DKK3_HUMAN
ID DKK3_HUMAN Reviewed; 350 AA.
AC Q9UBP4; A8K1I2; D3DQW1; Q9ULB7;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 2.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Dickkopf-related protein 3;
DE Short=Dickkopf-3;
DE Short=Dkk-3;
DE Short=hDkk-3;
DE Flags: Precursor;
GN Name=DKK3; Synonyms=REIC; ORFNames=UNQ258/PRO295;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, POSSIBLE FUNCTION,
RP GLYCOSYLATION, AND VARIANT GLY-335.
RC TISSUE=Fetal brain;
RX PubMed=10570958; DOI=10.1016/s0378-1119(99)00365-0;
RA Krupnik V.E., Sharp J.D., Jiang C., Robison K., Chickering T.W.,
RA Amaravadi L., Brown D.E., Guyot D., Mays G., Leiby K., Chang B., Duong T.,
RA Goodearl A.D.J., Gearing D.P., Sokol S.Y., McCarthy S.A.;
RT "Functional and structural diversity of the human Dickkopf gene family.";
RL Gene 238:301-313(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLY-335.
RX PubMed=10652205; DOI=10.1006/bbrc.1999.2067;
RA Tsuji T., Miyazaki M., Sakaguchi M., Inoue Y., Namba M.;
RT "A REIC gene shows down-regulation in human immortalized cells and human
RT tumor-derived cell lines.";
RL Biochem. Biophys. Res. Commun. 268:20-24(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT GLY-335.
RX PubMed=11814687; DOI=10.1016/s0378-1119(01)00838-1;
RA Kobayashi K., Ouchida M., Tsuji T., Hanafusa H., Miyazaki M., Namba M.,
RA Shimizu N., Shimizu K.;
RT "Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in
RT human tumor cells.";
RL Gene 282:151-158(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND VARIANT GLY-335.
RA Tanaka S., Sugimachi K., Sugimachi K.;
RT "Human homologue of Dickkopf-3.";
RL Submitted (OCT-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Tate G., Mitsuya T.;
RT "Human Dickkopf-3, genomic sequence.";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-335.
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-335.
RC TISSUE=Corpus callosum;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLY-335.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLY-335.
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 22-36.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [12]
RP REVIEW OF THE DKK FAMILY.
RX PubMed=17143291; DOI=10.1038/sj.onc.1210054;
RA Niehrs C.;
RT "Function and biological roles of the Dickkopf family of Wnt modulators.";
RL Oncogene 25:7469-7481(2006).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS], SIGNAL SEQUENCE CLEAVAGE SITE, AND
RP STRUCTURE OF CARBOHYDRATES.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G.,
RA Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [14]
RP GLYCOSYLATION AT THR-26 AND THR-28, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures
RT of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
CC -!- FUNCTION: Antagonizes canonical Wnt signaling by inhibiting LRP5/6
CC interaction with Wnt and by forming a ternary complex with the
CC transmembrane protein KREMEN that promotes internalization of LRP5/6.
CC DKKs play an important role in vertebrate development, where they
CC locally inhibit Wnt regulated processes such as antero-posterior axial
CC patterning, limb development, somitogenesis and eye formation. In the
CC adult, Dkks are implicated in bone formation and bone disease, cancer
CC and Alzheimer disease (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Interacts with LRP5 and LRP6. {ECO:0000250}.
CC -!- INTERACTION:
CC Q9UBP4; P46379-2: BAG6; NbExp=3; IntAct=EBI-954409, EBI-10988864;
CC Q9UBP4; O75190-2: DNAJB6; NbExp=3; IntAct=EBI-954409, EBI-12593112;
CC Q9UBP4; O14901: KLF11; NbExp=3; IntAct=EBI-954409, EBI-948266;
CC Q9UBP4; O43765: SGTA; NbExp=3; IntAct=EBI-954409, EBI-347996;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Highest expression in heart, brain, and spinal
CC cord. {ECO:0000269|PubMed:10570958, ECO:0000269|Ref.4}.
CC -!- DOMAIN: The C-terminal cysteine-rich domain mediates interaction with
CC LRP5 and LRP6. {ECO:0000250}.
CC -!- PTM: N- and O-glycosylated. {ECO:0000269|PubMed:10570958,
CC ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:23234360}.
CC -!- SIMILARITY: Belongs to the dickkopf family. {ECO:0000305}.
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DR EMBL; AF177396; AAF02676.1; -; mRNA.
DR EMBL; AB034203; BAA90548.1; -; mRNA.
DR EMBL; AB057591; BAB84360.1; -; mRNA.
DR EMBL; AB057804; BAB84361.1; -; Genomic_DNA.
DR EMBL; AB033421; BAA85488.1; -; mRNA.
DR EMBL; AB035182; BAA87044.2; -; Genomic_DNA.
DR EMBL; AY358378; AAQ88744.1; -; mRNA.
DR EMBL; AK289897; BAF82586.1; -; mRNA.
DR EMBL; AC124276; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW68534.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68535.1; -; Genomic_DNA.
DR EMBL; CH471064; EAW68537.1; -; Genomic_DNA.
DR EMBL; BC007660; AAH07660.1; -; mRNA.
DR CCDS; CCDS7808.1; -.
DR PIR; JC7188; JC7188.
DR RefSeq; NP_001018067.1; NM_001018057.1.
DR RefSeq; NP_001317149.1; NM_001330220.1.
DR RefSeq; NP_037385.2; NM_013253.4.
DR RefSeq; NP_056965.3; NM_015881.5.
DR RefSeq; XP_006718241.1; XM_006718178.2.
DR AlphaFoldDB; Q9UBP4; -.
DR BioGRID; 118013; 76.
DR IntAct; Q9UBP4; 65.
DR MINT; Q9UBP4; -.
DR STRING; 9606.ENSP00000379762; -.
DR GlyConnect; 822; 4 N-Linked glycans (2 sites), 1 O-Linked glycan (2 sites).
DR GlyGen; Q9UBP4; 8 sites, 4 N-linked glycans (2 sites), 3 O-linked glycans (3 sites).
DR iPTMnet; Q9UBP4; -.
DR PhosphoSitePlus; Q9UBP4; -.
DR BioMuta; DKK3; -.
DR DMDM; 311033372; -.
DR EPD; Q9UBP4; -.
DR jPOST; Q9UBP4; -.
DR MassIVE; Q9UBP4; -.
DR MaxQB; Q9UBP4; -.
DR PaxDb; Q9UBP4; -.
DR PeptideAtlas; Q9UBP4; -.
DR PRIDE; Q9UBP4; -.
DR ProteomicsDB; 84024; -.
DR Antibodypedia; 2166; 642 antibodies from 41 providers.
DR DNASU; 27122; -.
DR Ensembl; ENST00000326932.8; ENSP00000314910.4; ENSG00000050165.19.
DR Ensembl; ENST00000396505.7; ENSP00000379762.2; ENSG00000050165.19.
DR Ensembl; ENST00000683431.1; ENSP00000506835.1; ENSG00000050165.19.
DR GeneID; 27122; -.
DR KEGG; hsa:27122; -.
DR MANE-Select; ENST00000683431.1; ENSP00000506835.1; NM_001018057.2; NP_001018067.1.
DR UCSC; uc001mjv.4; human.
DR CTD; 27122; -.
DR DisGeNET; 27122; -.
DR GeneCards; DKK3; -.
DR HGNC; HGNC:2893; DKK3.
DR HPA; ENSG00000050165; Tissue enriched (heart).
DR MIM; 605416; gene.
DR neXtProt; NX_Q9UBP4; -.
DR OpenTargets; ENSG00000050165; -.
DR PharmGKB; PA27347; -.
DR VEuPathDB; HostDB:ENSG00000050165; -.
DR eggNOG; KOG1218; Eukaryota.
DR GeneTree; ENSGT00390000000221; -.
DR HOGENOM; CLU_055300_0_0_1; -.
DR InParanoid; Q9UBP4; -.
DR OMA; QCQPHGR; -.
DR PhylomeDB; Q9UBP4; -.
DR TreeFam; TF337340; -.
DR PathwayCommons; Q9UBP4; -.
DR SignaLink; Q9UBP4; -.
DR SIGNOR; Q9UBP4; -.
DR BioGRID-ORCS; 27122; 9 hits in 1077 CRISPR screens.
DR ChiTaRS; DKK3; human.
DR GeneWiki; DKK3; -.
DR GenomeRNAi; 27122; -.
DR Pharos; Q9UBP4; Tbio.
DR PRO; PR:Q9UBP4; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q9UBP4; protein.
DR Bgee; ENSG00000050165; Expressed in endothelial cell and 202 other tissues.
DR ExpressionAtlas; Q9UBP4; baseline and differential.
DR Genevisible; Q9UBP4; HS.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0039706; F:co-receptor binding; IBA:GO_Central.
DR GO; GO:0048019; F:receptor antagonist activity; IBA:GO_Central.
DR GO; GO:0030325; P:adrenal gland development; IEP:UniProtKB.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0032348; P:negative regulation of aldosterone biosynthetic process; IDA:UniProtKB.
DR GO; GO:1902613; P:negative regulation of anti-Mullerian hormone signaling pathway; TAS:ParkinsonsUK-UCL.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL.
DR GO; GO:2000065; P:negative regulation of cortisol biosynthetic process; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; NAS:ParkinsonsUK-UCL.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR006796; Dickkopf_N.
DR InterPro; IPR039863; DKK-like.
DR PANTHER; PTHR12113; PTHR12113; 1.
DR Pfam; PF04706; Dickkopf_N; 1.
PE 1: Evidence at protein level;
KW Coiled coil; Developmental protein; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Reference proteome; Secreted; Signal;
KW Wnt signaling pathway.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:15340161,
FT ECO:0000269|PubMed:19838169"
FT CHAIN 22..350
FT /note="Dickkopf-related protein 3"
FT /id="PRO_0000007222"
FT REGION 29..46
FT /note="O-glycosylated at one site"
FT REGION 147..195
FT /note="DKK-type Cys-1"
FT REGION 208..284
FT /note="DKK-type Cys-2"
FT COILED 40..84
FT /evidence="ECO:0000255"
FT CARBOHYD 26
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:23234360"
FT CARBOHYD 28
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:23234360"
FT CARBOHYD 96
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 106
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 121
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 204
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 208..220
FT /evidence="ECO:0000250"
FT DISULFID 214..231
FT /evidence="ECO:0000250"
FT DISULFID 219..265
FT /evidence="ECO:0000250"
FT DISULFID 241..273
FT /evidence="ECO:0000250"
FT VARIANT 49
FT /note="E -> D (in dbSNP:rs11544816)"
FT /id="VAR_057516"
FT VARIANT 335
FT /note="R -> G (in dbSNP:rs3206824)"
FT /evidence="ECO:0000269|PubMed:10570958,
FT ECO:0000269|PubMed:10652205, ECO:0000269|PubMed:11814687,
FT ECO:0000269|PubMed:12975309, ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|Ref.4,
FT ECO:0000269|Ref.9"
FT /id="VAR_030787"
SQ SEQUENCE 350 AA; 38390 MW; 734504122B40AFEE CRC64;
MQRLGATLLC LLLAAAVPTA PAPAPTATSA PVKPGPALSY PQEEATLNEM FREVEELMED
TQHKLRSAVE EMEAEEAAAK ASSEVNLANL PPSYHNETNT DTKVGNNTIH VHREIHKITN
NQTGQMVFSE TVITSVGDEE GRRSHECIID EDCGPSMYCQ FASFQYTCQP CRGQRMLCTR
DSECCGDQLC VWGHCTKMAT RGSNGTICDN QRDCQPGLCC AFQRGLLFPV CTPLPVEGEL
CHDPASRLLD LITWELEPDG ALDRCPCASG LLCQPHSHSL VYVCKPTFVG SRDQDGEILL
PREVPDEYEV GSFMEEVRQE LEDLERSLTE EMALREPAAA AAALLGGEEI
