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 27-MAR-2024, entry version 181. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 SMR; Q9UBP4; -. DR BioGRID; 118013; 76. DR IntAct; Q9UBP4; 66. DR MINT; Q9UBP4; -. DR STRING; 9606.ENSP00000433112; -. DR GlyConnect; 822; 4 N-Linked glycans (2 sites), 1 O-Linked glycan (2 sites). DR GlyCosmos; Q9UBP4; 7 sites, 7 glycans. DR GlyGen; Q9UBP4; 9 sites, 4 N-linked glycans (2 sites), 4 O-linked glycans (4 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; 9606-ENSP00000379762; -. DR PeptideAtlas; Q9UBP4; -. DR ProteomicsDB; 84024; -. DR Pumba; Q9UBP4; -. DR Antibodypedia; 2166; 691 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 AGR; HGNC:2893; -. DR CTD; 27122; -. DR DisGeNET; 27122; -. DR GeneCards; DKK3; -. DR HGNC; HGNC:2893; DKK3. DR HPA; ENSG00000050165; Tissue enhanced (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 OrthoDB; 2903760at2759; -. DR PhylomeDB; Q9UBP4; -. DR TreeFam; TF337340; -. DR PathwayCommons; Q9UBP4; -. DR SignaLink; Q9UBP4; -. DR SIGNOR; Q9UBP4; -. DR BioGRID-ORCS; 27122; 9 hits in 1157 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 204 other cell types or tissues. DR ExpressionAtlas; Q9UBP4; baseline and differential. 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 DNA-templated transcription; 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 CDD; cd23274; Dkk3_Cys2; 1. DR CDD; cd23014; Dkk3_N_Cys1; 1. DR Gene3D; 2.10.80.10; Lipase, subunit A; 1. DR InterPro; IPR006796; Dickkopf_N. DR InterPro; IPR039863; DKK1-4. DR InterPro; IPR047300; Dkk3_Cys2. DR InterPro; IPR047301; Dkk3_N. DR PANTHER; PTHR12113:SF8; DICKKOPF-RELATED PROTEIN 3; 1. DR PANTHER; PTHR12113; DICKKOPF3-LIKE 3; 1. DR Pfam; PF04706; Dickkopf_N; 1. DR Genevisible; Q9UBP4; HS. 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 //