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Protein

Dickkopf-related protein 1

Gene

DKK1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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. receptor antagonist activity Source: BHF-UCL
  4. 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: UniProtKB
  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
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Wnt signaling pathway

Enzyme and pathway databases

ReactomeiREACT_264383. negative regulation of TCF-dependent signaling by WNT ligand antagonists.
REACT_264594. misspliced LRP5 mutants have enhanced beta-catenin-dependent signaling.
REACT_264596. 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 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:2891. DKK1.

Subcellular locationi

GO - Cellular componenti

  1. early endosome membrane Source: Reactome
  2. extracellular region Source: Reactome
  3. extracellular space Source: BHF-UCL
  4. plasma membrane Source: MGI
Complete GO annotation...

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

BgeeiO94907.
CleanExiHS_DKK1.
ExpressionAtlasiO94907. baseline and differential.
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. 14 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 – 1943Combined sources
Beta strandi199 – 2046Combined sources
Beta strandi207 – 2126Combined sources
Helixi226 – 2316Combined sources
Beta strandi243 – 2475Combined sources
Beta strandi261 – 2655Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
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.
GeneTreeiENSGT00390000007000.
HOGENOMiHOG000246998.
HOVERGENiHBG000441.
InParanoidiO94907.
KOiK02165.
OMAiRSSDCAT.
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

        10         20         30         40         50
MMALGAAGAT RVFVAMVAAA LGGHPLLGVS ATLNSVLNSN AIKNLPPPLG
60 70 80 90 100
GAAGHPGSAV SAAPGILYPG GNKYQTIDNY QPYPCAEDEE CGTDEYCASP
110 120 130 140 150
TRGGDAGVQI CLACRKRRKR CMRHAMCCPG NYCKNGICVS SDQNHFRGEI
160 170 180 190 200
EETITESFGN DHSTLDGYSR RTTLSSKMYH TKGQEGSVCL RSSDCASGLC
210 220 230 240 250
CARHFWSKIC KPVLKEGQVC TKHRRKGSHG LEIFQRCYCG EGLSCRIQKD
260
HHQASNSSRL HTCQRH
Length:266
Mass (Da):28,672
Last modified:May 1, 1999 - v1
Checksum:i5E878B2CCE4236BA
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

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

Protein-protein interaction databases

BioGridi116599. 14 interactions.
DIPiDIP-46461N.
IntActiO94907. 5 interactions.
MINTiMINT-1196808.
STRINGi9606.ENSP00000363081.

Chemistry

BindingDBiO94907.
ChEMBLiCHEMBL6024.

Proteomic databases

MaxQBiO94907.
PaxDbiO94907.
PRIDEiO94907.

Protocols and materials databases

DNASUi22943.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi22943.
GeneCardsiGC10P054074.
HGNCiHGNC:2891. DKK1.
HPAiCAB009726.
HPA018995.
MIMi605189. gene.
neXtProtiNX_O94907.
Orphaneti85193. Idiopathic juvenile osteoporosis.
PharmGKBiPA27345.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG289067.
GeneTreeiENSGT00390000007000.
HOGENOMiHOG000246998.
HOVERGENiHBG000441.
InParanoidiO94907.
KOiK02165.
OMAiRSSDCAT.
OrthoDBiEOG7K3TMT.
PhylomeDBiO94907.
TreeFamiTF330916.

Enzyme and pathway databases

ReactomeiREACT_264383. negative regulation of TCF-dependent signaling by WNT ligand antagonists.
REACT_264594. misspliced LRP5 mutants have enhanced beta-catenin-dependent signaling.
REACT_264596. TCF dependent signaling in response to WNT.
SignaLinkiO94907.

Miscellaneous databases

ChiTaRSiDKK1. human.
GeneWikiiDKK1.
GenomeRNAii22943.
NextBioi43697.
PMAP-CutDBO94907.
PROiO94907.
SOURCEiSearch...

Gene expression databases

BgeeiO94907.
CleanExiHS_DKK1.
ExpressionAtlasiO94907. baseline and differential.
GenevestigatoriO94907.

Family and domain databases

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

Publicationsi

« Hide 'large scale' publications
  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(1998) [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 (OCT-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(1999) [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(2003) [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(2003) [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(2003) [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(2000) [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(2005) [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(2008) [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(2009) [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(2010) [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(2010) [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: April 1, 2015
This is version 135 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.