Full text data of ABCC4
ABCC4
(MRP4)
[Confidence: high (present in two of the MS resources)]
Multidrug resistance-associated protein 4 (ATP-binding cassette sub-family C member 4; MRP/cMOAT-related ABC transporter; Multi-specific organic anion transporter B; MOAT-B)
Multidrug resistance-associated protein 4 (ATP-binding cassette sub-family C member 4; MRP/cMOAT-related ABC transporter; Multi-specific organic anion transporter B; MOAT-B)
hRBCD
IPI00006675
IPI00006675 Multidrug resistance-associated protein 4 Multidrug resistance-associated protein 4 membrane n/a 2 6 2 9 n/a 4 1 n/a n/a 7 3 2 7 1 4 3 n/a 2 2 integral membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00006675 Multidrug resistance-associated protein 4 Multidrug resistance-associated protein 4 membrane n/a 2 6 2 9 n/a 4 1 n/a n/a 7 3 2 7 1 4 3 n/a 2 2 integral membrane protein n/a found at its expected molecular weight found at molecular weight
UniProt
O15439
ID MRP4_HUMAN Reviewed; 1325 AA.
AC O15439; A9Z1Z7; Q8IVZ4; Q8IZN6; Q8NEW8; Q9Y6J2;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-SEP-2008, sequence version 3.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Multidrug resistance-associated protein 4;
DE AltName: Full=ATP-binding cassette sub-family C member 4;
DE AltName: Full=MRP/cMOAT-related ABC transporter;
DE AltName: Full=Multi-specific organic anion transporter B;
DE Short=MOAT-B;
GN Name=ABCC4; Synonyms=MRP4;
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 1), AND VARIANT ILE-18.
RX PubMed=9661885;
RA Lee K., Belinsky M.G., Bell D.W., Testa J.R., Kruh G.D.;
RT "Isolation of MOAT-B, a widely expressed multidrug resistance-
RT associated protein/canalicular multispecific organic anion
RT transporter-related transporter.";
RL Cancer Res. 58:2741-2747(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ILE-18.
RX PubMed=12105214; DOI=10.1074/jbc.M203262200;
RA Adachi M., Sampath J., Lan L.B., Sun D., Hargrove P., Flatley R.,
RA Tatum A., Edwards M.Z., Wezeman M., Matherly L., Drake R., Schuetz J.;
RT "Expression of MRP4 confers resistance to ganciclovir and compromises
RT bystander cell killing.";
RL J. Biol. Chem. 277:38998-39004(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney;
RA Kato R., Ishikawa T.;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [5]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1155-1316 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=9270026;
RA Kool M., de Haas M., Scheffer G.L., Scheper R.J., van Eijk M.J.,
RA Juijn J.A., Baas F., Borst P.;
RT "Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5,
RT homologues of the multidrug resistance-associated protein gene (MRP1),
RT in human cancer cell lines.";
RL Cancer Res. 57:3537-3547(1997).
RN [8]
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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, 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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, 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 [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
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 [13]
RP INTERACTION WITH SNX27.
RX PubMed=22411990; DOI=10.1074/jbc.M111.337931;
RA Hayashi H., Naoi S., Nakagawa T., Nishikawa T., Fukuda H.,
RA Imajoh-Ohmi S., Kondo A., Kubo K., Yabuki T., Hattori A., Hirouchi M.,
RA Sugiyama Y.;
RT "Sorting nexin 27 interacts with multidrug resistance-associated
RT protein 4 (MRP4) and mediates internalization of MRP4.";
RL J. Biol. Chem. 287:15054-15065(2012).
RN [14]
RP VARIANTS CYS-556; ILE-776; ILE-820; PHE-854 AND VAL-866, AND
RP CHARACTERIZATION OF VARIANTS TRP-187; ASN-304; GLU-487; CYS-556;
RP LYS-757; ILE-776; ILE-820; PHE-854; VAL-866 AND MET-1142.
RX PubMed=18300232; DOI=10.1002/humu.20694;
RA Janke D., Mehralivand S., Strand D., Goedtel-Armbrust U.,
RA Habermeier A., Gradhand U., Fischer C., Toliat M.R., Fritz P.,
RA Zanger U.M., Schwab M., Fromm M.F., Nuernberg P., Wojnowski L.,
RA Closs E.I., Lang T.;
RT "6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA)
RT transport altered by two missense mutations in the drug transporter
RT gene ABCC4.";
RL Hum. Mutat. 29:659-669(2008).
RN [15]
RP VARIANT LYS-757.
RX PubMed=20547088; DOI=10.1016/j.legalmed.2010.04.001;
RA Yuasa I., Umetsu K., Matsusue A., Nishimukai H., Harihara S.,
RA Fukumori Y., Saitou N., Jin F., Chattopadhyay P.K., Henke L.,
RA Henke J.;
RT "A Japanese-specific allele in the GALNT11 gene.";
RL Leg. Med. 12:208-211(2010).
CC -!- FUNCTION: May be an organic anion pump relevant to cellular
CC detoxification.
CC -!- SUBUNIT: Interacts (via PDZ-binding motif) with SNX27 (via PDZ
CC domain).
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O15439-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15439-2; Sequence=VSP_035426;
CC Name=3;
CC IsoId=O15439-3; Sequence=VSP_043283, VSP_043284;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed, with particularly high
CC levels in prostate, but is barely detectable in liver.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCC
CC family. Conjugate transporter (TC 3.A.1.208) subfamily.
CC -!- SIMILARITY: Contains 2 ABC transmembrane type-1 domains.
CC -!- SIMILARITY: Contains 2 ABC transporter domains.
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC
CC proteins;
CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=O15439";
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DR EMBL; AF071202; AAC27076.1; -; mRNA.
DR EMBL; AY081219; AAL88745.1; -; mRNA.
DR EMBL; AY207008; AAO37649.1; -; mRNA.
DR EMBL; AF541977; AAN17334.1; -; mRNA.
DR EMBL; AL157818; CAC36037.2; -; Genomic_DNA.
DR EMBL; AL139381; CAC36037.2; JOINED; Genomic_DNA.
DR EMBL; AL356257; CAC36037.2; JOINED; Genomic_DNA.
DR EMBL; AL139381; CAI16589.1; -; Genomic_DNA.
DR EMBL; AL157818; CAI16589.1; JOINED; Genomic_DNA.
DR EMBL; AL356257; CAI16589.1; JOINED; Genomic_DNA.
DR EMBL; AL356257; CAI16722.1; -; Genomic_DNA.
DR EMBL; AL139381; CAI16722.1; JOINED; Genomic_DNA.
DR EMBL; AL157818; CAI16722.1; JOINED; Genomic_DNA.
DR EMBL; AL359750; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471085; EAX08951.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX08950.1; -; Genomic_DNA.
DR EMBL; BC041560; AAH41560.1; -; mRNA.
DR EMBL; U83660; AAB71757.1; -; mRNA.
DR RefSeq; NP_001098985.1; NM_001105515.1.
DR RefSeq; NP_005836.2; NM_005845.3.
DR RefSeq; XP_005254083.1; XM_005254026.1.
DR UniGene; Hs.508423; -.
DR ProteinModelPortal; O15439; -.
DR SMR; O15439; 110-650, 743-1290.
DR IntAct; O15439; 1.
DR STRING; 9606.ENSP00000366084; -.
DR ChEMBL; CHEMBL1743128; -.
DR DrugBank; DB01327; Cefazolin.
DR TCDB; 3.A.1.208.7; the atp-binding cassette (abc) superfamily.
DR PhosphoSite; O15439; -.
DR PaxDb; O15439; -.
DR PRIDE; O15439; -.
DR Ensembl; ENST00000376887; ENSP00000366084; ENSG00000125257.
DR Ensembl; ENST00000412704; ENSP00000388657; ENSG00000125257.
DR Ensembl; ENST00000431522; ENSP00000398562; ENSG00000125257.
DR GeneID; 10257; -.
DR KEGG; hsa:10257; -.
DR UCSC; uc001vmd.4; human.
DR CTD; 10257; -.
DR GeneCards; GC13M095672; -.
DR HGNC; HGNC:55; ABCC4.
DR HPA; CAB002751; -.
DR HPA; HPA002476; -.
DR MIM; 605250; gene.
DR neXtProt; NX_O15439; -.
DR PharmGKB; PA397; -.
DR eggNOG; COG1132; -.
DR HOVERGEN; HBG108314; -.
DR InParanoid; O15439; -.
DR KO; K05673; -.
DR OMA; CAMFVII; -.
DR OrthoDB; EOG7MWGW0; -.
DR PhylomeDB; O15439; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR GeneWiki; ABCC4; -.
DR GenomeRNAi; 10257; -.
DR NextBio; 38868; -.
DR PRO; PR:O15439; -.
DR ArrayExpress; O15439; -.
DR Bgee; O15439; -.
DR CleanEx; HS_ABCC4; -.
DR Genevestigator; O15439; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0031088; C:platelet dense granule membrane; IDA:MGI.
DR GO; GO:0016404; F:15-hydroxyprostaglandin dehydrogenase (NAD+) activity; NAS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042626; F:ATPase activity, coupled to transmembrane movement of substances; IEA:InterPro.
DR GO; GO:0006200; P:ATP catabolic process; IEA:GOC.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR003439; ABC_transporter-like.
DR InterPro; IPR017871; ABC_transporter_CS.
DR InterPro; IPR001140; ABC_transptr_TM_dom.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Complete proteome; Glycoprotein;
KW Membrane; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1 1325 Multidrug resistance-associated protein
FT 4.
FT /FTId=PRO_0000093362.
FT TRANSMEM 93 113 Helical; (Potential).
FT TRANSMEM 136 156 Helical; (Potential).
FT TRANSMEM 207 227 Helical; (Potential).
FT TRANSMEM 228 248 Helical; (Potential).
FT TRANSMEM 328 348 Helical; (Potential).
FT TRANSMEM 351 371 Helical; (Potential).
FT TRANSMEM 440 460 Helical; (Potential).
FT TRANSMEM 710 730 Helical; (Potential).
FT TRANSMEM 771 791 Helical; (Potential).
FT TRANSMEM 836 856 Helical; (Potential).
FT TRANSMEM 858 878 Helical; (Potential).
FT TRANSMEM 954 974 Helical; (Potential).
FT TRANSMEM 977 997 Helical; (Potential).
FT TRANSMEM 1038 1058 Helical; (Potential).
FT DOMAIN 92 377 ABC transmembrane type-1 1.
FT DOMAIN 410 633 ABC transporter 1.
FT DOMAIN 714 1005 ABC transmembrane type-1 2.
FT DOMAIN 1041 1274 ABC transporter 2.
FT NP_BIND 445 452 ATP 1 (Potential).
FT NP_BIND 1075 1082 ATP 2 (Potential).
FT MOTIF 1322 1325 PDZ-binding.
FT MOD_RES 646 646 Phosphothreonine.
FT CARBOHYD 651 651 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 690 690 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 746 746 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 754 754 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 792 792 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1176 1176 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1309 1309 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 679 725 Missing (in isoform 2).
FT /FTId=VSP_035426.
FT VAR_SEQ 846 859 TLLQVVGVVSVAVA -> RWDLAVLSWLVSNS (in
FT isoform 3).
FT /FTId=VSP_043283.
FT VAR_SEQ 860 1325 Missing (in isoform 3).
FT /FTId=VSP_043284.
FT VARIANT 18 18 L -> I (in dbSNP:rs11568681).
FT /FTId=VAR_046445.
FT VARIANT 78 78 P -> A (in dbSNP:rs11568689).
FT /FTId=VAR_029121.
FT VARIANT 171 171 C -> G (in dbSNP:rs4148460).
FT /FTId=VAR_046446.
FT VARIANT 184 184 M -> T (in dbSNP:rs45454092).
FT /FTId=VAR_020241.
FT VARIANT 187 187 G -> W (transport properties comparable
FT to wild-type; dbSNP:rs11568658).
FT /FTId=VAR_020242.
FT VARIANT 293 293 K -> E (in dbSNP:rs11568684).
FT /FTId=VAR_046447.
FT VARIANT 304 304 K -> N (transport properties comparable
FT to wild-type; dbSNP:rs2274407).
FT /FTId=VAR_022072.
FT VARIANT 356 356 T -> M (in dbSNP:rs11568701).
FT /FTId=VAR_046448.
FT VARIANT 403 403 P -> L (in dbSNP:rs11568705).
FT /FTId=VAR_029122.
FT VARIANT 487 487 G -> E (transport properties comparable
FT to wild-type; dbSNP:rs11568668).
FT /FTId=VAR_029123.
FT VARIANT 498 498 K -> E (in dbSNP:rs11568669).
FT /FTId=VAR_020243.
FT VARIANT 556 556 Y -> C (40% reduced expression level
FT compared to wild-type; higher transport
FT of 9-(2-phosphonyl-methoxyethyl) adenine
FT than wild-type).
FT /FTId=VAR_045684.
FT VARIANT 625 625 I -> M (in dbSNP:rs11568699).
FT /FTId=VAR_029124.
FT VARIANT 667 667 P -> L (in dbSNP:rs11568697).
FT /FTId=VAR_029125.
FT VARIANT 744 744 M -> V (in dbSNP:rs9282570).
FT /FTId=VAR_020244.
FT VARIANT 757 757 E -> K (10% reduced expression level
FT compared to wild-type; transport
FT properties comparable to wild-type;
FT dbSNP:rs3765534).
FT /FTId=VAR_022073.
FT VARIANT 776 776 V -> I (20% reduced expression level
FT compared to wild-type; significant lower
FT activity in 6-mercaptopurine transport
FT than wild-type).
FT /FTId=VAR_045685.
FT VARIANT 820 820 R -> I (transport properties comparable
FT to wild-type; dbSNP:rs11568659).
FT /FTId=VAR_045686.
FT VARIANT 854 854 V -> F (transport properties comparable
FT to wild-type; dbSNP:rs11568694).
FT /FTId=VAR_045687.
FT VARIANT 860 860 V -> M (in dbSNP:rs45477596).
FT /FTId=VAR_020245.
FT VARIANT 866 866 I -> V (transport properties comparable
FT to wild-type; dbSNP:rs139970608).
FT /FTId=VAR_045688.
FT VARIANT 900 900 V -> L (in dbSNP:rs45504892).
FT /FTId=VAR_020246.
FT VARIANT 1142 1142 T -> M (10% reduced expression level
FT compared to wild-type; transport
FT properties comparable to wild-type;
FT dbSNP:rs11568644).
FT /FTId=VAR_029126.
FT CONFLICT 703 703 N -> S (in Ref. 2; AAL88745).
FT CONFLICT 757 757 E -> G (in Ref. 2; AAL88745).
FT CONFLICT 893 893 E -> G (in Ref. 2; AAL88745).
FT CONFLICT 1139 1139 N -> K (in Ref. 1; AAC27076).
FT CONFLICT 1302 1302 H -> D (in Ref. 7; AAB71757).
SQ SEQUENCE 1325 AA; 149527 MW; BF2D53136B78C0BA CRC64;
MLPVYQEVKP NPLQDANLCS RVFFWWLNPL FKIGHKRRLE EDDMYSVLPE DRSQHLGEEL
QGFWDKEVLR AENDAQKPSL TRAIIKCYWK SYLVLGIFTL IEESAKVIQP IFLGKIINYF
ENYDPMDSVA LNTAYAYATV LTFCTLILAI LHHLYFYHVQ CAGMRLRVAM CHMIYRKALR
LSNMAMGKTT TGQIVNLLSN DVNKFDQVTV FLHFLWAGPL QAIAVTALLW MEIGISCLAG
MAVLIILLPL QSCFGKLFSS LRSKTATFTD ARIRTMNEVI TGIRIIKMYA WEKSFSNLIT
NLRKKEISKI LRSSCLRGMN LASFFSASKI IVFVTFTTYV LLGSVITASR VFVAVTLYGA
VRLTVTLFFP SAIERVSEAI VSIRRIQTFL LLDEISQRNR QLPSDGKKMV HVQDFTAFWD
KASETPTLQG LSFTVRPGEL LAVVGPVGAG KSSLLSAVLG ELAPSHGLVS VHGRIAYVSQ
QPWVFSGTLR SNILFGKKYE KERYEKVIKA CALKKDLQLL EDGDLTVIGD RGTTLSGGQK
ARVNLARAVY QDADIYLLDD PLSAVDAEVS RHLFELCICQ ILHEKITILV THQLQYLKAA
SQILILKDGK MVQKGTYTEF LKSGIDFGSL LKKDNEESEQ PPVPGTPTLR NRTFSESSVW
SQQSSRPSLK DGALESQDTE NVPVTLSEEN RSEGKVGFQA YKNYFRAGAH WIVFIFLILL
NTAAQVAYVL QDWWLSYWAN KQSMLNVTVN GGGNVTEKLD LNWYLGIYSG LTVATVLFGI
ARSLLVFYVL VNSSQTLHNK MFESILKAPV LFFDRNPIGR ILNRFSKDIG HLDDLLPLTF
LDFIQTLLQV VGVVSVAVAV IPWIAIPLVP LGIIFIFLRR YFLETSRDVK RLESTTRSPV
FSHLSSSLQG LWTIRAYKAE ERCQELFDAH QDLHSEAWFL FLTTSRWFAV RLDAICAMFV
IIVAFGSLIL AKTLDAGQVG LALSYALTLM GMFQWCVRQS AEVENMMISV ERVIEYTDLE
KEAPWEYQKR PPPAWPHEGV IIFDNVNFMY SPGGPLVLKH LTALIKSQEK VGIVGRTGAG
KSSLISALFR LSEPEGKIWI DKILTTEIGL HDLRKKMSII PQEPVLFTGT MRKNLDPFNE
HTDEELWNAL QEVQLKETIE DLPGKMDTEL AESGSNFSVG QRQLVCLARA ILRKNQILII
DEATANVDPR TDELIQKKIR EKFAHCTVLT IAHRLNTIID SDKIMVLDSG RLKEYDEPYV
LLQNKESLFY KMVQQLGKAE AAALTETAKQ VYFKRNYPHI GHTDHMVTNT SNGQPSTLTI
FETAL
//
ID MRP4_HUMAN Reviewed; 1325 AA.
AC O15439; A9Z1Z7; Q8IVZ4; Q8IZN6; Q8NEW8; Q9Y6J2;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-SEP-2008, sequence version 3.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Multidrug resistance-associated protein 4;
DE AltName: Full=ATP-binding cassette sub-family C member 4;
DE AltName: Full=MRP/cMOAT-related ABC transporter;
DE AltName: Full=Multi-specific organic anion transporter B;
DE Short=MOAT-B;
GN Name=ABCC4; Synonyms=MRP4;
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 1), AND VARIANT ILE-18.
RX PubMed=9661885;
RA Lee K., Belinsky M.G., Bell D.W., Testa J.R., Kruh G.D.;
RT "Isolation of MOAT-B, a widely expressed multidrug resistance-
RT associated protein/canalicular multispecific organic anion
RT transporter-related transporter.";
RL Cancer Res. 58:2741-2747(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ILE-18.
RX PubMed=12105214; DOI=10.1074/jbc.M203262200;
RA Adachi M., Sampath J., Lan L.B., Sun D., Hargrove P., Flatley R.,
RA Tatum A., Edwards M.Z., Wezeman M., Matherly L., Drake R., Schuetz J.;
RT "Expression of MRP4 confers resistance to ganciclovir and compromises
RT bystander cell killing.";
RL J. Biol. Chem. 277:38998-39004(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Kidney;
RA Kato R., Ishikawa T.;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [5]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1155-1316 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=9270026;
RA Kool M., de Haas M., Scheffer G.L., Scheper R.J., van Eijk M.J.,
RA Juijn J.A., Baas F., Borst P.;
RT "Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5,
RT homologues of the multidrug resistance-associated protein gene (MRP1),
RT in human cancer cell lines.";
RL Cancer Res. 57:3537-3547(1997).
RN [8]
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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, 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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, 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 [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-646, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
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 [13]
RP INTERACTION WITH SNX27.
RX PubMed=22411990; DOI=10.1074/jbc.M111.337931;
RA Hayashi H., Naoi S., Nakagawa T., Nishikawa T., Fukuda H.,
RA Imajoh-Ohmi S., Kondo A., Kubo K., Yabuki T., Hattori A., Hirouchi M.,
RA Sugiyama Y.;
RT "Sorting nexin 27 interacts with multidrug resistance-associated
RT protein 4 (MRP4) and mediates internalization of MRP4.";
RL J. Biol. Chem. 287:15054-15065(2012).
RN [14]
RP VARIANTS CYS-556; ILE-776; ILE-820; PHE-854 AND VAL-866, AND
RP CHARACTERIZATION OF VARIANTS TRP-187; ASN-304; GLU-487; CYS-556;
RP LYS-757; ILE-776; ILE-820; PHE-854; VAL-866 AND MET-1142.
RX PubMed=18300232; DOI=10.1002/humu.20694;
RA Janke D., Mehralivand S., Strand D., Goedtel-Armbrust U.,
RA Habermeier A., Gradhand U., Fischer C., Toliat M.R., Fritz P.,
RA Zanger U.M., Schwab M., Fromm M.F., Nuernberg P., Wojnowski L.,
RA Closs E.I., Lang T.;
RT "6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA)
RT transport altered by two missense mutations in the drug transporter
RT gene ABCC4.";
RL Hum. Mutat. 29:659-669(2008).
RN [15]
RP VARIANT LYS-757.
RX PubMed=20547088; DOI=10.1016/j.legalmed.2010.04.001;
RA Yuasa I., Umetsu K., Matsusue A., Nishimukai H., Harihara S.,
RA Fukumori Y., Saitou N., Jin F., Chattopadhyay P.K., Henke L.,
RA Henke J.;
RT "A Japanese-specific allele in the GALNT11 gene.";
RL Leg. Med. 12:208-211(2010).
CC -!- FUNCTION: May be an organic anion pump relevant to cellular
CC detoxification.
CC -!- SUBUNIT: Interacts (via PDZ-binding motif) with SNX27 (via PDZ
CC domain).
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O15439-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15439-2; Sequence=VSP_035426;
CC Name=3;
CC IsoId=O15439-3; Sequence=VSP_043283, VSP_043284;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed, with particularly high
CC levels in prostate, but is barely detectable in liver.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCC
CC family. Conjugate transporter (TC 3.A.1.208) subfamily.
CC -!- SIMILARITY: Contains 2 ABC transmembrane type-1 domains.
CC -!- SIMILARITY: Contains 2 ABC transporter domains.
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC
CC proteins;
CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=O15439";
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DR EMBL; AF071202; AAC27076.1; -; mRNA.
DR EMBL; AY081219; AAL88745.1; -; mRNA.
DR EMBL; AY207008; AAO37649.1; -; mRNA.
DR EMBL; AF541977; AAN17334.1; -; mRNA.
DR EMBL; AL157818; CAC36037.2; -; Genomic_DNA.
DR EMBL; AL139381; CAC36037.2; JOINED; Genomic_DNA.
DR EMBL; AL356257; CAC36037.2; JOINED; Genomic_DNA.
DR EMBL; AL139381; CAI16589.1; -; Genomic_DNA.
DR EMBL; AL157818; CAI16589.1; JOINED; Genomic_DNA.
DR EMBL; AL356257; CAI16589.1; JOINED; Genomic_DNA.
DR EMBL; AL356257; CAI16722.1; -; Genomic_DNA.
DR EMBL; AL139381; CAI16722.1; JOINED; Genomic_DNA.
DR EMBL; AL157818; CAI16722.1; JOINED; Genomic_DNA.
DR EMBL; AL359750; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471085; EAX08951.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX08950.1; -; Genomic_DNA.
DR EMBL; BC041560; AAH41560.1; -; mRNA.
DR EMBL; U83660; AAB71757.1; -; mRNA.
DR RefSeq; NP_001098985.1; NM_001105515.1.
DR RefSeq; NP_005836.2; NM_005845.3.
DR RefSeq; XP_005254083.1; XM_005254026.1.
DR UniGene; Hs.508423; -.
DR ProteinModelPortal; O15439; -.
DR SMR; O15439; 110-650, 743-1290.
DR IntAct; O15439; 1.
DR STRING; 9606.ENSP00000366084; -.
DR ChEMBL; CHEMBL1743128; -.
DR DrugBank; DB01327; Cefazolin.
DR TCDB; 3.A.1.208.7; the atp-binding cassette (abc) superfamily.
DR PhosphoSite; O15439; -.
DR PaxDb; O15439; -.
DR PRIDE; O15439; -.
DR Ensembl; ENST00000376887; ENSP00000366084; ENSG00000125257.
DR Ensembl; ENST00000412704; ENSP00000388657; ENSG00000125257.
DR Ensembl; ENST00000431522; ENSP00000398562; ENSG00000125257.
DR GeneID; 10257; -.
DR KEGG; hsa:10257; -.
DR UCSC; uc001vmd.4; human.
DR CTD; 10257; -.
DR GeneCards; GC13M095672; -.
DR HGNC; HGNC:55; ABCC4.
DR HPA; CAB002751; -.
DR HPA; HPA002476; -.
DR MIM; 605250; gene.
DR neXtProt; NX_O15439; -.
DR PharmGKB; PA397; -.
DR eggNOG; COG1132; -.
DR HOVERGEN; HBG108314; -.
DR InParanoid; O15439; -.
DR KO; K05673; -.
DR OMA; CAMFVII; -.
DR OrthoDB; EOG7MWGW0; -.
DR PhylomeDB; O15439; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR GeneWiki; ABCC4; -.
DR GenomeRNAi; 10257; -.
DR NextBio; 38868; -.
DR PRO; PR:O15439; -.
DR ArrayExpress; O15439; -.
DR Bgee; O15439; -.
DR CleanEx; HS_ABCC4; -.
DR Genevestigator; O15439; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0031088; C:platelet dense granule membrane; IDA:MGI.
DR GO; GO:0016404; F:15-hydroxyprostaglandin dehydrogenase (NAD+) activity; NAS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042626; F:ATPase activity, coupled to transmembrane movement of substances; IEA:InterPro.
DR GO; GO:0006200; P:ATP catabolic process; IEA:GOC.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR003439; ABC_transporter-like.
DR InterPro; IPR017871; ABC_transporter_CS.
DR InterPro; IPR001140; ABC_transptr_TM_dom.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Complete proteome; Glycoprotein;
KW Membrane; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix;
KW Transport.
FT CHAIN 1 1325 Multidrug resistance-associated protein
FT 4.
FT /FTId=PRO_0000093362.
FT TRANSMEM 93 113 Helical; (Potential).
FT TRANSMEM 136 156 Helical; (Potential).
FT TRANSMEM 207 227 Helical; (Potential).
FT TRANSMEM 228 248 Helical; (Potential).
FT TRANSMEM 328 348 Helical; (Potential).
FT TRANSMEM 351 371 Helical; (Potential).
FT TRANSMEM 440 460 Helical; (Potential).
FT TRANSMEM 710 730 Helical; (Potential).
FT TRANSMEM 771 791 Helical; (Potential).
FT TRANSMEM 836 856 Helical; (Potential).
FT TRANSMEM 858 878 Helical; (Potential).
FT TRANSMEM 954 974 Helical; (Potential).
FT TRANSMEM 977 997 Helical; (Potential).
FT TRANSMEM 1038 1058 Helical; (Potential).
FT DOMAIN 92 377 ABC transmembrane type-1 1.
FT DOMAIN 410 633 ABC transporter 1.
FT DOMAIN 714 1005 ABC transmembrane type-1 2.
FT DOMAIN 1041 1274 ABC transporter 2.
FT NP_BIND 445 452 ATP 1 (Potential).
FT NP_BIND 1075 1082 ATP 2 (Potential).
FT MOTIF 1322 1325 PDZ-binding.
FT MOD_RES 646 646 Phosphothreonine.
FT CARBOHYD 651 651 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 690 690 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 746 746 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 754 754 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 792 792 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1176 1176 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1309 1309 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 679 725 Missing (in isoform 2).
FT /FTId=VSP_035426.
FT VAR_SEQ 846 859 TLLQVVGVVSVAVA -> RWDLAVLSWLVSNS (in
FT isoform 3).
FT /FTId=VSP_043283.
FT VAR_SEQ 860 1325 Missing (in isoform 3).
FT /FTId=VSP_043284.
FT VARIANT 18 18 L -> I (in dbSNP:rs11568681).
FT /FTId=VAR_046445.
FT VARIANT 78 78 P -> A (in dbSNP:rs11568689).
FT /FTId=VAR_029121.
FT VARIANT 171 171 C -> G (in dbSNP:rs4148460).
FT /FTId=VAR_046446.
FT VARIANT 184 184 M -> T (in dbSNP:rs45454092).
FT /FTId=VAR_020241.
FT VARIANT 187 187 G -> W (transport properties comparable
FT to wild-type; dbSNP:rs11568658).
FT /FTId=VAR_020242.
FT VARIANT 293 293 K -> E (in dbSNP:rs11568684).
FT /FTId=VAR_046447.
FT VARIANT 304 304 K -> N (transport properties comparable
FT to wild-type; dbSNP:rs2274407).
FT /FTId=VAR_022072.
FT VARIANT 356 356 T -> M (in dbSNP:rs11568701).
FT /FTId=VAR_046448.
FT VARIANT 403 403 P -> L (in dbSNP:rs11568705).
FT /FTId=VAR_029122.
FT VARIANT 487 487 G -> E (transport properties comparable
FT to wild-type; dbSNP:rs11568668).
FT /FTId=VAR_029123.
FT VARIANT 498 498 K -> E (in dbSNP:rs11568669).
FT /FTId=VAR_020243.
FT VARIANT 556 556 Y -> C (40% reduced expression level
FT compared to wild-type; higher transport
FT of 9-(2-phosphonyl-methoxyethyl) adenine
FT than wild-type).
FT /FTId=VAR_045684.
FT VARIANT 625 625 I -> M (in dbSNP:rs11568699).
FT /FTId=VAR_029124.
FT VARIANT 667 667 P -> L (in dbSNP:rs11568697).
FT /FTId=VAR_029125.
FT VARIANT 744 744 M -> V (in dbSNP:rs9282570).
FT /FTId=VAR_020244.
FT VARIANT 757 757 E -> K (10% reduced expression level
FT compared to wild-type; transport
FT properties comparable to wild-type;
FT dbSNP:rs3765534).
FT /FTId=VAR_022073.
FT VARIANT 776 776 V -> I (20% reduced expression level
FT compared to wild-type; significant lower
FT activity in 6-mercaptopurine transport
FT than wild-type).
FT /FTId=VAR_045685.
FT VARIANT 820 820 R -> I (transport properties comparable
FT to wild-type; dbSNP:rs11568659).
FT /FTId=VAR_045686.
FT VARIANT 854 854 V -> F (transport properties comparable
FT to wild-type; dbSNP:rs11568694).
FT /FTId=VAR_045687.
FT VARIANT 860 860 V -> M (in dbSNP:rs45477596).
FT /FTId=VAR_020245.
FT VARIANT 866 866 I -> V (transport properties comparable
FT to wild-type; dbSNP:rs139970608).
FT /FTId=VAR_045688.
FT VARIANT 900 900 V -> L (in dbSNP:rs45504892).
FT /FTId=VAR_020246.
FT VARIANT 1142 1142 T -> M (10% reduced expression level
FT compared to wild-type; transport
FT properties comparable to wild-type;
FT dbSNP:rs11568644).
FT /FTId=VAR_029126.
FT CONFLICT 703 703 N -> S (in Ref. 2; AAL88745).
FT CONFLICT 757 757 E -> G (in Ref. 2; AAL88745).
FT CONFLICT 893 893 E -> G (in Ref. 2; AAL88745).
FT CONFLICT 1139 1139 N -> K (in Ref. 1; AAC27076).
FT CONFLICT 1302 1302 H -> D (in Ref. 7; AAB71757).
SQ SEQUENCE 1325 AA; 149527 MW; BF2D53136B78C0BA CRC64;
MLPVYQEVKP NPLQDANLCS RVFFWWLNPL FKIGHKRRLE EDDMYSVLPE DRSQHLGEEL
QGFWDKEVLR AENDAQKPSL TRAIIKCYWK SYLVLGIFTL IEESAKVIQP IFLGKIINYF
ENYDPMDSVA LNTAYAYATV LTFCTLILAI LHHLYFYHVQ CAGMRLRVAM CHMIYRKALR
LSNMAMGKTT TGQIVNLLSN DVNKFDQVTV FLHFLWAGPL QAIAVTALLW MEIGISCLAG
MAVLIILLPL QSCFGKLFSS LRSKTATFTD ARIRTMNEVI TGIRIIKMYA WEKSFSNLIT
NLRKKEISKI LRSSCLRGMN LASFFSASKI IVFVTFTTYV LLGSVITASR VFVAVTLYGA
VRLTVTLFFP SAIERVSEAI VSIRRIQTFL LLDEISQRNR QLPSDGKKMV HVQDFTAFWD
KASETPTLQG LSFTVRPGEL LAVVGPVGAG KSSLLSAVLG ELAPSHGLVS VHGRIAYVSQ
QPWVFSGTLR SNILFGKKYE KERYEKVIKA CALKKDLQLL EDGDLTVIGD RGTTLSGGQK
ARVNLARAVY QDADIYLLDD PLSAVDAEVS RHLFELCICQ ILHEKITILV THQLQYLKAA
SQILILKDGK MVQKGTYTEF LKSGIDFGSL LKKDNEESEQ PPVPGTPTLR NRTFSESSVW
SQQSSRPSLK DGALESQDTE NVPVTLSEEN RSEGKVGFQA YKNYFRAGAH WIVFIFLILL
NTAAQVAYVL QDWWLSYWAN KQSMLNVTVN GGGNVTEKLD LNWYLGIYSG LTVATVLFGI
ARSLLVFYVL VNSSQTLHNK MFESILKAPV LFFDRNPIGR ILNRFSKDIG HLDDLLPLTF
LDFIQTLLQV VGVVSVAVAV IPWIAIPLVP LGIIFIFLRR YFLETSRDVK RLESTTRSPV
FSHLSSSLQG LWTIRAYKAE ERCQELFDAH QDLHSEAWFL FLTTSRWFAV RLDAICAMFV
IIVAFGSLIL AKTLDAGQVG LALSYALTLM GMFQWCVRQS AEVENMMISV ERVIEYTDLE
KEAPWEYQKR PPPAWPHEGV IIFDNVNFMY SPGGPLVLKH LTALIKSQEK VGIVGRTGAG
KSSLISALFR LSEPEGKIWI DKILTTEIGL HDLRKKMSII PQEPVLFTGT MRKNLDPFNE
HTDEELWNAL QEVQLKETIE DLPGKMDTEL AESGSNFSVG QRQLVCLARA ILRKNQILII
DEATANVDPR TDELIQKKIR EKFAHCTVLT IAHRLNTIID SDKIMVLDSG RLKEYDEPYV
LLQNKESLFY KMVQQLGKAE AAALTETAKQ VYFKRNYPHI GHTDHMVTNT SNGQPSTLTI
FETAL
//
MIM
605250
*RECORD*
*FIELD* NO
605250
*FIELD* TI
*605250 ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 4; ABCC4
;;MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 4; MRP4;;
read moreMULTISPECIFIC ORGANIC ANION TRANSPORTER B; MOATB
*FIELD* TX
DESCRIPTION
ABCC4, also known as MRP4, belongs to a large family of transmembrane
proteins involved in active transport of substrates out of cells. ABCC4
acts as an independent regulator of intracellular cyclic nucleotide
levels and as a mediator of cAMP-dependent signal transduction to the
nucleus (Sassi et al., 2008).
CLONING
By EST database searching with N-terminal PGY1 (ABCB1; 171050) and CFTR
(602421) as probes, Allikmets et al. (1996) isolated 21 cDNAs, including
a cDNA encoding a 65-amino acid fragment of ABCC4. Using a similar
strategy with C-terminal MRP1 (ABCC1; 158343) and CMOAT (ABCC2; 601107)
as probes, Kool et al. (1997) obtained cDNAs encoding the C-terminal
portion of MRP3 (ABCC3; 604323), ABCC4, and MRP5 (ABCC5; 605251). By
degenerative PCR based on the N-terminal sequences of MRP1, followed by
plaque hybridization of breast and ovarian bacteriophage libraries, Lee
et al. (1998) obtained a cDNA encoding ABCC4, which they termed MOATB.
Sequence analysis predicted that the 1,325-amino acid protein, like
other ABC transporters, contains nucleotide-binding folds and 12
transmembrane-spanning helices in 2 hydrophobic domains. Northern blot
analysis revealed ubiquitous expression of an approximately 6.0-kb
transcript that is highest in prostate and lowest in liver and
peripheral blood leukocytes (Lee et al., 1998). RNase protection
analysis showed only low level expression in a few tissues (Kool et al.,
1997). Unlike ABCC2, which is overexpressed in several
multidrug-resistant cell lines, ABCC3 and ABCC5 are overexpressed in
only a few such cell lines, and ABCC4 is overexpressed in none (Kool et
al., 1997).
Lamba et al. (2003) isolated an ABCC4 cDNA encoding a nonfunctional
protein due to an insertion. The insertion was attributed to 2
additional exons, designated 1a and 1b, that produced premature
termination codons (PTCs). A comparison of human, monkey, and rodent
ABCC4 genes revealed that these same PTC-producing exons were also
highly conserved in evolution. In vitro inhibition of protein synthesis
(using puromycin or anisomycin) selectively reduced nonsense-mediated
mRNA decay of PTC-containing ABCC4 transcripts in all cell lines tested.
Lamba et al. (2003) concluded that the highly conserved PTC-containing
exons of the ABCC4 gene may dictate its expression.
GENE FUNCTION
Schuetz et al. (1999) found that MRP4 confers resistance to acyclic
nucleoside monophosphates, such as 9-(2-phosphonylmethoxyethyl)guanine
(PMEG), and to the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine
(PMEA).
Chen and Klaassen (2004) found that expression of rat Mrp4 mRNA in liver
or kidney was not readily induced by several classes of prototypical
microsomal enzyme inducers. However, it was induced by a limited number
of electrophile response element activators.
Sassi et al. (2008) found that expression of MRP4, but not MRP5, was
upregulated during proliferation of isolated human coronary artery
smooth muscle cells and following injury of rat carotid arteries in
vivo. MRP4 inhibition significantly increased intracellular cAMP and
cGMP levels and was sufficient to block proliferation and to prevent
neointimal growth in injured rat carotid arteries. The antiproliferative
effect of MRP4 inhibition was related to cAMP-dependent PKA (see 176911)
activation and CREB (123810) phosphorylation. Sassi et al. (2008)
concluded that MRP4 regulates intracellular cyclic nucleotide levels and
mediates cAMP-dependent signal transduction.
The capacity of dendritic cells (DCs) to migrate from peripheral organs
to lymph nodes is important in the initiation of a T cell-mediated
immune response. By immunohistochemical analysis of human skin biopsies,
van de Ven et al. (2008) showed that epidermal and dermal DCs expressed
MRP4. Using cultured human DC lines and human skin explants, they showed
that MRP4 contributed to the migratory capacity of DCs. Pharmacologic
inhibition of MRP4 activity or knockdown of MRP4 via RNA interference
resulted in reduced migration of DCs from human skin explants and of in
vitro-generated Langerhans cells. Van de Ven et al. (2008) concluded
that MRP4 contributes to migration of DCs toward draining lymph nodes
and therefore has a role in the initiation of an immune response.
MAPPING
By radiation hybrid analysis, Kool et al. (1997) mapped the ABCC4 gene
to chromosome 13. Using FISH, Lee et al. (1998) refined the localization
to chromosome 13q32.
*FIELD* RF
1. Allikmets, R.; Gerrard, B.; Hutchinson, A.; Dean, M.: Characterization
of the human ABC superfamily: isolation and mapping of 21 new genes
using the expressed sequence tags database. Hum. Molec. Genet. 5:
1649-1655, 1996.
2. Chen, C.; Klaassen, C. D.: Rat multidrug resistance protein 4
(Mrp4, Abcc4): molecular cloning, organ distribution, postnatal renal
expression, and chemical inducibility. Biochem. Biophys. Res. Commun. 317:
46-53, 2004.
3. Kool, M.; de Haas, M.; Scheffer, G. L.; Scheper, R. J.; van Eijk,
M. J.; Juijn, J. A.; Baas, F.; Borst, P.: Analysis of expression
of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug
resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer
Res. 57: 3537-3547, 1997.
4. Lamba, J. K.; Adachi, M.; Sun, D.; Tammur, J.; Schuetz, E. G.;
Allikmets, R.; Schuetz, J. D.: Nonsense mediated decay downregulates
conserved alternatively spliced ABCC4 transcripts bearing nonsense
codons. Hum. Molec. Genet. 12: 99-109, 2003.
5. Lee, K.; Belinsky, M. G.; Bell, D. W.; Testa, J. R.; Kruh, G. D.
: Isolation of MOAT-B, a widely expressed multidrug resistance-associated
protein/canalicular multispecific organic anion transporter-related
transporter. Cancer Res. 58: 2741-2747, 1998.
6. Sassi, Y.; Lipskaia, L.; Vandecasteele, G.; Nikolaev, V. O.; Hatem,
S. N.; Aubart, F. C.; Russel, F. G.; Mougenot, N.; Vrignaud, C.; Lechat,
P.; Lompre, A.-M.; Hulot, J.-S.: Multidrug resistance-associated
protein 4 regulates cAMP-dependent signaling pathways and controls
human and rat SMC proliferation. J. Clin. Invest. 118: 2747-2757,
2008.
7. Schuetz, J. D.; Connelly, M. C.; Sun, D.; Paibir, S. G.; Flynn,
P. M.; Srinivas, R. V.; Kumar, A.; Fridland, A.: MRP4: a previously
unidentified factor in resistance to nucleoside-based antiviral drugs. Nature
Med. 5: 1048-1051, 1999.
8. van de Ven, R.; Scheffer, G. L.; Reurs, A. W.; Lindenberg, J. J.;
Oerlemans, R.; Jansen, G.; Gillet, J.-P.; Glasgow, J. N.; Pereboev,
A.; Curiel, D. T.; Scheper, R. J.; de Gruijl, T. D.: A role for multidrug
resistance protein 4 (MRP4;ABCC4) in human dendritic cell migration. Blood 112:
2353-2359, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 10/29/2009
Patricia A. Hartz - updated: 3/23/2009
George E. Tiller - updated: 10/26/2004
Victor A. McKusick - updated: 9/1/2000
*FIELD* CD
Paul J. Converse: 8/31/2000
*FIELD* ED
mgross: 11/05/2009
terry: 10/29/2009
mgross: 3/24/2009
terry: 3/23/2009
tkritzer: 11/2/2004
terry: 10/26/2004
carol: 9/1/2000
*RECORD*
*FIELD* NO
605250
*FIELD* TI
*605250 ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 4; ABCC4
;;MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 4; MRP4;;
read moreMULTISPECIFIC ORGANIC ANION TRANSPORTER B; MOATB
*FIELD* TX
DESCRIPTION
ABCC4, also known as MRP4, belongs to a large family of transmembrane
proteins involved in active transport of substrates out of cells. ABCC4
acts as an independent regulator of intracellular cyclic nucleotide
levels and as a mediator of cAMP-dependent signal transduction to the
nucleus (Sassi et al., 2008).
CLONING
By EST database searching with N-terminal PGY1 (ABCB1; 171050) and CFTR
(602421) as probes, Allikmets et al. (1996) isolated 21 cDNAs, including
a cDNA encoding a 65-amino acid fragment of ABCC4. Using a similar
strategy with C-terminal MRP1 (ABCC1; 158343) and CMOAT (ABCC2; 601107)
as probes, Kool et al. (1997) obtained cDNAs encoding the C-terminal
portion of MRP3 (ABCC3; 604323), ABCC4, and MRP5 (ABCC5; 605251). By
degenerative PCR based on the N-terminal sequences of MRP1, followed by
plaque hybridization of breast and ovarian bacteriophage libraries, Lee
et al. (1998) obtained a cDNA encoding ABCC4, which they termed MOATB.
Sequence analysis predicted that the 1,325-amino acid protein, like
other ABC transporters, contains nucleotide-binding folds and 12
transmembrane-spanning helices in 2 hydrophobic domains. Northern blot
analysis revealed ubiquitous expression of an approximately 6.0-kb
transcript that is highest in prostate and lowest in liver and
peripheral blood leukocytes (Lee et al., 1998). RNase protection
analysis showed only low level expression in a few tissues (Kool et al.,
1997). Unlike ABCC2, which is overexpressed in several
multidrug-resistant cell lines, ABCC3 and ABCC5 are overexpressed in
only a few such cell lines, and ABCC4 is overexpressed in none (Kool et
al., 1997).
Lamba et al. (2003) isolated an ABCC4 cDNA encoding a nonfunctional
protein due to an insertion. The insertion was attributed to 2
additional exons, designated 1a and 1b, that produced premature
termination codons (PTCs). A comparison of human, monkey, and rodent
ABCC4 genes revealed that these same PTC-producing exons were also
highly conserved in evolution. In vitro inhibition of protein synthesis
(using puromycin or anisomycin) selectively reduced nonsense-mediated
mRNA decay of PTC-containing ABCC4 transcripts in all cell lines tested.
Lamba et al. (2003) concluded that the highly conserved PTC-containing
exons of the ABCC4 gene may dictate its expression.
GENE FUNCTION
Schuetz et al. (1999) found that MRP4 confers resistance to acyclic
nucleoside monophosphates, such as 9-(2-phosphonylmethoxyethyl)guanine
(PMEG), and to the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine
(PMEA).
Chen and Klaassen (2004) found that expression of rat Mrp4 mRNA in liver
or kidney was not readily induced by several classes of prototypical
microsomal enzyme inducers. However, it was induced by a limited number
of electrophile response element activators.
Sassi et al. (2008) found that expression of MRP4, but not MRP5, was
upregulated during proliferation of isolated human coronary artery
smooth muscle cells and following injury of rat carotid arteries in
vivo. MRP4 inhibition significantly increased intracellular cAMP and
cGMP levels and was sufficient to block proliferation and to prevent
neointimal growth in injured rat carotid arteries. The antiproliferative
effect of MRP4 inhibition was related to cAMP-dependent PKA (see 176911)
activation and CREB (123810) phosphorylation. Sassi et al. (2008)
concluded that MRP4 regulates intracellular cyclic nucleotide levels and
mediates cAMP-dependent signal transduction.
The capacity of dendritic cells (DCs) to migrate from peripheral organs
to lymph nodes is important in the initiation of a T cell-mediated
immune response. By immunohistochemical analysis of human skin biopsies,
van de Ven et al. (2008) showed that epidermal and dermal DCs expressed
MRP4. Using cultured human DC lines and human skin explants, they showed
that MRP4 contributed to the migratory capacity of DCs. Pharmacologic
inhibition of MRP4 activity or knockdown of MRP4 via RNA interference
resulted in reduced migration of DCs from human skin explants and of in
vitro-generated Langerhans cells. Van de Ven et al. (2008) concluded
that MRP4 contributes to migration of DCs toward draining lymph nodes
and therefore has a role in the initiation of an immune response.
MAPPING
By radiation hybrid analysis, Kool et al. (1997) mapped the ABCC4 gene
to chromosome 13. Using FISH, Lee et al. (1998) refined the localization
to chromosome 13q32.
*FIELD* RF
1. Allikmets, R.; Gerrard, B.; Hutchinson, A.; Dean, M.: Characterization
of the human ABC superfamily: isolation and mapping of 21 new genes
using the expressed sequence tags database. Hum. Molec. Genet. 5:
1649-1655, 1996.
2. Chen, C.; Klaassen, C. D.: Rat multidrug resistance protein 4
(Mrp4, Abcc4): molecular cloning, organ distribution, postnatal renal
expression, and chemical inducibility. Biochem. Biophys. Res. Commun. 317:
46-53, 2004.
3. Kool, M.; de Haas, M.; Scheffer, G. L.; Scheper, R. J.; van Eijk,
M. J.; Juijn, J. A.; Baas, F.; Borst, P.: Analysis of expression
of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug
resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer
Res. 57: 3537-3547, 1997.
4. Lamba, J. K.; Adachi, M.; Sun, D.; Tammur, J.; Schuetz, E. G.;
Allikmets, R.; Schuetz, J. D.: Nonsense mediated decay downregulates
conserved alternatively spliced ABCC4 transcripts bearing nonsense
codons. Hum. Molec. Genet. 12: 99-109, 2003.
5. Lee, K.; Belinsky, M. G.; Bell, D. W.; Testa, J. R.; Kruh, G. D.
: Isolation of MOAT-B, a widely expressed multidrug resistance-associated
protein/canalicular multispecific organic anion transporter-related
transporter. Cancer Res. 58: 2741-2747, 1998.
6. Sassi, Y.; Lipskaia, L.; Vandecasteele, G.; Nikolaev, V. O.; Hatem,
S. N.; Aubart, F. C.; Russel, F. G.; Mougenot, N.; Vrignaud, C.; Lechat,
P.; Lompre, A.-M.; Hulot, J.-S.: Multidrug resistance-associated
protein 4 regulates cAMP-dependent signaling pathways and controls
human and rat SMC proliferation. J. Clin. Invest. 118: 2747-2757,
2008.
7. Schuetz, J. D.; Connelly, M. C.; Sun, D.; Paibir, S. G.; Flynn,
P. M.; Srinivas, R. V.; Kumar, A.; Fridland, A.: MRP4: a previously
unidentified factor in resistance to nucleoside-based antiviral drugs. Nature
Med. 5: 1048-1051, 1999.
8. van de Ven, R.; Scheffer, G. L.; Reurs, A. W.; Lindenberg, J. J.;
Oerlemans, R.; Jansen, G.; Gillet, J.-P.; Glasgow, J. N.; Pereboev,
A.; Curiel, D. T.; Scheper, R. J.; de Gruijl, T. D.: A role for multidrug
resistance protein 4 (MRP4;ABCC4) in human dendritic cell migration. Blood 112:
2353-2359, 2008.
*FIELD* CN
Patricia A. Hartz - updated: 10/29/2009
Patricia A. Hartz - updated: 3/23/2009
George E. Tiller - updated: 10/26/2004
Victor A. McKusick - updated: 9/1/2000
*FIELD* CD
Paul J. Converse: 8/31/2000
*FIELD* ED
mgross: 11/05/2009
terry: 10/29/2009
mgross: 3/24/2009
terry: 3/23/2009
tkritzer: 11/2/2004
terry: 10/26/2004
carol: 9/1/2000