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O94907

- DKK1_HUMAN

UniProt

O94907 - DKK1_HUMAN

Protein

Dickkopf-related protein 1

Gene

DKK1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 129 (01 Oct 2014)
      Sequence version 1 (01 May 1999)
      Previous versions | rss
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    Functioni

    Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease.1 Publication

    GO - Molecular functioni

    1. growth factor activity Source: ProtInc
    2. low-density lipoprotein particle receptor binding Source: MGI
    3. protein binding Source: IntAct
    4. receptor antagonist activity Source: BHF-UCL
    5. signal transducer activity Source: ProtInc

    GO - Biological processi

    1. cell morphogenesis involved in differentiation Source: Ensembl
    2. embryonic limb morphogenesis Source: Ensembl
    3. endoderm formation Source: Ensembl
    4. extracellular negative regulation of signal transduction Source: GOC
    5. face morphogenesis Source: Ensembl
    6. forebrain development Source: Ensembl
    7. hair follicle development Source: Ensembl
    8. mesoderm formation Source: Ensembl
    9. negative regulation of BMP signaling pathway Source: Ensembl
    10. negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
    11. negative regulation of canonical Wnt signaling pathway involved in cardiac muscle cell fate commitment Source: BHF-UCL
    12. negative regulation of cardiac muscle cell differentiation Source: BHF-UCL
    13. negative regulation of mesodermal cell fate specification Source: BHF-UCL
    14. negative regulation of pathway-restricted SMAD protein phosphorylation Source: BHF-UCL
    15. negative regulation of peptidyl-serine phosphorylation Source: BHF-UCL
    16. negative regulation of protein complex assembly Source: BHF-UCL
    17. negative regulation of skeletal muscle tissue development Source: Ensembl
    18. negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    19. negative regulation of Wnt signaling pathway Source: UniProt
    20. positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
    21. regulation of endodermal cell fate specification Source: BHF-UCL
    22. regulation of receptor internalization Source: BHF-UCL
    23. response to retinoic acid Source: Ensembl
    24. Wnt signaling pathway involved in somitogenesis Source: Ensembl

    Keywords - Molecular functioni

    Developmental protein

    Keywords - Biological processi

    Wnt signaling pathway

    Enzyme and pathway databases

    ReactomeiREACT_200643. negative regulation of TCF-dependent signaling by WNT ligand antagonists.
    REACT_200777. TCF dependent signaling in response to WNT.
    SignaLinkiO94907.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dickkopf-related protein 1
    Short name:
    Dickkopf-1
    Short name:
    Dkk-1
    Short name:
    hDkk-1
    Alternative name(s):
    SK
    Gene namesi
    Name:DKK1
    ORF Names:UNQ492/PRO1008
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 10

    Organism-specific databases

    HGNCiHGNC:2891. DKK1.

    Subcellular locationi

    GO - Cellular componenti

    1. extracellular space Source: BHF-UCL
    2. plasma membrane Source: MGI

    Keywords - Cellular componenti

    Secreted

    Pathology & Biotechi

    Organism-specific databases

    Orphaneti85193. Idiopathic juvenile osteoporosis.
    PharmGKBiPA27345.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 31311 PublicationAdd
    BLAST
    Chaini32 – 266235Dickkopf-related protein 1PRO_0000007218Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Glycosylationi61 – 611O-linked (GalNAc...)1 Publication
    Disulfide bondi85 ↔ 97
    Disulfide bondi91 ↔ 111
    Disulfide bondi114 ↔ 128
    Disulfide bondi121 ↔ 133
    Disulfide bondi127 ↔ 138
    Disulfide bondi189 ↔ 201
    Disulfide bondi195 ↔ 210
    Disulfide bondi200 ↔ 237
    Disulfide bondi220 ↔ 245
    Disulfide bondi239 ↔ 263
    Glycosylationi256 – 2561N-linked (GlcNAc...)1 Publication

    Keywords - PTMi

    Disulfide bond, Glycoprotein

    Proteomic databases

    MaxQBiO94907.
    PaxDbiO94907.
    PRIDEiO94907.

    Miscellaneous databases

    PMAP-CutDBO94907.

    Expressioni

    Tissue specificityi

    Placenta.

    Gene expression databases

    ArrayExpressiO94907.
    BgeeiO94907.
    CleanExiHS_DKK1.
    GenevestigatoriO94907.

    Organism-specific databases

    HPAiCAB009726.
    HPA018995.

    Interactioni

    Subunit structurei

    Interacts with LRP6. Interacts (via the C-termianl Cys-rich domain) with LRP5 (via beta-propeller regions 3 and 4); the interaction, enhanced by MESD and or KREMEN, antagonizes Wnt-mediated signaling.4 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    LRP6O755813EBI-742864,EBI-910915
    MDFIQ997503EBI-742864,EBI-724076

    Protein-protein interaction databases

    BioGridi116599. 6 interactions.
    DIPiDIP-46461N.
    IntActiO94907. 5 interactions.
    MINTiMINT-1196808.
    STRINGi9606.ENSP00000363081.

    Structurei

    Secondary structure

    1
    266
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi192 – 1943
    Beta strandi199 – 2046
    Beta strandi207 – 2126
    Helixi226 – 2316
    Beta strandi243 – 2475
    Beta strandi261 – 2655

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3S2KX-ray2.80C178-266[»]
    3S8VX-ray3.10X183-266[»]
    ProteinModelPortaliO94907.
    SMRiO94907. Positions 182-266.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni85 – 13854DKK-type Cys-1Add
    BLAST
    Regioni189 – 26375DKK-type Cys-2Add
    BLAST

    Domaini

    The C-terminal cysteine-rich domain mediates interaction with LRP5 and LRP6.By similarity

    Sequence similaritiesi

    Belongs to the dickkopf family.Curated

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiNOG289067.
    HOGENOMiHOG000246998.
    HOVERGENiHBG000441.
    InParanoidiO94907.
    KOiK02165.
    OMAiGQEGSVC.
    OrthoDBiEOG7K3TMT.
    PhylomeDBiO94907.
    TreeFamiTF330916.

    Family and domain databases

    InterProiIPR006796. Dickkopf_N.
    [Graphical view]
    PfamiPF04706. Dickkopf_N. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    O94907-1 [UniParc]FASTAAdd to Basket

    « Hide

    MMALGAAGAT RVFVAMVAAA LGGHPLLGVS ATLNSVLNSN AIKNLPPPLG    50
    GAAGHPGSAV SAAPGILYPG GNKYQTIDNY QPYPCAEDEE CGTDEYCASP 100
    TRGGDAGVQI CLACRKRRKR CMRHAMCCPG NYCKNGICVS SDQNHFRGEI 150
    EETITESFGN DHSTLDGYSR RTTLSSKMYH TKGQEGSVCL RSSDCASGLC 200
    CARHFWSKIC KPVLKEGQVC TKHRRKGSHG LEIFQRCYCG EGLSCRIQKD 250
    HHQASNSSRL HTCQRH 266
    Length:266
    Mass (Da):28,672
    Last modified:May 1, 1999 - v1
    Checksum:i5E878B2CCE4236BA
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF127563 mRNA. Translation: AAD21087.1.
    AF177394 mRNA. Translation: AAF02674.1.
    AB020315 Genomic DNA. Translation: BAA34651.1.
    AF261158, AF261157 Genomic DNA. Translation: AAG15544.1.
    AY359005 mRNA. Translation: AAQ89364.1.
    AK314902 mRNA. Translation: BAG37416.1.
    CH471083 Genomic DNA. Translation: EAW54144.1.
    BC001539 mRNA. Translation: AAH01539.1.
    CCDSiCCDS7246.1.
    RefSeqiNP_036374.1. NM_012242.2.
    UniGeneiHs.40499.

    Genome annotation databases

    EnsembliENST00000373970; ENSP00000363081; ENSG00000107984.
    GeneIDi22943.
    KEGGihsa:22943.
    UCSCiuc001jjr.3. human.

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF127563 mRNA. Translation: AAD21087.1 .
    AF177394 mRNA. Translation: AAF02674.1 .
    AB020315 Genomic DNA. Translation: BAA34651.1 .
    AF261158 , AF261157 Genomic DNA. Translation: AAG15544.1 .
    AY359005 mRNA. Translation: AAQ89364.1 .
    AK314902 mRNA. Translation: BAG37416.1 .
    CH471083 Genomic DNA. Translation: EAW54144.1 .
    BC001539 mRNA. Translation: AAH01539.1 .
    CCDSi CCDS7246.1.
    RefSeqi NP_036374.1. NM_012242.2.
    UniGenei Hs.40499.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3S2K X-ray 2.80 C 178-266 [» ]
    3S8V X-ray 3.10 X 183-266 [» ]
    ProteinModelPortali O94907.
    SMRi O94907. Positions 182-266.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 116599. 6 interactions.
    DIPi DIP-46461N.
    IntActi O94907. 5 interactions.
    MINTi MINT-1196808.
    STRINGi 9606.ENSP00000363081.

    Chemistry

    BindingDBi O94907.
    ChEMBLi CHEMBL6024.

    Proteomic databases

    MaxQBi O94907.
    PaxDbi O94907.
    PRIDEi O94907.

    Protocols and materials databases

    DNASUi 22943.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000373970 ; ENSP00000363081 ; ENSG00000107984 .
    GeneIDi 22943.
    KEGGi hsa:22943.
    UCSCi uc001jjr.3. human.

    Organism-specific databases

    CTDi 22943.
    GeneCardsi GC10P054074.
    HGNCi HGNC:2891. DKK1.
    HPAi CAB009726.
    HPA018995.
    MIMi 605189. gene.
    neXtProti NX_O94907.
    Orphaneti 85193. Idiopathic juvenile osteoporosis.
    PharmGKBi PA27345.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG289067.
    HOGENOMi HOG000246998.
    HOVERGENi HBG000441.
    InParanoidi O94907.
    KOi K02165.
    OMAi GQEGSVC.
    OrthoDBi EOG7K3TMT.
    PhylomeDBi O94907.
    TreeFami TF330916.

    Enzyme and pathway databases

    Reactomei REACT_200643. negative regulation of TCF-dependent signaling by WNT ligand antagonists.
    REACT_200777. TCF dependent signaling in response to WNT.
    SignaLinki O94907.

    Miscellaneous databases

    ChiTaRSi DKK1. human.
    GeneWikii DKK1.
    GenomeRNAii 22943.
    NextBioi 43697.
    PMAP-CutDB O94907.
    PROi O94907.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O94907.
    Bgeei O94907.
    CleanExi HS_DKK1.
    Genevestigatori O94907.

    Family and domain databases

    InterProi IPR006796. Dickkopf_N.
    [Graphical view ]
    Pfami PF04706. Dickkopf_N. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling."
      Fedi P., Bafico A., Nieto Soria A., Burgess W.H., Miki T., Bottaro D.P., Kraus M.H., Aaronson S.A.
      J. Biol. Chem. 274:19465-19472(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Leiomyosarcoma.
    2. Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Fetal kidney.
    3. Tate G., Suzuki T., Mitsuya T.
      Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "The genomic structure, chromosome location, and analysis of the human DKK1 head inducer gene as a candidate for holoprosencephaly."
      Roessler E., Du Y., Glinka A., Dutra A., Niehrs C., Muenke M.
      Cytogenet. Cell Genet. 89:220-224(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    6. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Cerebellum.
    7. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    8. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Brain.
    9. "Signal peptide prediction based on analysis of experimentally verified cleavage sites."
      Zhang Z., Henzel W.J.
      Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 32-46.
    10. "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6."
      Semenov M.V., Tamai K., Brott B.K., Kuhl M., Sokol S., He X.
      Curr. Biol. 11:951-961(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LRP6.
    11. "Function and biological roles of the Dickkopf family of Wnt modulators."
      Niehrs C.
      Oncogene 25:7469-7481(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW OF THE DKK FAMILY.
    12. "A cell-based Dkk1 binding assay reveals roles for extracellular domains of LRP5 in Dkk1 interaction and highlights differences between wild-type and the high bone mass mutant LRP5(G171V)."
      Murrills R.J., Matteo J.J., Bhat B.M., Coleburn V.E., Allen K.M., Chen W., Damagnez V., Bhat R.A., Bex F.J., Bodine P.V.
      J. Cell. Biochem. 108:1066-1075(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LRP5.
    13. "Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6."
      Bourhis E., Tam C., Franke Y., Bazan J.F., Ernst J., Hwang J., Costa M., Cochran A.G., Hannoush R.N.
      J. Biol. Chem. 285:9172-9179(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LRP6.
    14. "Human Dickkopf-1 (huDKK1) protein: characterization of glycosylation and determination of disulfide linkages in the two cysteine-rich domains."
      Haniu M., Horan T., Spahr C., Hui J., Fan W., Chen C., Richards W.G., Lu H.S.
      Protein Sci. 20:1802-1813(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: GLYCOSYLATION AT SER-61 AND ASN-256, DISULFIDE BONDS.
    15. "Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6."
      Ahn V.E., Chu M.L., Choi H.J., Tran D., Abo A., Weis W.I.
      Dev. Cell 21:862-873(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 178-266 IN COMPLEX WITH LRP6, FUNCTION, DISULFIDE BONDS.

    Entry informationi

    Entry nameiDKK1_HUMAN
    AccessioniPrimary (citable) accession number: O94907
    Secondary accession number(s): B2RC19
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 21, 2001
    Last sequence update: May 1, 1999
    Last modified: October 1, 2014
    This is version 129 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 10
      Human chromosome 10: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3