Full text data of STEAP3
STEAP3
(TSAP6)
[Confidence: low (only semi-automatic identification from reviews)]
Metalloreductase STEAP3; 1.16.1.- (Dudulin-2; Six-transmembrane epithelial antigen of prostate 3; Tumor suppressor-activated pathway protein 6; hTSAP6; pHyde; hpHyde)
Metalloreductase STEAP3; 1.16.1.- (Dudulin-2; Six-transmembrane epithelial antigen of prostate 3; Tumor suppressor-activated pathway protein 6; hTSAP6; pHyde; hpHyde)
UniProt
Q658P3
ID STEA3_HUMAN Reviewed; 488 AA.
AC Q658P3; A8K6E3; Q4VBR2; Q4ZG36; Q53SQ8; Q7Z389; Q86SF6; Q8NEW6;
read moreAC Q8TDP3; Q8TF03; Q9NVB5;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 2.
DT 22-JAN-2014, entry version 93.
DE RecName: Full=Metalloreductase STEAP3;
DE EC=1.16.1.-;
DE AltName: Full=Dudulin-2;
DE AltName: Full=Six-transmembrane epithelial antigen of prostate 3;
DE AltName: Full=Tumor suppressor-activated pathway protein 6;
DE Short=hTSAP6;
DE AltName: Full=pHyde;
DE Short=hpHyde;
GN Name=STEAP3; Synonyms=TSAP6;
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), TISSUE SPECIFICITY, INDUCTION,
RP AND INTERACTION WITH BNIP3L AND MYT1.
RX PubMed=12606722; DOI=10.1073/pnas.0530298100;
RA Passer B.J., Nancy-Portebois V., Amzallag N., Prieur S., Cans C.,
RA Roborel de Climens A., Fiucci G., Bouvard V., Tuynder M., Susini L.,
RA Morchoisne S., Crible V., Lespagnol A., Dausset J., Oren M., Amson R.,
RA Telerman A.;
RT "The p53-inducible TSAP6 gene product regulates apoptosis and the cell
RT cycle and interacts with Nix and the Myt1 kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:2284-2289(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=15897894; DOI=10.1038/sj.onc.1208677;
RA Korkmaz C.G., Korkmaz K.S., Kurys P., Elbi C., Wang L., Klokk T.I.,
RA Hammarstrom C., Troen G., Svindland A., Hager G.L., Saatcioglu F.;
RT "Molecular cloning and characterization of STAMP2, an androgen-
RT regulated six transmembrane protein that is overexpressed in prostate
RT cancer.";
RL Oncogene 24:4934-4945(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
RX PubMed=10969787;
RA Steiner M.S., Zhang X., Wang Y., Lu Y.;
RT "Growth inhibition of prostate cancer by an adenovirus expressing a
RT novel tumor suppressor gene, pHyde.";
RL Cancer Res. 60:4419-4425(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Serru V., Manivet P., Lenoir C., Eschwege P., Lamblin D.,
RA Vaubourdolle M., Kellermann O., Loric S.;
RT "Dudulin 2, a new tumor antigen expressed in various human tumors.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Lu Y., Beheshti B., Squire J.A., Yang X.J.;
RT "Characterization of a novel apoptosis-inducing gene, hpHyde, that
RT inhibits prostate cancer cell growth.";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon endothelium, and Endometrial adenocarcinoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
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 [11]
RP LACK OF TUMOR SUPPRESSOR FUNCTION.
RX PubMed=12866033; DOI=10.1002/ijc.11278;
RA Porkka K.P., Nupponen N.N., Tammela T.L., Vessella R.L., Visakorpi T.;
RT "Human pHyde is not a classical tumor suppressor gene in prostate
RT cancer.";
RL Int. J. Cancer 106:729-735(2003).
RN [12]
RP FUNCTION, AND INTERACTION WITH TCTP.
RX PubMed=15319436; DOI=10.1074/jbc.M404850200;
RA Amzallag N., Passer B.J., Allanic D., Segura E., Thery C., Goud B.,
RA Amson R., Telerman A.;
RT "TSAP6 facilitates the secretion of translationally controlled tumor
RT protein/histamine-releasing factor via a nonclassical pathway.";
RL J. Biol. Chem. 279:46104-46112(2004).
RN [13]
RP TISSUE SPECIFICITY.
RX PubMed=15885357; DOI=10.1016/j.jhep.2005.01.027;
RA Coulouarn C., Derambure C., Lefebvre G., Daveau R., Hiron M.,
RA Scotte M., Francois A., Daveau M., Salier J.-P.;
RT "Global gene repression in hepatocellular carcinoma and fetal liver,
RT and suppression of dudulin-2 mRNA as a possible marker for the
RT cirrhosis-to-tumor transition.";
RL J. Hepatol. 42:860-869(2005).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=16227996; DOI=10.1038/ng1658;
RA Ohgami R.S., Campagna D.R., Greer E.L., Antiochos B., McDonald A.,
RA Chen J., Sharp J.J., Fujiwara Y., Barker J.E., Fleming M.D.;
RT "Identification of a ferrireductase required for efficient
RT transferrin-dependent iron uptake in erythroid cells.";
RL Nat. Genet. 37:1264-1269(2005).
RN [15]
RP FUNCTION.
RX PubMed=16651434; DOI=10.1158/0008-5472.CAN-05-4579;
RA Yu X., Harris S.L., Levine A.J.;
RT "The regulation of exosome secretion: a novel function of the p53
RT protein.";
RL Cancer Res. 66:4795-4801(2006).
RN [16]
RP INVOLVEMENT IN AHMIO2.
RX PubMed=22031863; DOI=10.1182/blood-2011-01-329011;
RA Grandchamp B., Hetet G., Kannengiesser C., Oudin C., Beaumont C.,
RA Rodrigues-Ferreira S., Amson R., Telerman A., Nielsen P., Kohne E.,
RA Balser C., Heimpel H.;
RT "A novel type of congenital hypochromic anemia associated with a
RT nonsense mutation in the STEAP3/TSAP6 gene.";
RL Blood 118:6660-6666(2011).
RN [17]
RP CLEAVAGE BY RHBDD1, INTERACTION WITH RHBDD1, GLYCOSYLATION AT ASN-256
RP AND ASN-344, AND MUTAGENESIS OF ASN-256; LEU-325 AND ASN-344.
RX PubMed=22624035; DOI=10.1371/journal.pone.0037452;
RA Wan C., Fu J., Wang Y., Miao S., Song W., Wang L.;
RT "Exosome-related multi-pass transmembrane protein TSAP6 is a target of
RT rhomboid protease RHBDD1-induced proteolysis.";
RL PLoS ONE 7:E37452-E37452(2012).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-215 ALONE AND IN COMPLEX
RP WITH NADPH, COFACTOR, AND SUBUNIT.
RX PubMed=18495927; DOI=10.1073/pnas.0801318105;
RA Sendamarai A.K., Ohgami R.S., Fleming M.D., Lawrence C.M.;
RT "Structure of the membrane proximal oxidoreductase domain of human
RT Steap3, the dominant ferrireductase of the erythroid transferrin
RT cycle.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:7410-7415(2008).
CC -!- FUNCTION: Endosomal ferrireductase required for efficient
CC transferrin-dependent iron uptake in erythroid cells. Participates
CC in erythroid iron homeostasis by reducing Fe(3+) to Fe(2+). Can
CC also reduce of Cu(2+) to Cu(1+), suggesting that it participates
CC in copper homeostasis. Uses NADP(+) as acceptor. May play a role
CC downstream of p53/TP53 to interface apoptosis and cell cycle
CC progression. Indirectly involved in exosome secretion by
CC facilitating the secretion of proteins such as TCTP.
CC -!- COFACTOR: FAD (By similarity).
CC -!- COFACTOR: NADP.
CC -!- SUBUNIT: Homodimer. Interacts with BNIP3L, MYT1, RHBDL4/RHBDD1 and
CC TCTP.
CC -!- SUBCELLULAR LOCATION: Endosome membrane; Multi-pass membrane
CC protein (By similarity). Note=Localizes to vesicular-like
CC structures at the plasma membrane and around the nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q658P3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q658P3-2; Sequence=VSP_024829;
CC Name=3;
CC IsoId=Q658P3-3; Sequence=VSP_024830;
CC Name=4; Synonyms=pHyde II;
CC IsoId=Q658P3-4; Sequence=VSP_024830, VSP_024831;
CC -!- TISSUE SPECIFICITY: Expressed in adult bone marrow, placenta,
CC liver, skeletal muscle and pancreas. Down-regulated in
CC hepatocellular carcinoma.
CC -!- INDUCTION: By p53/TP53.
CC -!- PTM: Proteolytically cleaved by RHBDL4/RHBDD1. RHBDL4/RHBDD1-
CC induced cleavage occurs at multiple sites in a glycosylation-
CC independent manner.
CC -!- PTM: Glycosylated.
CC -!- DISEASE: Anemia, hypochromic microcytic, with iron overload 2
CC (AHMIO2) [MIM:615234]: A hematologic disease characterized by
CC abnormal hemoglobin content in the erythrocytes which are reduced
CC in size, severe anemia, erythropoietic hyperplasia of bone marrow,
CC massive hepatic iron deposition, and hepatosplenomegaly. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the STEAP family.
CC -!- SIMILARITY: Contains 1 ferric oxidoreductase domain.
CC -!- CAUTION: Was initially thought to have tumor suppressor function
CC in prostate cancer. However, it was shown that it is probably not
CC the case (PubMed:12866033).
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DR EMBL; AY214461; AAO38238.1; -; mRNA.
DR EMBL; AF423424; AAQ04065.1; -; mRNA.
DR EMBL; AF238864; AAL78206.1; -; mRNA.
DR EMBL; AF262322; AAM08128.1; -; mRNA.
DR EMBL; AY029585; AAK50538.1; -; mRNA.
DR EMBL; AY082673; AAM45136.1; -; mRNA.
DR EMBL; AK001691; BAA91839.1; -; mRNA.
DR EMBL; AK291608; BAF84297.1; -; mRNA.
DR EMBL; AL833624; CAH56204.1; -; mRNA.
DR EMBL; BX538047; CAD97986.1; -; mRNA.
DR EMBL; AC016673; AAX88963.1; -; Genomic_DNA.
DR EMBL; AC016736; AAY14872.1; -; Genomic_DNA.
DR EMBL; CH471103; EAW95209.1; -; Genomic_DNA.
DR EMBL; BC042150; AAH42150.1; -; mRNA.
DR EMBL; BC095421; AAH95421.2; -; mRNA.
DR RefSeq; NP_001008410.1; NM_001008410.1.
DR RefSeq; NP_060704.2; NM_018234.2.
DR RefSeq; NP_878919.2; NM_182915.2.
DR UniGene; Hs.647822; -.
DR PDB; 2VNS; X-ray; 2.00 A; A/B=1-215.
DR PDB; 2VQ3; X-ray; 2.00 A; A/B=1-215.
DR PDBsum; 2VNS; -.
DR PDBsum; 2VQ3; -.
DR ProteinModelPortal; Q658P3; -.
DR SMR; Q658P3; 29-209.
DR IntAct; Q658P3; 2.
DR TCDB; 9.B.66.1.1; the animal nonclassical protein secretion (nps) family.
DR PhosphoSite; Q658P3; -.
DR DMDM; 146325737; -.
DR PaxDb; Q658P3; -.
DR PRIDE; Q658P3; -.
DR DNASU; 55240; -.
DR Ensembl; ENST00000354888; ENSP00000346961; ENSG00000115107.
DR Ensembl; ENST00000393106; ENSP00000376818; ENSG00000115107.
DR Ensembl; ENST00000393107; ENSP00000376819; ENSG00000115107.
DR Ensembl; ENST00000393108; ENSP00000376820; ENSG00000115107.
DR Ensembl; ENST00000393110; ENSP00000376822; ENSG00000115107.
DR Ensembl; ENST00000425223; ENSP00000396214; ENSG00000115107.
DR GeneID; 55240; -.
DR KEGG; hsa:55240; -.
DR UCSC; uc002tlp.3; human.
DR CTD; 55240; -.
DR GeneCards; GC02P119981; -.
DR HGNC; HGNC:24592; STEAP3.
DR HPA; HPA050510; -.
DR MIM; 609671; gene.
DR MIM; 615234; phenotype.
DR neXtProt; NX_Q658P3; -.
DR Orphanet; 300298; Severe congenital hypochromic anemia with ringed sideroblasts.
DR PharmGKB; PA142670863; -.
DR eggNOG; COG2085; -.
DR HOVERGEN; HBG054379; -.
DR InParanoid; Q658P3; -.
DR KO; K10142; -.
DR OMA; GWKVPAL; -.
DR OrthoDB; EOG7Z0JWH; -.
DR PhylomeDB; Q658P3; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; STEAP3; human.
DR EvolutionaryTrace; Q658P3; -.
DR GeneWiki; STEAP3; -.
DR GenomeRNAi; 55240; -.
DR NextBio; 59270; -.
DR PRO; PR:Q658P3; -.
DR ArrayExpress; Q658P3; -.
DR Bgee; Q658P3; -.
DR Genevestigator; Q658P3; -.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005771; C:multivesicular body; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0000293; F:ferric-chelate reductase activity; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0009306; P:protein secretion; IMP:UniProtKB.
DR GO; GO:0033572; P:transferrin transport; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR013130; Fe3_Rdtase_TM_dom.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR Pfam; PF01794; Ferric_reduct; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Cell cycle;
KW Complete proteome; Copper; Endosome; FAD; Flavoprotein; Glycoprotein;
KW Ion transport; Iron; Iron transport; Membrane; Metal-binding; NADP;
KW Oxidoreductase; Phosphoprotein; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 488 Metalloreductase STEAP3.
FT /FTId=PRO_0000285171.
FT TOPO_DOM 1 207 Cytoplasmic (Potential).
FT TRANSMEM 208 228 Helical; (Potential).
FT TOPO_DOM 229 258 Vesicular (Potential).
FT TRANSMEM 259 279 Helical; (Potential).
FT TOPO_DOM 280 304 Cytoplasmic (Potential).
FT TRANSMEM 305 325 Helical; (Potential).
FT TOPO_DOM 326 358 Vesicular (Potential).
FT TRANSMEM 359 379 Helical; (Potential).
FT TOPO_DOM 380 390 Cytoplasmic (Potential).
FT TRANSMEM 391 411 Helical; (Potential).
FT TOPO_DOM 412 433 Vesicular (Potential).
FT TRANSMEM 434 454 Helical; (Potential).
FT TOPO_DOM 455 488 Cytoplasmic (Potential).
FT DOMAIN 259 407 Ferric oxidoreductase.
FT METAL 316 316 Iron (heme axial ligand) (Probable).
FT METAL 409 409 Iron (heme axial ligand) (Probable).
FT BINDING 36 36 NADP.
FT BINDING 38 38 NADP; via amide nitrogen.
FT BINDING 39 39 NADP; via amide nitrogen.
FT BINDING 58 58 NADP.
FT BINDING 59 59 NADP.
FT BINDING 91 91 NADP; via carbonyl oxygen.
FT BINDING 116 116 NADP; via amide nitrogen.
FT BINDING 151 151 NADP; via amide nitrogen.
FT SITE 325 326 Cleavage; by RHBDL4/RHBDD1 (Probable).
FT MOD_RES 17 17 Phosphoserine (By similarity).
FT MOD_RES 20 20 Phosphoserine (By similarity).
FT CARBOHYD 256 256 N-linked (GlcNAc...) (Probable).
FT CARBOHYD 344 344 N-linked (GlcNAc...) (Probable).
FT VAR_SEQ 1 1 M -> MSHQPAVATKM (in isoform 2).
FT /FTId=VSP_024829.
FT VAR_SEQ 351 351 Missing (in isoform 3 and isoform 4).
FT /FTId=VSP_024830.
FT VAR_SEQ 396 488 SSLGFVALVLSTLHTLTYGWTRAFEESRYKFYLPPTFTLTL
FT LVPCVVILAKALFLLPCISRRLARIRRGWERESTIKFTLPT
FT DHALAEKTSHV -> CVATSSAGNTGSGTRRPESQSQDPHL
FT PAPHHQTSFLGPRSFCCSLVPVSTPYGHQEDLSWTR (in
FT isoform 4).
FT /FTId=VSP_024831.
FT VARIANT 184 184 A -> T (in dbSNP:rs17013371).
FT /FTId=VAR_031975.
FT MUTAGEN 256 256 N->I: Inhibits glycosylation and does not
FT inhibit RHBDL4/RHBDD1-induced cleavage;
FT when associated with A-344.
FT MUTAGEN 325 325 L->F: Strongly inhibits RHBDL4/RHBDD1-
FT induced cleavage.
FT MUTAGEN 344 344 N->I: Inhibits glycosylation and does not
FT inhibit RHBDL4/RHBDD1-induced cleavage;
FT when associated with A-256.
FT CONFLICT 32 32 G -> S (in Ref. 3; AAL78206/AAM08128 and
FT 6; AAM45136).
FT CONFLICT 68 68 F -> Y (in Ref. 4; AAK50538 and 7;
FT BAA91839).
FT CONFLICT 163 163 R -> G (in Ref. 3; AAL78206/AAM08128).
FT CONFLICT 478 478 D -> G (in Ref. 8; CAD97986).
FT STRAND 31 34
FT HELIX 38 49
FT STRAND 54 60
FT HELIX 61 67
FT STRAND 72 76
FT HELIX 77 80
FT STRAND 85 89
FT HELIX 93 95
FT HELIX 97 102
FT HELIX 103 106
FT STRAND 110 113
FT HELIX 119 124
FT HELIX 129 136
FT STRAND 140 145
FT HELIX 151 155
FT STRAND 164 170
FT HELIX 172 184
FT STRAND 188 191
FT HELIX 195 197
FT HELIX 198 203
SQ SEQUENCE 488 AA; 54601 MW; C89EB0D0430F9BFB CRC64;
MPEEMDKPLI SLHLVDSDSS LAKVPDEAPK VGILGSGDFA RSLATRLVGS GFKVVVGSRN
PKRTARLFPS AAQVTFQEEA VSSPEVIFVA VFREHYSSLC SLSDQLAGKI LVDVSNPTEQ
EHLQHRESNA EYLASLFPTC TVVKAFNVIS AWTLQAGPRD GNRQVPICGD QPEAKRAVSE
MALAMGFMPV DMGSLASAWE VEAMPLRLLP AWKVPTLLAL GLFVCFYAYN FVRDVLQPYV
QESQNKFFKL PVSVVNTTLP CVAYVLLSLV YLPGVLAAAL QLRRGTKYQR FPDWLDHWLQ
HRKQIGLLSF FCAALHALYS FCLPLRRAHR YDLVNLAVKQ VLANKSHLWV EEEVWRMEIY
LSLGVLALGT LSLLAVTSLP SIANSLNWRE FSFVQSSLGF VALVLSTLHT LTYGWTRAFE
ESRYKFYLPP TFTLTLLVPC VVILAKALFL LPCISRRLAR IRRGWEREST IKFTLPTDHA
LAEKTSHV
//
ID STEA3_HUMAN Reviewed; 488 AA.
AC Q658P3; A8K6E3; Q4VBR2; Q4ZG36; Q53SQ8; Q7Z389; Q86SF6; Q8NEW6;
read moreAC Q8TDP3; Q8TF03; Q9NVB5;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 2.
DT 22-JAN-2014, entry version 93.
DE RecName: Full=Metalloreductase STEAP3;
DE EC=1.16.1.-;
DE AltName: Full=Dudulin-2;
DE AltName: Full=Six-transmembrane epithelial antigen of prostate 3;
DE AltName: Full=Tumor suppressor-activated pathway protein 6;
DE Short=hTSAP6;
DE AltName: Full=pHyde;
DE Short=hpHyde;
GN Name=STEAP3; Synonyms=TSAP6;
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), TISSUE SPECIFICITY, INDUCTION,
RP AND INTERACTION WITH BNIP3L AND MYT1.
RX PubMed=12606722; DOI=10.1073/pnas.0530298100;
RA Passer B.J., Nancy-Portebois V., Amzallag N., Prieur S., Cans C.,
RA Roborel de Climens A., Fiucci G., Bouvard V., Tuynder M., Susini L.,
RA Morchoisne S., Crible V., Lespagnol A., Dausset J., Oren M., Amson R.,
RA Telerman A.;
RT "The p53-inducible TSAP6 gene product regulates apoptosis and the cell
RT cycle and interacts with Nix and the Myt1 kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:2284-2289(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=15897894; DOI=10.1038/sj.onc.1208677;
RA Korkmaz C.G., Korkmaz K.S., Kurys P., Elbi C., Wang L., Klokk T.I.,
RA Hammarstrom C., Troen G., Svindland A., Hager G.L., Saatcioglu F.;
RT "Molecular cloning and characterization of STAMP2, an androgen-
RT regulated six transmembrane protein that is overexpressed in prostate
RT cancer.";
RL Oncogene 24:4934-4945(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
RX PubMed=10969787;
RA Steiner M.S., Zhang X., Wang Y., Lu Y.;
RT "Growth inhibition of prostate cancer by an adenovirus expressing a
RT novel tumor suppressor gene, pHyde.";
RL Cancer Res. 60:4419-4425(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Serru V., Manivet P., Lenoir C., Eschwege P., Lamblin D.,
RA Vaubourdolle M., Kellermann O., Loric S.;
RT "Dudulin 2, a new tumor antigen expressed in various human tumors.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Lu Y., Beheshti B., Squire J.A., Yang X.J.;
RT "Characterization of a novel apoptosis-inducing gene, hpHyde, that
RT inhibits prostate cancer cell growth.";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon endothelium, and Endometrial adenocarcinoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
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 [11]
RP LACK OF TUMOR SUPPRESSOR FUNCTION.
RX PubMed=12866033; DOI=10.1002/ijc.11278;
RA Porkka K.P., Nupponen N.N., Tammela T.L., Vessella R.L., Visakorpi T.;
RT "Human pHyde is not a classical tumor suppressor gene in prostate
RT cancer.";
RL Int. J. Cancer 106:729-735(2003).
RN [12]
RP FUNCTION, AND INTERACTION WITH TCTP.
RX PubMed=15319436; DOI=10.1074/jbc.M404850200;
RA Amzallag N., Passer B.J., Allanic D., Segura E., Thery C., Goud B.,
RA Amson R., Telerman A.;
RT "TSAP6 facilitates the secretion of translationally controlled tumor
RT protein/histamine-releasing factor via a nonclassical pathway.";
RL J. Biol. Chem. 279:46104-46112(2004).
RN [13]
RP TISSUE SPECIFICITY.
RX PubMed=15885357; DOI=10.1016/j.jhep.2005.01.027;
RA Coulouarn C., Derambure C., Lefebvre G., Daveau R., Hiron M.,
RA Scotte M., Francois A., Daveau M., Salier J.-P.;
RT "Global gene repression in hepatocellular carcinoma and fetal liver,
RT and suppression of dudulin-2 mRNA as a possible marker for the
RT cirrhosis-to-tumor transition.";
RL J. Hepatol. 42:860-869(2005).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=16227996; DOI=10.1038/ng1658;
RA Ohgami R.S., Campagna D.R., Greer E.L., Antiochos B., McDonald A.,
RA Chen J., Sharp J.J., Fujiwara Y., Barker J.E., Fleming M.D.;
RT "Identification of a ferrireductase required for efficient
RT transferrin-dependent iron uptake in erythroid cells.";
RL Nat. Genet. 37:1264-1269(2005).
RN [15]
RP FUNCTION.
RX PubMed=16651434; DOI=10.1158/0008-5472.CAN-05-4579;
RA Yu X., Harris S.L., Levine A.J.;
RT "The regulation of exosome secretion: a novel function of the p53
RT protein.";
RL Cancer Res. 66:4795-4801(2006).
RN [16]
RP INVOLVEMENT IN AHMIO2.
RX PubMed=22031863; DOI=10.1182/blood-2011-01-329011;
RA Grandchamp B., Hetet G., Kannengiesser C., Oudin C., Beaumont C.,
RA Rodrigues-Ferreira S., Amson R., Telerman A., Nielsen P., Kohne E.,
RA Balser C., Heimpel H.;
RT "A novel type of congenital hypochromic anemia associated with a
RT nonsense mutation in the STEAP3/TSAP6 gene.";
RL Blood 118:6660-6666(2011).
RN [17]
RP CLEAVAGE BY RHBDD1, INTERACTION WITH RHBDD1, GLYCOSYLATION AT ASN-256
RP AND ASN-344, AND MUTAGENESIS OF ASN-256; LEU-325 AND ASN-344.
RX PubMed=22624035; DOI=10.1371/journal.pone.0037452;
RA Wan C., Fu J., Wang Y., Miao S., Song W., Wang L.;
RT "Exosome-related multi-pass transmembrane protein TSAP6 is a target of
RT rhomboid protease RHBDD1-induced proteolysis.";
RL PLoS ONE 7:E37452-E37452(2012).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-215 ALONE AND IN COMPLEX
RP WITH NADPH, COFACTOR, AND SUBUNIT.
RX PubMed=18495927; DOI=10.1073/pnas.0801318105;
RA Sendamarai A.K., Ohgami R.S., Fleming M.D., Lawrence C.M.;
RT "Structure of the membrane proximal oxidoreductase domain of human
RT Steap3, the dominant ferrireductase of the erythroid transferrin
RT cycle.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:7410-7415(2008).
CC -!- FUNCTION: Endosomal ferrireductase required for efficient
CC transferrin-dependent iron uptake in erythroid cells. Participates
CC in erythroid iron homeostasis by reducing Fe(3+) to Fe(2+). Can
CC also reduce of Cu(2+) to Cu(1+), suggesting that it participates
CC in copper homeostasis. Uses NADP(+) as acceptor. May play a role
CC downstream of p53/TP53 to interface apoptosis and cell cycle
CC progression. Indirectly involved in exosome secretion by
CC facilitating the secretion of proteins such as TCTP.
CC -!- COFACTOR: FAD (By similarity).
CC -!- COFACTOR: NADP.
CC -!- SUBUNIT: Homodimer. Interacts with BNIP3L, MYT1, RHBDL4/RHBDD1 and
CC TCTP.
CC -!- SUBCELLULAR LOCATION: Endosome membrane; Multi-pass membrane
CC protein (By similarity). Note=Localizes to vesicular-like
CC structures at the plasma membrane and around the nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q658P3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q658P3-2; Sequence=VSP_024829;
CC Name=3;
CC IsoId=Q658P3-3; Sequence=VSP_024830;
CC Name=4; Synonyms=pHyde II;
CC IsoId=Q658P3-4; Sequence=VSP_024830, VSP_024831;
CC -!- TISSUE SPECIFICITY: Expressed in adult bone marrow, placenta,
CC liver, skeletal muscle and pancreas. Down-regulated in
CC hepatocellular carcinoma.
CC -!- INDUCTION: By p53/TP53.
CC -!- PTM: Proteolytically cleaved by RHBDL4/RHBDD1. RHBDL4/RHBDD1-
CC induced cleavage occurs at multiple sites in a glycosylation-
CC independent manner.
CC -!- PTM: Glycosylated.
CC -!- DISEASE: Anemia, hypochromic microcytic, with iron overload 2
CC (AHMIO2) [MIM:615234]: A hematologic disease characterized by
CC abnormal hemoglobin content in the erythrocytes which are reduced
CC in size, severe anemia, erythropoietic hyperplasia of bone marrow,
CC massive hepatic iron deposition, and hepatosplenomegaly. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the STEAP family.
CC -!- SIMILARITY: Contains 1 ferric oxidoreductase domain.
CC -!- CAUTION: Was initially thought to have tumor suppressor function
CC in prostate cancer. However, it was shown that it is probably not
CC the case (PubMed:12866033).
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DR EMBL; AY214461; AAO38238.1; -; mRNA.
DR EMBL; AF423424; AAQ04065.1; -; mRNA.
DR EMBL; AF238864; AAL78206.1; -; mRNA.
DR EMBL; AF262322; AAM08128.1; -; mRNA.
DR EMBL; AY029585; AAK50538.1; -; mRNA.
DR EMBL; AY082673; AAM45136.1; -; mRNA.
DR EMBL; AK001691; BAA91839.1; -; mRNA.
DR EMBL; AK291608; BAF84297.1; -; mRNA.
DR EMBL; AL833624; CAH56204.1; -; mRNA.
DR EMBL; BX538047; CAD97986.1; -; mRNA.
DR EMBL; AC016673; AAX88963.1; -; Genomic_DNA.
DR EMBL; AC016736; AAY14872.1; -; Genomic_DNA.
DR EMBL; CH471103; EAW95209.1; -; Genomic_DNA.
DR EMBL; BC042150; AAH42150.1; -; mRNA.
DR EMBL; BC095421; AAH95421.2; -; mRNA.
DR RefSeq; NP_001008410.1; NM_001008410.1.
DR RefSeq; NP_060704.2; NM_018234.2.
DR RefSeq; NP_878919.2; NM_182915.2.
DR UniGene; Hs.647822; -.
DR PDB; 2VNS; X-ray; 2.00 A; A/B=1-215.
DR PDB; 2VQ3; X-ray; 2.00 A; A/B=1-215.
DR PDBsum; 2VNS; -.
DR PDBsum; 2VQ3; -.
DR ProteinModelPortal; Q658P3; -.
DR SMR; Q658P3; 29-209.
DR IntAct; Q658P3; 2.
DR TCDB; 9.B.66.1.1; the animal nonclassical protein secretion (nps) family.
DR PhosphoSite; Q658P3; -.
DR DMDM; 146325737; -.
DR PaxDb; Q658P3; -.
DR PRIDE; Q658P3; -.
DR DNASU; 55240; -.
DR Ensembl; ENST00000354888; ENSP00000346961; ENSG00000115107.
DR Ensembl; ENST00000393106; ENSP00000376818; ENSG00000115107.
DR Ensembl; ENST00000393107; ENSP00000376819; ENSG00000115107.
DR Ensembl; ENST00000393108; ENSP00000376820; ENSG00000115107.
DR Ensembl; ENST00000393110; ENSP00000376822; ENSG00000115107.
DR Ensembl; ENST00000425223; ENSP00000396214; ENSG00000115107.
DR GeneID; 55240; -.
DR KEGG; hsa:55240; -.
DR UCSC; uc002tlp.3; human.
DR CTD; 55240; -.
DR GeneCards; GC02P119981; -.
DR HGNC; HGNC:24592; STEAP3.
DR HPA; HPA050510; -.
DR MIM; 609671; gene.
DR MIM; 615234; phenotype.
DR neXtProt; NX_Q658P3; -.
DR Orphanet; 300298; Severe congenital hypochromic anemia with ringed sideroblasts.
DR PharmGKB; PA142670863; -.
DR eggNOG; COG2085; -.
DR HOVERGEN; HBG054379; -.
DR InParanoid; Q658P3; -.
DR KO; K10142; -.
DR OMA; GWKVPAL; -.
DR OrthoDB; EOG7Z0JWH; -.
DR PhylomeDB; Q658P3; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; STEAP3; human.
DR EvolutionaryTrace; Q658P3; -.
DR GeneWiki; STEAP3; -.
DR GenomeRNAi; 55240; -.
DR NextBio; 59270; -.
DR PRO; PR:Q658P3; -.
DR ArrayExpress; Q658P3; -.
DR Bgee; Q658P3; -.
DR Genevestigator; Q658P3; -.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005771; C:multivesicular body; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0000293; F:ferric-chelate reductase activity; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0009306; P:protein secretion; IMP:UniProtKB.
DR GO; GO:0033572; P:transferrin transport; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR013130; Fe3_Rdtase_TM_dom.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR Pfam; PF01794; Ferric_reduct; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Cell cycle;
KW Complete proteome; Copper; Endosome; FAD; Flavoprotein; Glycoprotein;
KW Ion transport; Iron; Iron transport; Membrane; Metal-binding; NADP;
KW Oxidoreductase; Phosphoprotein; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 488 Metalloreductase STEAP3.
FT /FTId=PRO_0000285171.
FT TOPO_DOM 1 207 Cytoplasmic (Potential).
FT TRANSMEM 208 228 Helical; (Potential).
FT TOPO_DOM 229 258 Vesicular (Potential).
FT TRANSMEM 259 279 Helical; (Potential).
FT TOPO_DOM 280 304 Cytoplasmic (Potential).
FT TRANSMEM 305 325 Helical; (Potential).
FT TOPO_DOM 326 358 Vesicular (Potential).
FT TRANSMEM 359 379 Helical; (Potential).
FT TOPO_DOM 380 390 Cytoplasmic (Potential).
FT TRANSMEM 391 411 Helical; (Potential).
FT TOPO_DOM 412 433 Vesicular (Potential).
FT TRANSMEM 434 454 Helical; (Potential).
FT TOPO_DOM 455 488 Cytoplasmic (Potential).
FT DOMAIN 259 407 Ferric oxidoreductase.
FT METAL 316 316 Iron (heme axial ligand) (Probable).
FT METAL 409 409 Iron (heme axial ligand) (Probable).
FT BINDING 36 36 NADP.
FT BINDING 38 38 NADP; via amide nitrogen.
FT BINDING 39 39 NADP; via amide nitrogen.
FT BINDING 58 58 NADP.
FT BINDING 59 59 NADP.
FT BINDING 91 91 NADP; via carbonyl oxygen.
FT BINDING 116 116 NADP; via amide nitrogen.
FT BINDING 151 151 NADP; via amide nitrogen.
FT SITE 325 326 Cleavage; by RHBDL4/RHBDD1 (Probable).
FT MOD_RES 17 17 Phosphoserine (By similarity).
FT MOD_RES 20 20 Phosphoserine (By similarity).
FT CARBOHYD 256 256 N-linked (GlcNAc...) (Probable).
FT CARBOHYD 344 344 N-linked (GlcNAc...) (Probable).
FT VAR_SEQ 1 1 M -> MSHQPAVATKM (in isoform 2).
FT /FTId=VSP_024829.
FT VAR_SEQ 351 351 Missing (in isoform 3 and isoform 4).
FT /FTId=VSP_024830.
FT VAR_SEQ 396 488 SSLGFVALVLSTLHTLTYGWTRAFEESRYKFYLPPTFTLTL
FT LVPCVVILAKALFLLPCISRRLARIRRGWERESTIKFTLPT
FT DHALAEKTSHV -> CVATSSAGNTGSGTRRPESQSQDPHL
FT PAPHHQTSFLGPRSFCCSLVPVSTPYGHQEDLSWTR (in
FT isoform 4).
FT /FTId=VSP_024831.
FT VARIANT 184 184 A -> T (in dbSNP:rs17013371).
FT /FTId=VAR_031975.
FT MUTAGEN 256 256 N->I: Inhibits glycosylation and does not
FT inhibit RHBDL4/RHBDD1-induced cleavage;
FT when associated with A-344.
FT MUTAGEN 325 325 L->F: Strongly inhibits RHBDL4/RHBDD1-
FT induced cleavage.
FT MUTAGEN 344 344 N->I: Inhibits glycosylation and does not
FT inhibit RHBDL4/RHBDD1-induced cleavage;
FT when associated with A-256.
FT CONFLICT 32 32 G -> S (in Ref. 3; AAL78206/AAM08128 and
FT 6; AAM45136).
FT CONFLICT 68 68 F -> Y (in Ref. 4; AAK50538 and 7;
FT BAA91839).
FT CONFLICT 163 163 R -> G (in Ref. 3; AAL78206/AAM08128).
FT CONFLICT 478 478 D -> G (in Ref. 8; CAD97986).
FT STRAND 31 34
FT HELIX 38 49
FT STRAND 54 60
FT HELIX 61 67
FT STRAND 72 76
FT HELIX 77 80
FT STRAND 85 89
FT HELIX 93 95
FT HELIX 97 102
FT HELIX 103 106
FT STRAND 110 113
FT HELIX 119 124
FT HELIX 129 136
FT STRAND 140 145
FT HELIX 151 155
FT STRAND 164 170
FT HELIX 172 184
FT STRAND 188 191
FT HELIX 195 197
FT HELIX 198 203
SQ SEQUENCE 488 AA; 54601 MW; C89EB0D0430F9BFB CRC64;
MPEEMDKPLI SLHLVDSDSS LAKVPDEAPK VGILGSGDFA RSLATRLVGS GFKVVVGSRN
PKRTARLFPS AAQVTFQEEA VSSPEVIFVA VFREHYSSLC SLSDQLAGKI LVDVSNPTEQ
EHLQHRESNA EYLASLFPTC TVVKAFNVIS AWTLQAGPRD GNRQVPICGD QPEAKRAVSE
MALAMGFMPV DMGSLASAWE VEAMPLRLLP AWKVPTLLAL GLFVCFYAYN FVRDVLQPYV
QESQNKFFKL PVSVVNTTLP CVAYVLLSLV YLPGVLAAAL QLRRGTKYQR FPDWLDHWLQ
HRKQIGLLSF FCAALHALYS FCLPLRRAHR YDLVNLAVKQ VLANKSHLWV EEEVWRMEIY
LSLGVLALGT LSLLAVTSLP SIANSLNWRE FSFVQSSLGF VALVLSTLHT LTYGWTRAFE
ESRYKFYLPP TFTLTLLVPC VVILAKALFL LPCISRRLAR IRRGWEREST IKFTLPTDHA
LAEKTSHV
//
MIM
609671
*RECORD*
*FIELD* NO
609671
*FIELD* TI
*609671 SIX-TRANSMEMBRANE EPITHELIAL ANTIGEN OF PROSTATE 3; STEAP3
;;TUMOR SUPPRESSOR-ACTIVATED PATHWAY 6; TSAP6
read more*FIELD* TX
CLONING
Passer et al. (2003) cloned human STEAP3, which they called TSAP6, from
a pooled-tissue cDNA library. The deduced 488-amino acid protein
contains an N-terminal motif associated with oxidoreductases and
dehydrogenases and 5 or 6 transmembrane domains. Human TSAP6 shares 87%
amino acid identity with mouse Tsap6. Northern blot analysis of human
tissues detected a 4.3-kb transcript expressed highly in liver and at a
lower level in skeletal muscle. Heart, brain, placenta, lung, kidney,
and pancreas expressed little to no TSAP6. Northern blot analysis of
mouse tissues detected expression predominantly in heart, spleen, lung,
liver, and skeletal muscle. Western blot analysis of mouse and human
cell lines detected TSAP6 at an apparent molecular mass of 50 to 55 kD.
Using Western blot analysis, Lespagnol et al. (2008) detected Tsap6
proteins of 46 and 52 kD in mouse NIH3T3 cells, and they showed that the
larger protein resulted from glycosylation. Confocal microscopy of mouse
embryonic fibroblasts showed colocalization of endogenous Tsap6 with the
trans-Golgi network maker Tgn38 (TGOLN; 603062). Punctuated cytoplasmic
and plasma membrane staining of Tsap6 partially colocalized with
transferrin receptor (TFRC; 190010) and Eea1 (605070), suggesting that
Tsap6 is expressed in the endosomal compartment.
MAPPING
By FISH, Passer et al. (2003) mapped the STEAP3 gene to chromosome
2q14.2. They mapped the mouse Steap3 gene to chromosome 1.
GENE FUNCTION
Using Northern blot analysis, Passer et al. (2003) found that p53 (TP53;
191170) upregulated TSAP6 expression in mouse and human cell lines. They
identified a p53-responsive element upstream of the first exon of the
mouse Tsap6 gene. TSAP6 antisense cDNA decreased the level of
p53-induced apoptosis, and TSAP6 small interfering RNA inhibited
apoptosis in TSAP6-overexpressing cells. Yeast 2-hybrid analysis,
protein pull-down assays, and coimmunoprecipitation analysis revealed
that TSAP6 interacted with NIX (BNIP3; 605368), a proapoptotic BCL2
(151430)-related protein, and with MYT1 kinase (602474), a negative
regulator of G2/M transition. Moreover, TSAP6 enhanced the
susceptibility of cells to apoptosis and cooperated with NIX to
exacerbate this effect. Cell cycle studies indicated that TSAP6 could
augment MYT1 activity. Passer et al. (2003) concluded that TSAP6 may act
downstream of p53 to interface apoptosis and cell cycle progression.
Histamine-releasing factor (TPT1; 600763) is a secreted protein that
participates in inflammatory responses by promoting the release of
histamine. Amzallag et al. (2004) found that secretion of TPT1 proceeded
by a nonclassical pathway independent of the endoplasmic reticulum and
Golgi apparatus. They determined that TSAP6 interacted with TPT1 in
several protein interaction assays, and the 2 proteins codistributed to
small vesicles called exosomes at the plasma membrane and around the
nucleus in several human cell lines. Overexpression of TSAP6 increased
the level of TPT1 in exosome preparations and consistently enhanced TPT1
secretion. Amzallag et al. (2004) concluded that TSAP6 has a role in the
export of TPT1 via a nonclassical pathway and suggested that TSAP6 may
have a general role in the regulation of vesicular trafficking and
secretion.
MOLECULAR GENETICS
In 3 sibs with hypochromic microcytic anemia and iron overload (615234),
born of nonconsanguineous Pakistani parents, Grandchamp et al. (2011)
analyzed 7 candidate genes and identified heterozygosity for a nonsense
mutation in the STEAP3 gene (C100X; 609671.0001) that was inherited from
their unaffected father. Quantitative analysis of mRNA levels suggested
that the father was heterozygous with 1 null allele and 1 normal, highly
expressed allele, whereas their unaffected mother had 2 weakly expressed
alleles, and each affected offspring had inherited the mutated allele
from their father and 1 of the weakly expressed alleles from their
mother. Using two 3-prime common polymorphisms in high linkage
disequilibrium as markers to perform quantitative sequencing of cDNA
from the blood of 20 control individuals, Grandchamp et al. (2011)
demonstrated a 2.5-fold variation in the C/T and A/C ratios among 17
individuals informative for dbSNP rs6753006 and 12 individuals
informative for dbSNP rs3731603, respectively, thus confirming
variability of STEAP3 expression in the general population.
ANIMAL MODEL
The reduction of iron is an essential step in the transferrin (TF;
190000) cycle, which is the dominant pathway for iron uptake by red
blood cell precursors. A deficiency in iron acquisition by red blood
cells leads to hypochromic, microcytic anemia. Using a positional
cloning strategy, Ohgami et al. (2005) identified the Steap3 gene as
responsible for the iron deficiency anemia in the mouse mutant nm1054.
They showed that Steap3 is expressed highly in hematopoietic tissues,
colocalizes with the transferrin cycle endosome, and facilitates
transferrin-bound iron uptake. Overexpression of Steap3 stimulated the
reduction of iron, and mice lacking Steap3 were deficient in erythroid
ferrireductase activity. These findings taken together were interpreted
as indicating that Steap3 is an endosomal ferrireductase required for
efficient transferrin-dependent iron uptake in erythroid cells.
Lespagnol et al. (2008) generated Tsap6 -/- mice and found that Tsap6
-/- splenocytes accumulated Tctp (TPT1) and Tfrc. Spleens of Tsap6 -/-
mice were enlarged with altered splenic architecture on histopathologic
analysis, and reticulocytes and erythrocytes were small and abnormally
shaped, consistent with microcytic anemia. Analysis of reticulocyte
maturation revealed a delay in Tfrc expulsion and reduced secretion of
exosomes. Induction of p53-mediated apoptosis, but not of p53- dependent
p21 (CDKN1A; 116899) expression, was attenuated in Tsap6 -/- spleen.
Following activation of p53 by DNA damage, Tsap6 -/- cells exhibited a
significant reduction in exosome secretion and an absence of exosomal
protein upregulation compared with wildtype controls. Lespagnol et al.
(2008) concluded that increased p53-mediated secretion of exosomes
following DNA damage is dependent on TSAP6 and that TSAP6 is needed to
expel proteins no longer required by cells.
*FIELD* AV
.0001
ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 2 (1 family)
STEAP3, CYS100TER
In 3 sibs with hypochromic microcytic anemia and iron overload (615234),
born of nonconsanguineous Pakistani parents, Grandchamp et al. (2011)
identified heterozygosity for a c.300C-A transition in exon 3 of the
STEAP3 gene, resulting in a cys100-to-ter (C100X) substitution. The
mutation was inherited from their unaffected father and was not found in
their unaffected mother or 200 control chromosomes. Quantitative RT-PCR
from blood mRNA of all 5 family members and 10 controls showed that the
STEAP3 mRNA level was considerably lower in the 3 patients, whereas both
parents had a level of STEAP3 mRNA corresponding to the low-normal range
found in controls. In B lymphocyte-cell lines treated to prevent
degradation due to nonsense-mediated mRNA decay, quantitative sequencing
of a cDNA fragment encompassing the mutated nucleotide demonstrated that
expression of the normal allele relative to that of the mutated allele
was significantly higher in the father than in the 3 sibs. Grandchamp et
al. (2011) suggested that the father was heterozygous with 1 null allele
and 1 normal, highly expressed allele, whereas the mother had 2 weakly
expressed alleles, and each affected offspring had inherited the mutated
allele from their father and 1 of the weakly expressed alleles from
their mother. This was supported by the fact that expression of both
alleles from the mother produced an amount of mRNA that was roughly
equivalent to the expression products from the single normal allele of
the father.
*FIELD* RF
1. Amzallag, N.; Passer, B. J.; Allanic, D.; Segurai, E.; Thery, C.;
Goud, B.; Amson, R.; Telerman, A.: TSAP6 facilitates the secretion
of translationally controlled tumor protein/histamine-releasing factor
via a nonclassical pathway. J. Biol. Chem. 279: 46104-46112, 2004.
2. Grandchamp, B.; Hetet, G.; Kannengiesser, C.; Oudin, C.; Beaumont,
C.; Rodrigues-Ferreira, S.; Amson, R.; Telerman, A.; Nielsen, P.;
Kohne, E.; Balser, C.; Heimpel, H.: A novel type of congenital hypochromic
anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 118:
6660-6666, 2011.
3. Lespagnol, A.; Duflaut, D.; Beekman, C.; Blanc, L.; Fiucci, G.;
Marine, J.-C.; Vidal, M.; Amson, R.; Telerman, A.: Exosome secretion,
including the DNA damage-induced p53-dependent secretory pathway,
is severely compromised in TSAP6/Steap3-null mice. Cell Death Diff. 15:
1723-1733, 2008.
4. Ohgami, R. S.; Campagna, D. R.; Greer, E. L.; Antiochos, B.; McDonald,
A.; Chen, J.; Sharp, J. J.; Fujiwara, Y.; Barker, J. E.; Fleming,
M. D.: Identification of a ferrireductase required for efficient
transferrin-dependent iron uptake in erythroid cells. Nature Genet. 37:
1264-1269, 2005.
5. Passer, B. J.; Nancy-Portebois, V.; Amzallag, N.; Prieur, S.; Cans,
C.; Roborel de Climens, A.; Fiucci, G.; Bouvard, V.; Tuynder, M.;
Susini, L.; Morchoisne, S.; Crible, V.; Lespagnol, A.; Dausset, J.;
Oren, M.; Amson, R.; Telerman, A.: The p53-inducible TSAP6 gene product
regulates apoptosis and the cell cycle and interacts with Nix and
the Myt1 kinase. Proc. Nat. Acad. Sci. 100: 2284-2289, 2003.
*FIELD* CN
Paul J. Converse - updated: 7/1/2013
Marla J. F. O'Neill - updated: 5/16/2013
Victor A. McKusick - updated: 11/17/2005
*FIELD* CD
Patricia A. Hartz: 10/21/2005
*FIELD* ED
mgross: 07/01/2013
mgross: 7/1/2013
carol: 5/16/2013
alopez: 11/21/2005
terry: 11/17/2005
mgross: 10/21/2005
*RECORD*
*FIELD* NO
609671
*FIELD* TI
*609671 SIX-TRANSMEMBRANE EPITHELIAL ANTIGEN OF PROSTATE 3; STEAP3
;;TUMOR SUPPRESSOR-ACTIVATED PATHWAY 6; TSAP6
read more*FIELD* TX
CLONING
Passer et al. (2003) cloned human STEAP3, which they called TSAP6, from
a pooled-tissue cDNA library. The deduced 488-amino acid protein
contains an N-terminal motif associated with oxidoreductases and
dehydrogenases and 5 or 6 transmembrane domains. Human TSAP6 shares 87%
amino acid identity with mouse Tsap6. Northern blot analysis of human
tissues detected a 4.3-kb transcript expressed highly in liver and at a
lower level in skeletal muscle. Heart, brain, placenta, lung, kidney,
and pancreas expressed little to no TSAP6. Northern blot analysis of
mouse tissues detected expression predominantly in heart, spleen, lung,
liver, and skeletal muscle. Western blot analysis of mouse and human
cell lines detected TSAP6 at an apparent molecular mass of 50 to 55 kD.
Using Western blot analysis, Lespagnol et al. (2008) detected Tsap6
proteins of 46 and 52 kD in mouse NIH3T3 cells, and they showed that the
larger protein resulted from glycosylation. Confocal microscopy of mouse
embryonic fibroblasts showed colocalization of endogenous Tsap6 with the
trans-Golgi network maker Tgn38 (TGOLN; 603062). Punctuated cytoplasmic
and plasma membrane staining of Tsap6 partially colocalized with
transferrin receptor (TFRC; 190010) and Eea1 (605070), suggesting that
Tsap6 is expressed in the endosomal compartment.
MAPPING
By FISH, Passer et al. (2003) mapped the STEAP3 gene to chromosome
2q14.2. They mapped the mouse Steap3 gene to chromosome 1.
GENE FUNCTION
Using Northern blot analysis, Passer et al. (2003) found that p53 (TP53;
191170) upregulated TSAP6 expression in mouse and human cell lines. They
identified a p53-responsive element upstream of the first exon of the
mouse Tsap6 gene. TSAP6 antisense cDNA decreased the level of
p53-induced apoptosis, and TSAP6 small interfering RNA inhibited
apoptosis in TSAP6-overexpressing cells. Yeast 2-hybrid analysis,
protein pull-down assays, and coimmunoprecipitation analysis revealed
that TSAP6 interacted with NIX (BNIP3; 605368), a proapoptotic BCL2
(151430)-related protein, and with MYT1 kinase (602474), a negative
regulator of G2/M transition. Moreover, TSAP6 enhanced the
susceptibility of cells to apoptosis and cooperated with NIX to
exacerbate this effect. Cell cycle studies indicated that TSAP6 could
augment MYT1 activity. Passer et al. (2003) concluded that TSAP6 may act
downstream of p53 to interface apoptosis and cell cycle progression.
Histamine-releasing factor (TPT1; 600763) is a secreted protein that
participates in inflammatory responses by promoting the release of
histamine. Amzallag et al. (2004) found that secretion of TPT1 proceeded
by a nonclassical pathway independent of the endoplasmic reticulum and
Golgi apparatus. They determined that TSAP6 interacted with TPT1 in
several protein interaction assays, and the 2 proteins codistributed to
small vesicles called exosomes at the plasma membrane and around the
nucleus in several human cell lines. Overexpression of TSAP6 increased
the level of TPT1 in exosome preparations and consistently enhanced TPT1
secretion. Amzallag et al. (2004) concluded that TSAP6 has a role in the
export of TPT1 via a nonclassical pathway and suggested that TSAP6 may
have a general role in the regulation of vesicular trafficking and
secretion.
MOLECULAR GENETICS
In 3 sibs with hypochromic microcytic anemia and iron overload (615234),
born of nonconsanguineous Pakistani parents, Grandchamp et al. (2011)
analyzed 7 candidate genes and identified heterozygosity for a nonsense
mutation in the STEAP3 gene (C100X; 609671.0001) that was inherited from
their unaffected father. Quantitative analysis of mRNA levels suggested
that the father was heterozygous with 1 null allele and 1 normal, highly
expressed allele, whereas their unaffected mother had 2 weakly expressed
alleles, and each affected offspring had inherited the mutated allele
from their father and 1 of the weakly expressed alleles from their
mother. Using two 3-prime common polymorphisms in high linkage
disequilibrium as markers to perform quantitative sequencing of cDNA
from the blood of 20 control individuals, Grandchamp et al. (2011)
demonstrated a 2.5-fold variation in the C/T and A/C ratios among 17
individuals informative for dbSNP rs6753006 and 12 individuals
informative for dbSNP rs3731603, respectively, thus confirming
variability of STEAP3 expression in the general population.
ANIMAL MODEL
The reduction of iron is an essential step in the transferrin (TF;
190000) cycle, which is the dominant pathway for iron uptake by red
blood cell precursors. A deficiency in iron acquisition by red blood
cells leads to hypochromic, microcytic anemia. Using a positional
cloning strategy, Ohgami et al. (2005) identified the Steap3 gene as
responsible for the iron deficiency anemia in the mouse mutant nm1054.
They showed that Steap3 is expressed highly in hematopoietic tissues,
colocalizes with the transferrin cycle endosome, and facilitates
transferrin-bound iron uptake. Overexpression of Steap3 stimulated the
reduction of iron, and mice lacking Steap3 were deficient in erythroid
ferrireductase activity. These findings taken together were interpreted
as indicating that Steap3 is an endosomal ferrireductase required for
efficient transferrin-dependent iron uptake in erythroid cells.
Lespagnol et al. (2008) generated Tsap6 -/- mice and found that Tsap6
-/- splenocytes accumulated Tctp (TPT1) and Tfrc. Spleens of Tsap6 -/-
mice were enlarged with altered splenic architecture on histopathologic
analysis, and reticulocytes and erythrocytes were small and abnormally
shaped, consistent with microcytic anemia. Analysis of reticulocyte
maturation revealed a delay in Tfrc expulsion and reduced secretion of
exosomes. Induction of p53-mediated apoptosis, but not of p53- dependent
p21 (CDKN1A; 116899) expression, was attenuated in Tsap6 -/- spleen.
Following activation of p53 by DNA damage, Tsap6 -/- cells exhibited a
significant reduction in exosome secretion and an absence of exosomal
protein upregulation compared with wildtype controls. Lespagnol et al.
(2008) concluded that increased p53-mediated secretion of exosomes
following DNA damage is dependent on TSAP6 and that TSAP6 is needed to
expel proteins no longer required by cells.
*FIELD* AV
.0001
ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 2 (1 family)
STEAP3, CYS100TER
In 3 sibs with hypochromic microcytic anemia and iron overload (615234),
born of nonconsanguineous Pakistani parents, Grandchamp et al. (2011)
identified heterozygosity for a c.300C-A transition in exon 3 of the
STEAP3 gene, resulting in a cys100-to-ter (C100X) substitution. The
mutation was inherited from their unaffected father and was not found in
their unaffected mother or 200 control chromosomes. Quantitative RT-PCR
from blood mRNA of all 5 family members and 10 controls showed that the
STEAP3 mRNA level was considerably lower in the 3 patients, whereas both
parents had a level of STEAP3 mRNA corresponding to the low-normal range
found in controls. In B lymphocyte-cell lines treated to prevent
degradation due to nonsense-mediated mRNA decay, quantitative sequencing
of a cDNA fragment encompassing the mutated nucleotide demonstrated that
expression of the normal allele relative to that of the mutated allele
was significantly higher in the father than in the 3 sibs. Grandchamp et
al. (2011) suggested that the father was heterozygous with 1 null allele
and 1 normal, highly expressed allele, whereas the mother had 2 weakly
expressed alleles, and each affected offspring had inherited the mutated
allele from their father and 1 of the weakly expressed alleles from
their mother. This was supported by the fact that expression of both
alleles from the mother produced an amount of mRNA that was roughly
equivalent to the expression products from the single normal allele of
the father.
*FIELD* RF
1. Amzallag, N.; Passer, B. J.; Allanic, D.; Segurai, E.; Thery, C.;
Goud, B.; Amson, R.; Telerman, A.: TSAP6 facilitates the secretion
of translationally controlled tumor protein/histamine-releasing factor
via a nonclassical pathway. J. Biol. Chem. 279: 46104-46112, 2004.
2. Grandchamp, B.; Hetet, G.; Kannengiesser, C.; Oudin, C.; Beaumont,
C.; Rodrigues-Ferreira, S.; Amson, R.; Telerman, A.; Nielsen, P.;
Kohne, E.; Balser, C.; Heimpel, H.: A novel type of congenital hypochromic
anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 118:
6660-6666, 2011.
3. Lespagnol, A.; Duflaut, D.; Beekman, C.; Blanc, L.; Fiucci, G.;
Marine, J.-C.; Vidal, M.; Amson, R.; Telerman, A.: Exosome secretion,
including the DNA damage-induced p53-dependent secretory pathway,
is severely compromised in TSAP6/Steap3-null mice. Cell Death Diff. 15:
1723-1733, 2008.
4. Ohgami, R. S.; Campagna, D. R.; Greer, E. L.; Antiochos, B.; McDonald,
A.; Chen, J.; Sharp, J. J.; Fujiwara, Y.; Barker, J. E.; Fleming,
M. D.: Identification of a ferrireductase required for efficient
transferrin-dependent iron uptake in erythroid cells. Nature Genet. 37:
1264-1269, 2005.
5. Passer, B. J.; Nancy-Portebois, V.; Amzallag, N.; Prieur, S.; Cans,
C.; Roborel de Climens, A.; Fiucci, G.; Bouvard, V.; Tuynder, M.;
Susini, L.; Morchoisne, S.; Crible, V.; Lespagnol, A.; Dausset, J.;
Oren, M.; Amson, R.; Telerman, A.: The p53-inducible TSAP6 gene product
regulates apoptosis and the cell cycle and interacts with Nix and
the Myt1 kinase. Proc. Nat. Acad. Sci. 100: 2284-2289, 2003.
*FIELD* CN
Paul J. Converse - updated: 7/1/2013
Marla J. F. O'Neill - updated: 5/16/2013
Victor A. McKusick - updated: 11/17/2005
*FIELD* CD
Patricia A. Hartz: 10/21/2005
*FIELD* ED
mgross: 07/01/2013
mgross: 7/1/2013
carol: 5/16/2013
alopez: 11/21/2005
terry: 11/17/2005
mgross: 10/21/2005
MIM
615234
*RECORD*
*FIELD* NO
615234
*FIELD* TI
#615234 ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 2; AHMIO2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morehypochromic microcytic anemia with iron overload-2 (AHMIO2) is caused by
heterozygous mutation in the STEAP3 gene (609671) on chromosome 2q14.
One such family has been reported.
For a discussion of genetic heterogeneity of hypochromic microcytic
anemia with iron overload, see AHMIO1 (206100).
CLINICAL FEATURES
Grandchamp et al. (2011) reported 3 sibs, born of nonconsanguineous
Pakistani parents, who had transfusion-dependent hypochromic microcytic
anemia with iron overload. The proband was a 24-year-old man who had
been pale since infancy and was documented to be anemic at 7.5 years of
age. Follow-up revealed chronic hypochromic anemia, and biochemical data
suggested the onset of iron overload. He presented with increasing
fatigue at 19 years of age, at which time his spleen was palpable and he
was severely anemic; regular transfusions were begun to maintain a
hemoglobin level permitting normal physical activity. Blood smears
revealed distinct aniso-poikilocytosis with hypochromasia and
microcytosis, ovalocytes, a few target cells, and basophilic stippled
cells, with single mature nucleated red cells present. There was
moderate erythropoietic hyperplasia of the bone marrow, with dysplastic
features in less than 3% of erythroblasts; late basophilic and
polychromatophilic erythroblasts had a small rim of poorly
hemoglobinized cytoplasm, with small inclusions in some cells. Perls
staining showed iron-positive inclusions in most red cell precursors,
with 40% ringed sideroblasts, and Pappenheimer bodies in a few red
cells. Under transmission electron microscopy, deposits of iron could be
seen inside as well as outside the mitochondria. The proband's 2
affected sibs had similar biochemical and morphologic data. The
23-year-old sister had only mild symptoms of anemia in childhood and
began regular transfusions at 15 years of age, whereas the 18-year-old
brother had a more severe form of anemia since infancy, requiring
transfusions beginning at 7 years of age, with growth retardation,
massive hepatosplenomegaly and high iron overload, and cafe-au-lait
spots visible on his skin. All 3 sibs had high serum ferritin and low
transferrin values, as well as distinctly increased transferrin
saturation despite regular treatment with deferasirox. In addition, they
all had hypogonadism, with azoospermia in the males and atrophy of the
gonads in the female; complex dysfunction of the
hypothalamo-pituitary-gonadal axis was present in all 3 patients,
suggesting a primary defect of the gonads in addition to secondary
hypogonadism. Latent adrenal and thyroid failure was also detected in
the younger brother. Their father had normal blood counts and iron data,
whereas their mother had mild microcytic anemia with a low serum
ferritin, which responded to iron supplementation. She had had 2
miscarriages in addition to the 3 live births.
MOLECULAR GENETICS
In 3 sibs with hypochromic microcytic anemia and iron overload, born of
nonconsanguineous Pakistani parents, Grandchamp et al. (2011) analyzed 7
candidate genes and identified heterozygosity for a nonsense mutation in
the STEAP3 gene (C100X; 609671.0001) that was inherited from their
unaffected father. Quantitative RT-PCR from blood mRNA of all 5 family
members and 10 controls showed that the STEAP3 mRNA level was
considerably lower in the 3 patients, whereas both parents had a level
of STEAP3 mRNA corresponding to the low-normal range found in controls.
In B-lymphocyte cell lines treated to prevent degradation due to
nonsense-mediated mRNA decay, quantitative sequencing of a cDNA fragment
encompassing the mutated nucleotide demonstrated that expression of the
normal allele relative to that of the mutated allele was significantly
higher in the father than in the 3 sibs. Grandchamp et al. (2011)
suggested that the father was heterozygous with 1 null allele and 1
normal, highly expressed allele, whereas the mother had 2 weakly
expressed alleles, and each affected offspring had inherited the mutated
allele from their father and 1 of the weakly expressed alleles from
their mother. This was supported by the fact that expression of both
alleles from the mother produced an amount of mRNA that was roughly
equivalent to the expression products from the single normal allele of
the father.
*FIELD* RF
1. Grandchamp, B.; Hetet, G.; Kannengiesser, C.; Oudin, C.; Beaumont,
C.; Rodrigues-Ferreira, S.; Amson, R.; Telerman, A.; Nielsen, P.;
Kohne, E.; Balser, C.; Heimpel, H.: A novel type of congenital hypochromic
anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 118:
6660-6666, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
Growth retardation (in some patients)
HEAD AND NECK:
[Eyes];
Marked pallor of mucous membranes;
[Mouth];
Marked pallor of mucous membranes
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
GENITOURINARY:
[External genitalia, male];
Hypogonadism;
[Internal genitalia, male];
Azoospermia;
[Internal genitalia, female];
Gonadal atrophy
SKIN, NAILS, HAIR:
[Skin];
Marked skin pallor;
Cafe au lait spots (in some patients)
ENDOCRINE FEATURES:
Dysfunction of hypothalamo-pituitary-gonadal axis;
Adrenal failure (in some patients);
Thyroid failure (in some patients)
HEMATOLOGY:
Anemia, severe;
Hypochromia;
Microcytosis;
Elevated serum ferritin;
Low serum transferrin;
Increased transferrin saturation;
Aniso-poikilocytosis on blood smear;
Erythropoietic hyperplasia of bone marrow
MISCELLANEOUS:
Patients have severe anemia requiring regular transfusions for normal
activity;
One family reported (last curated May 2013)
MOLECULAR BASIS:
Caused by mutation in the six-transmembrane epithelial antigen of
prostate 3 gene (STEAP3, 609671.0001)
*FIELD* CD
Marla J. F. O'Neill: 6/3/2013
*FIELD* ED
joanna: 06/03/2013
*FIELD* CD
Marla J. F. O'Neill: 5/16/2013
*FIELD* ED
carol: 05/16/2013
carol: 5/16/2013
*RECORD*
*FIELD* NO
615234
*FIELD* TI
#615234 ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 2; AHMIO2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read morehypochromic microcytic anemia with iron overload-2 (AHMIO2) is caused by
heterozygous mutation in the STEAP3 gene (609671) on chromosome 2q14.
One such family has been reported.
For a discussion of genetic heterogeneity of hypochromic microcytic
anemia with iron overload, see AHMIO1 (206100).
CLINICAL FEATURES
Grandchamp et al. (2011) reported 3 sibs, born of nonconsanguineous
Pakistani parents, who had transfusion-dependent hypochromic microcytic
anemia with iron overload. The proband was a 24-year-old man who had
been pale since infancy and was documented to be anemic at 7.5 years of
age. Follow-up revealed chronic hypochromic anemia, and biochemical data
suggested the onset of iron overload. He presented with increasing
fatigue at 19 years of age, at which time his spleen was palpable and he
was severely anemic; regular transfusions were begun to maintain a
hemoglobin level permitting normal physical activity. Blood smears
revealed distinct aniso-poikilocytosis with hypochromasia and
microcytosis, ovalocytes, a few target cells, and basophilic stippled
cells, with single mature nucleated red cells present. There was
moderate erythropoietic hyperplasia of the bone marrow, with dysplastic
features in less than 3% of erythroblasts; late basophilic and
polychromatophilic erythroblasts had a small rim of poorly
hemoglobinized cytoplasm, with small inclusions in some cells. Perls
staining showed iron-positive inclusions in most red cell precursors,
with 40% ringed sideroblasts, and Pappenheimer bodies in a few red
cells. Under transmission electron microscopy, deposits of iron could be
seen inside as well as outside the mitochondria. The proband's 2
affected sibs had similar biochemical and morphologic data. The
23-year-old sister had only mild symptoms of anemia in childhood and
began regular transfusions at 15 years of age, whereas the 18-year-old
brother had a more severe form of anemia since infancy, requiring
transfusions beginning at 7 years of age, with growth retardation,
massive hepatosplenomegaly and high iron overload, and cafe-au-lait
spots visible on his skin. All 3 sibs had high serum ferritin and low
transferrin values, as well as distinctly increased transferrin
saturation despite regular treatment with deferasirox. In addition, they
all had hypogonadism, with azoospermia in the males and atrophy of the
gonads in the female; complex dysfunction of the
hypothalamo-pituitary-gonadal axis was present in all 3 patients,
suggesting a primary defect of the gonads in addition to secondary
hypogonadism. Latent adrenal and thyroid failure was also detected in
the younger brother. Their father had normal blood counts and iron data,
whereas their mother had mild microcytic anemia with a low serum
ferritin, which responded to iron supplementation. She had had 2
miscarriages in addition to the 3 live births.
MOLECULAR GENETICS
In 3 sibs with hypochromic microcytic anemia and iron overload, born of
nonconsanguineous Pakistani parents, Grandchamp et al. (2011) analyzed 7
candidate genes and identified heterozygosity for a nonsense mutation in
the STEAP3 gene (C100X; 609671.0001) that was inherited from their
unaffected father. Quantitative RT-PCR from blood mRNA of all 5 family
members and 10 controls showed that the STEAP3 mRNA level was
considerably lower in the 3 patients, whereas both parents had a level
of STEAP3 mRNA corresponding to the low-normal range found in controls.
In B-lymphocyte cell lines treated to prevent degradation due to
nonsense-mediated mRNA decay, quantitative sequencing of a cDNA fragment
encompassing the mutated nucleotide demonstrated that expression of the
normal allele relative to that of the mutated allele was significantly
higher in the father than in the 3 sibs. Grandchamp et al. (2011)
suggested that the father was heterozygous with 1 null allele and 1
normal, highly expressed allele, whereas the mother had 2 weakly
expressed alleles, and each affected offspring had inherited the mutated
allele from their father and 1 of the weakly expressed alleles from
their mother. This was supported by the fact that expression of both
alleles from the mother produced an amount of mRNA that was roughly
equivalent to the expression products from the single normal allele of
the father.
*FIELD* RF
1. Grandchamp, B.; Hetet, G.; Kannengiesser, C.; Oudin, C.; Beaumont,
C.; Rodrigues-Ferreira, S.; Amson, R.; Telerman, A.; Nielsen, P.;
Kohne, E.; Balser, C.; Heimpel, H.: A novel type of congenital hypochromic
anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 118:
6660-6666, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GROWTH:
Growth retardation (in some patients)
HEAD AND NECK:
[Eyes];
Marked pallor of mucous membranes;
[Mouth];
Marked pallor of mucous membranes
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly
GENITOURINARY:
[External genitalia, male];
Hypogonadism;
[Internal genitalia, male];
Azoospermia;
[Internal genitalia, female];
Gonadal atrophy
SKIN, NAILS, HAIR:
[Skin];
Marked skin pallor;
Cafe au lait spots (in some patients)
ENDOCRINE FEATURES:
Dysfunction of hypothalamo-pituitary-gonadal axis;
Adrenal failure (in some patients);
Thyroid failure (in some patients)
HEMATOLOGY:
Anemia, severe;
Hypochromia;
Microcytosis;
Elevated serum ferritin;
Low serum transferrin;
Increased transferrin saturation;
Aniso-poikilocytosis on blood smear;
Erythropoietic hyperplasia of bone marrow
MISCELLANEOUS:
Patients have severe anemia requiring regular transfusions for normal
activity;
One family reported (last curated May 2013)
MOLECULAR BASIS:
Caused by mutation in the six-transmembrane epithelial antigen of
prostate 3 gene (STEAP3, 609671.0001)
*FIELD* CD
Marla J. F. O'Neill: 6/3/2013
*FIELD* ED
joanna: 06/03/2013
*FIELD* CD
Marla J. F. O'Neill: 5/16/2013
*FIELD* ED
carol: 05/16/2013
carol: 5/16/2013