15310755; DOI=10.1074/jbc.M407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-92 AND SER-93, AND MASS
RP SPECTROMETRY.
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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-92 AND SER-93, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-463, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP STRUCTURE BY NMR OF 393-446 IN COMPLEX WITH RALB, AND INTERACTION WITH
RP RALB.
RX PubMed=20696399; DOI=10.1016/j.str.2010.05.013;
RA Fenwick R.B., Campbell L.J., Rajasekar K., Prasannan S.,
RA Nietlispach D., Camonis J., Owen D., Mott H.R.;
RT "The RalB-RLIP76 complex reveals a novel mode of ral-effector
RT interaction.";
RL Structure 18:985-995(2010).
CC -!- FUNCTION: Can activate specifically hydrolysis of GTP bound to
CC RAC1 and CDC42, but not RALA. Mediates ATP-dependent transport of
CC S-(2,4-dinitrophenyl)-glutathione (DNP-SG) and doxorubicin (DOX)
CC and is the major ATP-dependent transporter of glutathione
CC conjugates of electrophiles (GS-E) and DOX in erythrocytes. Can
CC catalyze transport of glutathione conjugates and xenobiotics, and
CC may contribute to the multidrug resistance phenomenon. Serves as a
CC scaffold protein that brings together proteins forming an
CC endocytotic complex during interphase and also with CDK1 to switch
CC off endocytosis, One of its substrates would be EPN1/Epsin.
CC -!- SUBUNIT: Interacts with the GTP-bound form of RALA, RALB, CDC42
CC and RAC1. Interacts with REPS1 and REPS2 and this does not affect
CC the Ral-binding activity. Interacts with DAB2IP. Interacts with
CC catalytically active CCNB1 and CDK1 during mitosis. Interacts with
CC EPN1, NUMB and TFAP2A during interphase and mitosis.
CC -!- INTERACTION:
CC P78556:CCL20; NbExp=2; IntAct=EBI-749285, EBI-3913209;
CC Q86VP1:TAX1BP1; NbExp=3; IntAct=EBI-749285, EBI-529518;
CC -!- SUBCELLULAR LOCATION: Membrane; Peripheral membrane protein.
CC -!- TISSUE SPECIFICITY: Expressed ubiquitously but at low levels.
CC Shows a strong expression in the erythrocytes.
CC -!- SIMILARITY: Contains 1 Rho-GAP domain.
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DR EMBL; L42542; AAB00103.1; -; mRNA.
DR EMBL; CH471113; EAX01601.1; -; Genomic_DNA.
DR EMBL; CH471113; EAX01602.1; -; Genomic_DNA.
DR EMBL; CH471113; EAX01604.1; -; Genomic_DNA.
DR EMBL; CH471113; EAX01605.1; -; Genomic_DNA.
DR EMBL; BC013126; AAH13126.1; -; mRNA.
DR PIR; F59435; F59435.
DR RefSeq; NP_006779.1; NM_006788.3.
DR UniGene; Hs.528993; -.
DR PDB; 2KWH; NMR; -; A=393-446.
DR PDB; 2KWI; NMR; -; B=393-446.
DR PDBsum; 2KWH; -.
DR PDBsum; 2KWI; -.
DR ProteinModelPortal; Q15311; -.
DR SMR; Q15311; 210-353, 393-446.
DR IntAct; Q15311; 9.
DR MINT; MINT-140436; -.
DR STRING; 9606.ENSP00000019317; -.
DR TCDB; 9.A.1.1.1; the non abc multidrug exporter (n-mde) family.
DR PhosphoSite; Q15311; -.
DR DMDM; 34098413; -.
DR PaxDb; Q15311; -.
DR PeptideAtlas; Q15311; -.
DR PRIDE; Q15311; -.
DR DNASU; 10928; -.
DR Ensembl; ENST00000019317; ENSP00000019317; ENSG00000017797.
DR Ensembl; ENST00000383432; ENSP00000372924; ENSG00000017797.
DR GeneID; 10928; -.
DR KEGG; hsa:10928; -.
DR UCSC; uc002kob.3; human.
DR CTD; 10928; -.
DR GeneCards; GC18P009465; -.
DR HGNC; HGNC:9841; RALBP1.
DR HPA; CAB046010; -.
DR HPA; HPA046651; -.
DR MIM; 605801; gene.
DR neXtProt; NX_Q15311; -.
DR PharmGKB; PA34199; -.
DR eggNOG; NOG295787; -.
DR HOGENOM; HOG000007929; -.
DR HOVERGEN; HBG044496; -.
DR InParanoid; Q15311; -.
DR KO; K08773; -.
DR OMA; TMMYDGV; -.
DR OrthoDB; EOG7V49ZT; -.
DR PhylomeDB; Q15311; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; Q15311; -.
DR ChiTaRS; RALBP1; human.
DR EvolutionaryTrace; Q15311; -.
DR GeneWiki; RALBP1; -.
DR GenomeRNAi; 10928; -.
DR NextBio; 41515; -.
DR PRO; PR:Q15311; -.
DR ArrayExpress; Q15311; -.
DR Bgee; Q15311; -.
DR CleanEx; HS_RALBP1; -.
DR Genevestigator; Q15311; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0043492; F:ATPase activity, coupled to movement of substances; IDA:UniProtKB.
DR GO; GO:0030675; F:Rac GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0006935; P:chemotaxis; TAS:ProtInc.
DR GO; GO:0043089; P:positive regulation of Cdc42 GTPase activity; IDA:UniProtKB.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; IPI:UniProtKB.
DR GO; GO:0006810; P:transport; IDA:UniProtKB.
DR Gene3D; 1.10.555.10; -; 1.
DR InterPro; IPR008936; Rho_GTPase_activation_prot.
DR InterPro; IPR000198; RhoGAP_dom.
DR Pfam; PF00620; RhoGAP; 1.
DR SMART; SM00324; RhoGAP; 1.
DR SUPFAM; SSF48350; SSF48350; 1.
DR PROSITE; PS50238; RHOGAP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; GTPase activation; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 655 RalA-binding protein 1.
FT /FTId=PRO_0000056733.
FT DOMAIN 192 380 Rho-GAP.
FT REGION 403 499 Interacts with RalA.
FT COMPBIAS 164 171 Poly-Lys.
FT MOD_RES 2 2 N-acetylthreonine.
FT MOD_RES 29 29 Phosphoserine (By similarity).
FT MOD_RES 62 62 Phosphoserine.
FT MOD_RES 92 92 Phosphoserine.
FT MOD_RES 93 93 Phosphoserine.
FT MOD_RES 463 463 Phosphoserine.
FT VARIANT 617 617 A -> V (in dbSNP:rs35867116).
FT /FTId=VAR_049147.
FT HELIX 395 414
FT HELIX 424 444
SQ SEQUENCE 655 AA; 76063 MW; EC6F75329FD8D062 CRC64;
MTECFLPPTS SPSEHRRVEH GSGLTRTPSS EEISPTKFPG LYRTGEPSPP HDILHEPPDV
VSDDEKDHGK KKGKFKKKEK RTEGYAAFQE DSSGDEAESP SKMKRSKGIH VFKKPSFSKK
KEKDFKIKEK PKEEKHKEEK HKEEKHKEKK SKDLTAADVV KQWKEKKKKK KPIQEPEVPQ
IDVPNLKPIF GIPLADAVER TMMYDGIRLP AVFRECIDYV EKYGMKCEGI YRVSGIKSKV
DELKAAYDRE ESTNLEDYEP NTVASLLKQY LRDLPENLLT KELMPRFEEA CGRTTETEKV
QEFQRLLKEL PECNYLLISW LIVHMDHVIA KELETKMNIQ NISIVLSPTV QISNRVLYVF
FTHVQELFGN VVLKQVMKPL RWSNMATMPT LPETQAGIKE EIRRQEFLLN CLHRDLQGGI
KDLSKEERLW EVQRILTALK RKLREAKRQE CETKIAQEIA SLSKEDVSKE EMNENEEVIN
ILLAQENEIL TEQEELLAME QFLRRQIASE KEEIERLRAE IAEIQSRQQH GRSETEEYSS
ESESESEDEE ELQIILEDLQ RQNEELEIKN NHLNQAIHEE REAIIELRVQ LRLLQMQRAK
AEQQAQEDEE PEWRGGAVQP PRDGVLEPKA AKEQPKAGKE PAKPSPSRDR KETSI
//
ID RBP1_HUMAN Reviewed; 655 AA.
AC Q15311; D3DUI0;
DT 15-AUG-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=RalA-binding protein 1;
DE Short=RalBP1;
DE AltName: Full=76 kDa Ral-interacting protein;
DE AltName: Full=Dinitrophenyl S-glutathione ATPase;
DE Short=DNP-SG ATPase;
DE AltName: Full=Ral-interacting protein 1;
GN Name=RALBP1; Synonyms=RLIP1, RLIP76;
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], FUNCTION, AND INTERACTION WITH RALA.
RX PubMed=7673236; DOI=10.1074/jbc.270.38.22473;
RA Jullien-Flores V., Dorseuil O., Romero F., Letourneur F.,
RA Saragosti S., Berger R., Tavitian A., Gacon G., Camonis J.H.;
RT "Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with
RT CDC42/Rac GTPase-activating protein activity.";
RL J. Biol. Chem. 270:22473-22477(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, AND PROTEIN SEQUENCE OF
RP 2-15; 409-438 AND 472-486.
RC TISSUE=Bone marrow;
RX PubMed=10924126; DOI=10.1021/bi992964c;
RA Awasthi S., Cheng J., Singhal S.S., Saini M.K., Pandya U., Pikula S.,
RA Bandorowicz-Pikula J., Singh S.V., Zimniak P., Awasthi Y.C.;
RT "Novel function of human RLIP76: ATP-dependent transport of
RT glutathione conjugates and doxorubicin.";
RL Biochemistry 39:9327-9334(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=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 [5]
RP INTERACTION WITH REPS2.
RC TISSUE=Brain;
RX PubMed=9422736; DOI=10.1074/jbc.273.2.814;
RA Ikeda M., Ishida O., Hinoi T., Kishida S., Kikuchi A.;
RT "Identification and characterization of a novel protein interacting
RT with Ral-binding protein 1, a putative effector protein of Ral.";
RL J. Biol. Chem. 273:814-821(1998).
RN [6]
RP FUNCTION, AND INTERACTION WITH CCNB1; CDK1; EPN1; NUMB AND TFAP2A.
RX PubMed=12775724; DOI=10.1074/jbc.M302191200;
RA Rosse C., L'Hoste S., Offner N., Picard A., Camonis J.;
RT "RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to
RT phosphorylate epsin during the switch off of endocytosis in mitosis.";
RL J. Biol. Chem. 278:30597-30604(2003).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=11437348; DOI=10.1006/abbi.2001.2395;
RA Sharma R., Singhal S.S., Cheng J., Yang Y., Sharma A., Zimniak P.,
RA Awasthi S., Awasthi Y.C.;
RT "RLIP76 is the major ATP-dependent transporter of glutathione-
RT conjugates and doxorubicin in human erythrocytes.";
RL Arch. Biochem. Biophys. 391:171-179(2001).
RN [8]
RP INTERACTION WITH DAB2IP.
RX PubMed=15310755; DOI=10.1074/jbc.M407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-92 AND SER-93, AND MASS
RP SPECTROMETRY.
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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-92 AND SER-93, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-463, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP STRUCTURE BY NMR OF 393-446 IN COMPLEX WITH RALB, AND INTERACTION WITH
RP RALB.
RX PubMed=20696399; DOI=10.1016/j.str.2010.05.013;
RA Fenwick R.B., Campbell L.J., Rajasekar K., Prasannan S.,
RA Nietlispach D., Camonis J., Owen D., Mott H.R.;
RT "The RalB-RLIP76 complex reveals a novel mode of ral-effector
RT interaction.";
RL Structure 18:985-995(2010).
CC -!- FUNCTION: Can activate specifically hydrolysis of GTP bound to
CC RAC1 and CDC42, but not RALA. Mediates ATP-dependent transport of
CC S-(2,4-dinitrophenyl)-glutathione (DNP-SG) and doxorubicin (DOX)
CC and is the major ATP-dependent transporter of glutathione
CC conjugates of electrophiles (GS-E) and DOX in erythrocytes. Can
CC catalyze transport of glutathione conjugates and xenobiotics, and
CC may contribute to the multidrug resistance phenomenon. Serves as a
CC scaffold protein that brings together proteins forming an
CC endocytotic complex during interphase and also with CDK1 to switch
CC off endocytosis, One of its substrates would be EPN1/Epsin.
CC -!- SUBUNIT: Interacts with the GTP-bound form of RALA, RALB, CDC42
CC and RAC1. Interacts with REPS1 and REPS2 and this does not affect
CC the Ral-binding activity. Interacts with DAB2IP. Interacts with
CC catalytically active CCNB1 and CDK1 during mitosis. Interacts with
CC EPN1, NUMB and TFAP2A during interphase and mitosis.
CC -!- INTERACTION:
CC P78556:CCL20; NbExp=2; IntAct=EBI-749285, EBI-3913209;
CC Q86VP1:TAX1BP1; NbExp=3; IntAct=EBI-749285, EBI-529518;
CC -!- SUBCELLULAR LOCATION: Membrane; Peripheral membrane protein.
CC -!- TISSUE SPECIFICITY: Expressed ubiquitously but at low levels.
CC Shows a strong expression in the erythrocytes.
CC -!- SIMILARITY: Contains 1 Rho-GAP domain.
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; L42542; AAB00103.1; -; mRNA.
DR EMBL; CH471113; EAX01601.1; -; Genomic_DNA.
DR EMBL; CH471113; EAX01602.1; -; Genomic_DNA.
DR EMBL; CH471113; EAX01604.1; -; Genomic_DNA.
DR EMBL; CH471113; EAX01605.1; -; Genomic_DNA.
DR EMBL; BC013126; AAH13126.1; -; mRNA.
DR PIR; F59435; F59435.
DR RefSeq; NP_006779.1; NM_006788.3.
DR UniGene; Hs.528993; -.
DR PDB; 2KWH; NMR; -; A=393-446.
DR PDB; 2KWI; NMR; -; B=393-446.
DR PDBsum; 2KWH; -.
DR PDBsum; 2KWI; -.
DR ProteinModelPortal; Q15311; -.
DR SMR; Q15311; 210-353, 393-446.
DR IntAct; Q15311; 9.
DR MINT; MINT-140436; -.
DR STRING; 9606.ENSP00000019317; -.
DR TCDB; 9.A.1.1.1; the non abc multidrug exporter (n-mde) family.
DR PhosphoSite; Q15311; -.
DR DMDM; 34098413; -.
DR PaxDb; Q15311; -.
DR PeptideAtlas; Q15311; -.
DR PRIDE; Q15311; -.
DR DNASU; 10928; -.
DR Ensembl; ENST00000019317; ENSP00000019317; ENSG00000017797.
DR Ensembl; ENST00000383432; ENSP00000372924; ENSG00000017797.
DR GeneID; 10928; -.
DR KEGG; hsa:10928; -.
DR UCSC; uc002kob.3; human.
DR CTD; 10928; -.
DR GeneCards; GC18P009465; -.
DR HGNC; HGNC:9841; RALBP1.
DR HPA; CAB046010; -.
DR HPA; HPA046651; -.
DR MIM; 605801; gene.
DR neXtProt; NX_Q15311; -.
DR PharmGKB; PA34199; -.
DR eggNOG; NOG295787; -.
DR HOGENOM; HOG000007929; -.
DR HOVERGEN; HBG044496; -.
DR InParanoid; Q15311; -.
DR KO; K08773; -.
DR OMA; TMMYDGV; -.
DR OrthoDB; EOG7V49ZT; -.
DR PhylomeDB; Q15311; -.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; Q15311; -.
DR ChiTaRS; RALBP1; human.
DR EvolutionaryTrace; Q15311; -.
DR GeneWiki; RALBP1; -.
DR GenomeRNAi; 10928; -.
DR NextBio; 41515; -.
DR PRO; PR:Q15311; -.
DR ArrayExpress; Q15311; -.
DR Bgee; Q15311; -.
DR CleanEx; HS_RALBP1; -.
DR Genevestigator; Q15311; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0043492; F:ATPase activity, coupled to movement of substances; IDA:UniProtKB.
DR GO; GO:0030675; F:Rac GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0006935; P:chemotaxis; TAS:ProtInc.
DR GO; GO:0043089; P:positive regulation of Cdc42 GTPase activity; IDA:UniProtKB.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; IPI:UniProtKB.
DR GO; GO:0006810; P:transport; IDA:UniProtKB.
DR Gene3D; 1.10.555.10; -; 1.
DR InterPro; IPR008936; Rho_GTPase_activation_prot.
DR InterPro; IPR000198; RhoGAP_dom.
DR Pfam; PF00620; RhoGAP; 1.
DR SMART; SM00324; RhoGAP; 1.
DR SUPFAM; SSF48350; SSF48350; 1.
DR PROSITE; PS50238; RHOGAP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; GTPase activation; Membrane;
KW Phosphoprotein; Polymorphism; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 655 RalA-binding protein 1.
FT /FTId=PRO_0000056733.
FT DOMAIN 192 380 Rho-GAP.
FT REGION 403 499 Interacts with RalA.
FT COMPBIAS 164 171 Poly-Lys.
FT MOD_RES 2 2 N-acetylthreonine.
FT MOD_RES 29 29 Phosphoserine (By similarity).
FT MOD_RES 62 62 Phosphoserine.
FT MOD_RES 92 92 Phosphoserine.
FT MOD_RES 93 93 Phosphoserine.
FT MOD_RES 463 463 Phosphoserine.
FT VARIANT 617 617 A -> V (in dbSNP:rs35867116).
FT /FTId=VAR_049147.
FT HELIX 395 414
FT HELIX 424 444
SQ SEQUENCE 655 AA; 76063 MW; EC6F75329FD8D062 CRC64;
MTECFLPPTS SPSEHRRVEH GSGLTRTPSS EEISPTKFPG LYRTGEPSPP HDILHEPPDV
VSDDEKDHGK KKGKFKKKEK RTEGYAAFQE DSSGDEAESP SKMKRSKGIH VFKKPSFSKK
KEKDFKIKEK PKEEKHKEEK HKEEKHKEKK SKDLTAADVV KQWKEKKKKK KPIQEPEVPQ
IDVPNLKPIF GIPLADAVER TMMYDGIRLP AVFRECIDYV EKYGMKCEGI YRVSGIKSKV
DELKAAYDRE ESTNLEDYEP NTVASLLKQY LRDLPENLLT KELMPRFEEA CGRTTETEKV
QEFQRLLKEL PECNYLLISW LIVHMDHVIA KELETKMNIQ NISIVLSPTV QISNRVLYVF
FTHVQELFGN VVLKQVMKPL RWSNMATMPT LPETQAGIKE EIRRQEFLLN CLHRDLQGGI
KDLSKEERLW EVQRILTALK RKLREAKRQE CETKIAQEIA SLSKEDVSKE EMNENEEVIN
ILLAQENEIL TEQEELLAME QFLRRQIASE KEEIERLRAE IAEIQSRQQH GRSETEEYSS
ESESESEDEE ELQIILEDLQ RQNEELEIKN NHLNQAIHEE REAIIELRVQ LRLLQMQRAK
AEQQAQEDEE PEWRGGAVQP PRDGVLEPKA AKEQPKAGKE PAKPSPSRDR KETSI
//
MIM
605801
*RECORD*
*FIELD* NO
605801
*FIELD* TI
*605801 RALA-BINDING PROTEIN 1; RALBP1
;;RAL-INTERACTING PROTEIN, 76-KD; RLIP76;;
RAL-INTERACTING PROTEIN 1; RIP1;;
read moreDINITROPHENYL S-GLUTATHIONE ATPase;;
DNP-SG ATPase
*FIELD* TX
DESCRIPTION
RALBP1 plays a role in receptor-mediated endocytosis and is a downstream
effector of the small GTP-binding protein RAL (see RALA; 179550). Small
G proteins, such as RAL, have GDP-bound inactive and GTP-bound active
forms, which shift from the inactive to the active state through the
action of RALGDS (601619), which in turn is activated by RAS (see HRAS;
190020) (summary by Feig, 2003). RALBP1 is also the dominant transporter
of lipid peroxidation-derived glutathione conjugates (Singhal et al.,
2013) and participates in several mitotic events, including inactivation
of endocytosis and separation and polar movement of centrioles (Rosse et
al., 2003) and appropriate distribution of mitochondria to daughter
cells following mitosis (Kashatus et al., 2011).
CLONING
Using a mutant form of RALA lacking the C-terminal 27 amino acids as
bait in a yeast 2-hybrid screen of a Jurkat cDNA library, followed by
5-prime RACE and screening skeletal muscle and placenta cDNA libraries,
Jullien-Flores et al. (1995) obtained a cDNA encoding RALBP1, which they
termed RLIP76. The deduced 655-amino acid protein has a calculated
molecular mass of 76 kD. It is homologous in the central region to
proteins bearing a CDC42 (116952)/RHO (see 165390)/RAC (see RAC1;
602048) GTPase-activating protein (GAP) activity, such as BCR (see
151410). Sequence analysis predicted that RALBP1 has an N-terminal
alpha-helical region, the GAP-like region, the RAL-binding region, and
the C-terminal region. Northern blot analysis detected ubiquitous,
low-level expression of RALBP1.
Awasthi et al. (2000) cloned a dinitrophenyl glutathione ATPase
identical to RALBP1. They found that RALBP1 had an apparent molecular
mass of 95 kD by SDS-PAGE.
MAPPING
By FISH analysis, Jullien-Flores et al. (1995) mapped the RALBP1 gene to
chromosome 18p11.
GENE FUNCTION
Binding analysis by Jullien-Flores et al. (1995) showed that RALBP1
interacted with RALA and RALB (179551), but with no other GTPases except
RAC1.
Awasthi et al. (2000) reported that recombinant RALBP1 had ATPase
activity that was stimulated by doxorubicin (DOX), which it transported
in an ATP-dependent manner, and mediated resistance to DOX. They
concluded that, in addition to its role in signal transduction, RALBP1
can catalyze the transport of glutathione conjugates and xenobiotics,
potentially contributing to multidrug resistance.
Phosphorylation of epsin (EPN1; 607262), an endocytic accessory protein,
by CDK1 (116940) renders the molecule incompetent for endocytosis during
mitosis. Using yeast 2-hybrid screens of human placenta and Drosophila
embryo cDNA libraries, Rosse et al. (2003) found that RLIP76 interacted
with the CDK1 partner cyclin B (CCNB1; 123836). Cyclin B and RLIP76
interacted in vitro and in vivo in both fly and human, and RLIP76
associated with the active cyclin B1-CDK1 complex during mitosis. During
both interphase and mitosis, RLIP76 interacted with the endocytotic
proteins Numb (603728) and AP2 (see 601026) and both phosphorylated and
nonphosphorylated forms of epsin. Phosphorylation and inactivation of
epsin also required RAL signaling. Rosse et al. (2003) proposed that
RLIP76 serves as a scaffold to assemble an endocytotic complex during
interphase and recruits cyclin B-CDK1 to phosphorylate epsin and switch
off endocytosis during mitosis.
Singhal et al. (2009) stated that RLIP76 is frequently overexpressed in
malignant cells and functions to oppose apoptosis by limiting the
accumulation of endogenous or exogenous toxic electrophilic compounds.
They found that RLIP76 was overexpressed in Caki-2 human kidney cancer
cells compared with normal mesangial cells. Inside-out vesicles prepared
from Caki-2 cells showed higher ATP-dependent uptake of doxorubicin and
dinitrophenyl-S-glutathione than vesicles prepared from normal mesangial
cells. Depletion of RLIP76 via antisense RNA, small interfering RNA, or
anti-RLIP76 antibody caused extensive apoptosis of Caki-2 cells in
culture and regression of Caki-2 tumors in nude mice.
Equal distribution of mitochondria to daughter cells during mitosis
requires fission, which depends on recruitment of the large GTPase DRP1
(DNM1L; 603850) to the outer mitochondrial membrane and phosphorylation
of DRP1 by cyclin B-CDK1. Using M-phase HeLa cells, Kashatus et al.
(2011) found that the mitotic kinase Aurora A (AURKA; 603072)
phosphorylated RALA at ser194, resulting in redistribution of RALA to
mitochondria, where it recruited RALBP1 and DRP1. Subsequently, RALBP1
induced cyclin B-CDK1-dependent phosphorylation of DRP1. Knockdown of
RALBP1, but not RALA, decreased the amount of phosphorylated DRP1.
Knockdown of either RALA or RALBP1 blocked mitochondrial fission,
causing unequal partitioning of mitochondria between daughter cells,
reduced cellular content of ATP, and decreased numbers of metabolically
active cells. Kashatus et al. (2011) concluded that the mitotic kinases
Aurora A and cyclin B-CDK1 converge on RALA and RALBP1 to promote
mitochondrial fission and appropriate distribution of mitochondria to
daughter cells.
ANIMAL MODEL
Singhal et al. (2013) found that Rlip76 -/- mice were hypertensive and
showed significant increases in both systolic and diastolic blood
pressure compared with wildtype mice. Rlip76 -/- mice also showed poorer
renal filtration, with significant loss of glomeruli. Western blot
analysis and real-time quantitative PCR showed that hypertension was due
to overactive renin (REN; 179820)-angiotensin (106150) signaling.
However, Rlip76 -/- mice were also significantly resistant to obesity
and several other features of metabolic syndrome caused by ingesting a
high-fat diet. Rlip76 -/- mice showed reduced rates of insulin and
adipokine resistance, inflammation and fibrosis of adipose and kidney,
glucose tolerance and hyperlipidemia, metabolic derangements, and liver
abnormalities. Singhal et al. (2013) concluded that RLIP76 is necessary
for development of high-fat diet-induced obesity and metabolic syndrome.
*FIELD* RF
1. Awasthi, S.; Cheng, J.; Singhal, S. S.; Saini, M. K.; Pandya, U.;
Pikula, S.; Bandorowicz-Pikula, J.; Singh, S. V.; Zimniak, P.; Awasthi,
Y. C.: Novel function of human RLIP76: ATP-dependent transport of
glutathione conjugates and doxorubicin. Biochemistry 39: 9327-9334,
2000.
2. Feig, L. A.: Ral-GTPases: approaching their 15 minutes of fame. Trends.
Cell Biol. 13: 419-425, 2003.
3. Jullien-Flores, V.; Dorseuil, O.; Romero, R.; Letourneur, F.; Saragosti,
S.; Berger, R.; Tavitian, A.; Gacon, G.; Camonis, J. H.: Bridging
Ral GTPase to Rho pathways: RLIP76, a Ral effector with CDC42/Rac
GTPase-activating protein activity. J. Biol. Chem. 270: 22473-22477,
1995.
4. Kashatus, D. F.; Lim, K.-H.; Brady, D. C.; Pershing, N. L. K.;
Cox, A. D.; Counter, C. M.: RALA and RALBP1 regulate mitochondrial
fission at mitosis. Nature Cell Biol. 13: 1108-1115, 2011.
5. Rosse, C.; L'Hoste, S.; Offner, N.; Picard, A.; Camonis, J.: RLIP,
an effector of the Ral GTPases, is a platform for cdk1 to phosphorylate
epsin during the switch off of endocytosis in mitosis. J. Biol. Chem. 278:
30597-30604, 2003.
6. Singhal, S. S.; Figarola, J.; Singhal, J.; Reddy, M. A.; Liu, X.;
Berz, D.; Natarajan, R.; Awasthi, S.: RLIP76 protein knockdown attenuates
obesity due to a high-fat diet. J. Biol. Chem. 288: 23394-23406,
2013.
7. Singhal, S. S.; Singhal, J.; Yadav, S.; Sahu, M.; Awasthi, Y. C.;
Awasthi, S.: RLIP76: a target for kidney cancer therapy. Cancer
Res. 69: 4244-4251, 2009. Note: Erratum: Cancer Res. 69: 8832 only,
2009.
*FIELD* CN
Patricia A. Hartz - updated: 10/15/2013
Patricia A. Hartz - updated: 11/15/2010
*FIELD* CD
Paul J. Converse: 3/29/2001
*FIELD* ED
mgross: 11/08/2013
tpirozzi: 10/15/2013
carol: 4/22/2013
mgross: 11/16/2010
terry: 11/15/2010
wwang: 8/17/2010
mgross: 4/2/2001
*RECORD*
*FIELD* NO
605801
*FIELD* TI
*605801 RALA-BINDING PROTEIN 1; RALBP1
;;RAL-INTERACTING PROTEIN, 76-KD; RLIP76;;
RAL-INTERACTING PROTEIN 1; RIP1;;
read moreDINITROPHENYL S-GLUTATHIONE ATPase;;
DNP-SG ATPase
*FIELD* TX
DESCRIPTION
RALBP1 plays a role in receptor-mediated endocytosis and is a downstream
effector of the small GTP-binding protein RAL (see RALA; 179550). Small
G proteins, such as RAL, have GDP-bound inactive and GTP-bound active
forms, which shift from the inactive to the active state through the
action of RALGDS (601619), which in turn is activated by RAS (see HRAS;
190020) (summary by Feig, 2003). RALBP1 is also the dominant transporter
of lipid peroxidation-derived glutathione conjugates (Singhal et al.,
2013) and participates in several mitotic events, including inactivation
of endocytosis and separation and polar movement of centrioles (Rosse et
al., 2003) and appropriate distribution of mitochondria to daughter
cells following mitosis (Kashatus et al., 2011).
CLONING
Using a mutant form of RALA lacking the C-terminal 27 amino acids as
bait in a yeast 2-hybrid screen of a Jurkat cDNA library, followed by
5-prime RACE and screening skeletal muscle and placenta cDNA libraries,
Jullien-Flores et al. (1995) obtained a cDNA encoding RALBP1, which they
termed RLIP76. The deduced 655-amino acid protein has a calculated
molecular mass of 76 kD. It is homologous in the central region to
proteins bearing a CDC42 (116952)/RHO (see 165390)/RAC (see RAC1;
602048) GTPase-activating protein (GAP) activity, such as BCR (see
151410). Sequence analysis predicted that RALBP1 has an N-terminal
alpha-helical region, the GAP-like region, the RAL-binding region, and
the C-terminal region. Northern blot analysis detected ubiquitous,
low-level expression of RALBP1.
Awasthi et al. (2000) cloned a dinitrophenyl glutathione ATPase
identical to RALBP1. They found that RALBP1 had an apparent molecular
mass of 95 kD by SDS-PAGE.
MAPPING
By FISH analysis, Jullien-Flores et al. (1995) mapped the RALBP1 gene to
chromosome 18p11.
GENE FUNCTION
Binding analysis by Jullien-Flores et al. (1995) showed that RALBP1
interacted with RALA and RALB (179551), but with no other GTPases except
RAC1.
Awasthi et al. (2000) reported that recombinant RALBP1 had ATPase
activity that was stimulated by doxorubicin (DOX), which it transported
in an ATP-dependent manner, and mediated resistance to DOX. They
concluded that, in addition to its role in signal transduction, RALBP1
can catalyze the transport of glutathione conjugates and xenobiotics,
potentially contributing to multidrug resistance.
Phosphorylation of epsin (EPN1; 607262), an endocytic accessory protein,
by CDK1 (116940) renders the molecule incompetent for endocytosis during
mitosis. Using yeast 2-hybrid screens of human placenta and Drosophila
embryo cDNA libraries, Rosse et al. (2003) found that RLIP76 interacted
with the CDK1 partner cyclin B (CCNB1; 123836). Cyclin B and RLIP76
interacted in vitro and in vivo in both fly and human, and RLIP76
associated with the active cyclin B1-CDK1 complex during mitosis. During
both interphase and mitosis, RLIP76 interacted with the endocytotic
proteins Numb (603728) and AP2 (see 601026) and both phosphorylated and
nonphosphorylated forms of epsin. Phosphorylation and inactivation of
epsin also required RAL signaling. Rosse et al. (2003) proposed that
RLIP76 serves as a scaffold to assemble an endocytotic complex during
interphase and recruits cyclin B-CDK1 to phosphorylate epsin and switch
off endocytosis during mitosis.
Singhal et al. (2009) stated that RLIP76 is frequently overexpressed in
malignant cells and functions to oppose apoptosis by limiting the
accumulation of endogenous or exogenous toxic electrophilic compounds.
They found that RLIP76 was overexpressed in Caki-2 human kidney cancer
cells compared with normal mesangial cells. Inside-out vesicles prepared
from Caki-2 cells showed higher ATP-dependent uptake of doxorubicin and
dinitrophenyl-S-glutathione than vesicles prepared from normal mesangial
cells. Depletion of RLIP76 via antisense RNA, small interfering RNA, or
anti-RLIP76 antibody caused extensive apoptosis of Caki-2 cells in
culture and regression of Caki-2 tumors in nude mice.
Equal distribution of mitochondria to daughter cells during mitosis
requires fission, which depends on recruitment of the large GTPase DRP1
(DNM1L; 603850) to the outer mitochondrial membrane and phosphorylation
of DRP1 by cyclin B-CDK1. Using M-phase HeLa cells, Kashatus et al.
(2011) found that the mitotic kinase Aurora A (AURKA; 603072)
phosphorylated RALA at ser194, resulting in redistribution of RALA to
mitochondria, where it recruited RALBP1 and DRP1. Subsequently, RALBP1
induced cyclin B-CDK1-dependent phosphorylation of DRP1. Knockdown of
RALBP1, but not RALA, decreased the amount of phosphorylated DRP1.
Knockdown of either RALA or RALBP1 blocked mitochondrial fission,
causing unequal partitioning of mitochondria between daughter cells,
reduced cellular content of ATP, and decreased numbers of metabolically
active cells. Kashatus et al. (2011) concluded that the mitotic kinases
Aurora A and cyclin B-CDK1 converge on RALA and RALBP1 to promote
mitochondrial fission and appropriate distribution of mitochondria to
daughter cells.
ANIMAL MODEL
Singhal et al. (2013) found that Rlip76 -/- mice were hypertensive and
showed significant increases in both systolic and diastolic blood
pressure compared with wildtype mice. Rlip76 -/- mice also showed poorer
renal filtration, with significant loss of glomeruli. Western blot
analysis and real-time quantitative PCR showed that hypertension was due
to overactive renin (REN; 179820)-angiotensin (106150) signaling.
However, Rlip76 -/- mice were also significantly resistant to obesity
and several other features of metabolic syndrome caused by ingesting a
high-fat diet. Rlip76 -/- mice showed reduced rates of insulin and
adipokine resistance, inflammation and fibrosis of adipose and kidney,
glucose tolerance and hyperlipidemia, metabolic derangements, and liver
abnormalities. Singhal et al. (2013) concluded that RLIP76 is necessary
for development of high-fat diet-induced obesity and metabolic syndrome.
*FIELD* RF
1. Awasthi, S.; Cheng, J.; Singhal, S. S.; Saini, M. K.; Pandya, U.;
Pikula, S.; Bandorowicz-Pikula, J.; Singh, S. V.; Zimniak, P.; Awasthi,
Y. C.: Novel function of human RLIP76: ATP-dependent transport of
glutathione conjugates and doxorubicin. Biochemistry 39: 9327-9334,
2000.
2. Feig, L. A.: Ral-GTPases: approaching their 15 minutes of fame. Trends.
Cell Biol. 13: 419-425, 2003.
3. Jullien-Flores, V.; Dorseuil, O.; Romero, R.; Letourneur, F.; Saragosti,
S.; Berger, R.; Tavitian, A.; Gacon, G.; Camonis, J. H.: Bridging
Ral GTPase to Rho pathways: RLIP76, a Ral effector with CDC42/Rac
GTPase-activating protein activity. J. Biol. Chem. 270: 22473-22477,
1995.
4. Kashatus, D. F.; Lim, K.-H.; Brady, D. C.; Pershing, N. L. K.;
Cox, A. D.; Counter, C. M.: RALA and RALBP1 regulate mitochondrial
fission at mitosis. Nature Cell Biol. 13: 1108-1115, 2011.
5. Rosse, C.; L'Hoste, S.; Offner, N.; Picard, A.; Camonis, J.: RLIP,
an effector of the Ral GTPases, is a platform for cdk1 to phosphorylate
epsin during the switch off of endocytosis in mitosis. J. Biol. Chem. 278:
30597-30604, 2003.
6. Singhal, S. S.; Figarola, J.; Singhal, J.; Reddy, M. A.; Liu, X.;
Berz, D.; Natarajan, R.; Awasthi, S.: RLIP76 protein knockdown attenuates
obesity due to a high-fat diet. J. Biol. Chem. 288: 23394-23406,
2013.
7. Singhal, S. S.; Singhal, J.; Yadav, S.; Sahu, M.; Awasthi, Y. C.;
Awasthi, S.: RLIP76: a target for kidney cancer therapy. Cancer
Res. 69: 4244-4251, 2009. Note: Erratum: Cancer Res. 69: 8832 only,
2009.
*FIELD* CN
Patricia A. Hartz - updated: 10/15/2013
Patricia A. Hartz - updated: 11/15/2010
*FIELD* CD
Paul J. Converse: 3/29/2001
*FIELD* ED
mgross: 11/08/2013
tpirozzi: 10/15/2013
carol: 4/22/2013
mgross: 11/16/2010
terry: 11/15/2010
wwang: 8/17/2010
mgross: 4/2/2001