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O94907 (DKK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 127. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dickkopf-related protein 1

Short name=Dickkopf-1
Short name=Dkk-1
Short name=hDkk-1
Alternative name(s):
SK
Gene names
Name:DKK1
ORF Names:UNQ492/PRO1008
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length266 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.15

Subunit structure

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. Ref.10 Ref.12 Ref.13

Subcellular location

Secreted.

Tissue specificity

Placenta.

Domain

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

Sequence similarities

Belongs to the dickkopf family.

Ontologies

Keywords
   Biological processWnt signaling pathway
   Cellular componentSecreted
   DomainSignal
   Molecular functionDevelopmental protein
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway involved in somitogenesis

Inferred from electronic annotation. Source: Ensembl

cell morphogenesis involved in differentiation

Inferred from electronic annotation. Source: Ensembl

embryonic limb morphogenesis

Inferred from electronic annotation. Source: Ensembl

endoderm formation

Inferred from electronic annotation. Source: Ensembl

extracellular negative regulation of signal transduction

Inferred from direct assay PubMed 20723538. Source: GOC

face morphogenesis

Inferred from electronic annotation. Source: Ensembl

forebrain development

Inferred from electronic annotation. Source: Ensembl

hair follicle development

Inferred from electronic annotation. Source: Ensembl

mesoderm formation

Inferred from electronic annotation. Source: Ensembl

negative regulation of BMP signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of Wnt signaling pathway

Inferred from direct assay PubMed 22615920. Source: UniProt

negative regulation of canonical Wnt signaling pathway

Inferred from direct assay Ref.10PubMed 11742004PubMed 12857724PubMed 17804805PubMed 18044981PubMed 20039315. Source: BHF-UCL

negative regulation of canonical Wnt signaling pathway involved in cardiac muscle cell fate commitment

Inferred from direct assay PubMed 20559569. Source: BHF-UCL

negative regulation of cardiac muscle cell differentiation

Inferred from direct assay PubMed 20559569. Source: BHF-UCL

negative regulation of mesodermal cell fate specification

Inferred from direct assay PubMed 20559569. Source: BHF-UCL

negative regulation of pathway-restricted SMAD protein phosphorylation

Inferred from direct assay PubMed 20559569. Source: BHF-UCL

negative regulation of peptidyl-serine phosphorylation

Inferred from direct assay PubMed 20723538. Source: BHF-UCL

negative regulation of protein complex assembly

Inferred from direct assay Ref.10. Source: BHF-UCL

negative regulation of skeletal muscle tissue development

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 20723538. Source: BHF-UCL

positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway

Inferred from sequence or structural similarity. Source: BHF-UCL

regulation of endodermal cell fate specification

Inferred from direct assay PubMed 20559569. Source: BHF-UCL

regulation of receptor internalization

Inferred from direct assay PubMed 17804805. Source: BHF-UCL

response to retinoic acid

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentextracellular space

Inferred from direct assay Ref.10PubMed 11742004. Source: BHF-UCL

plasma membrane

Inferred from direct assay PubMed 16263759. Source: MGI

   Molecular_functiongrowth factor activity

Traceable author statement Ref.1. Source: ProtInc

low-density lipoprotein particle receptor binding

Inferred from direct assay PubMed 16263759. Source: MGI

protein binding

Inferred from physical interaction Ref.10PubMed 16189514PubMed 19060904. Source: IntAct

receptor antagonist activity

Inferred from direct assay PubMed 20723538. Source: BHF-UCL

signal transducer activity

Traceable author statement Ref.1. Source: ProtInc

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3131 Ref.9
Chain32 – 266235Dickkopf-related protein 1
PRO_0000007218

Regions

Region85 – 13854DKK-type Cys-1
Region189 – 26375DKK-type Cys-2

Amino acid modifications

Glycosylation611O-linked (GalNAc...) Ref.14
Glycosylation2561N-linked (GlcNAc...) Ref.14
Disulfide bond85 ↔ 97 Ref.14 Ref.15
Disulfide bond91 ↔ 111 Ref.14 Ref.15
Disulfide bond114 ↔ 128 Ref.14 Ref.15
Disulfide bond121 ↔ 133 Ref.14 Ref.15
Disulfide bond127 ↔ 138 Ref.14 Ref.15
Disulfide bond189 ↔ 201 Ref.14 Ref.15
Disulfide bond195 ↔ 210 Ref.14 Ref.15
Disulfide bond200 ↔ 237 Ref.14 Ref.15
Disulfide bond220 ↔ 245 Ref.14 Ref.15
Disulfide bond239 ↔ 263 Ref.14 Ref.15

Secondary structure

............. 266
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
O94907 [UniParc].

Last modified May 1, 1999. Version 1.
Checksum: 5E878B2CCE4236BA

FASTA26628,672
        10         20         30         40         50         60 
MMALGAAGAT RVFVAMVAAA LGGHPLLGVS ATLNSVLNSN AIKNLPPPLG GAAGHPGSAV 

        70         80         90        100        110        120 
SAAPGILYPG GNKYQTIDNY QPYPCAEDEE CGTDEYCASP TRGGDAGVQI CLACRKRRKR 

       130        140        150        160        170        180 
CMRHAMCCPG NYCKNGICVS SDQNHFRGEI EETITESFGN DHSTLDGYSR RTTLSSKMYH 

       190        200        210        220        230        240 
TKGQEGSVCL RSSDCASGLC CARHFWSKIC KPVLKEGQVC TKHRRKGSHG LEIFQRCYCG 

       250        260 
EGLSCRIQKD HHQASNSSRL HTCQRH 

« Hide

References

« Hide 'large scale' references
[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]"Functional and structural diversity of the human Dickkopf gene family."
Krupnik V.E., Sharp J.D., Jiang C., Robison K., Chickering T.W., Amaravadi L., Brown D.E., Guyot D., Mays G., Leiby K., Chang B., Duong T., Goodearl A.D.J., Gearing D.P., Sokol S.Y., McCarthy S.A.
Gene 238:301-313(1999) [PubMed] [Europe PMC] [Abstract]
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]"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment."
Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. expand/collapse author list , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.
Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract]
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. expand/collapse author list , 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]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS7246.1.
RefSeqNP_036374.1. NM_012242.2.
UniGeneHs.40499.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3S2KX-ray2.80C178-266[»]
3S8VX-ray3.10X183-266[»]
ProteinModelPortalO94907.
SMRO94907. Positions 182-266.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid116599. 6 interactions.
DIPDIP-46461N.
IntActO94907. 4 interactions.
MINTMINT-1196808.
STRING9606.ENSP00000363081.

Chemistry

BindingDBO94907.
ChEMBLCHEMBL6024.

Proteomic databases

MaxQBO94907.
PaxDbO94907.
PRIDEO94907.

Protocols and materials databases

DNASU22943.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000373970; ENSP00000363081; ENSG00000107984.
GeneID22943.
KEGGhsa:22943.
UCSCuc001jjr.3. human.

Organism-specific databases

CTD22943.
GeneCardsGC10P054074.
HGNCHGNC:2891. DKK1.
HPACAB009726.
HPA018995.
MIM605189. gene.
neXtProtNX_O94907.
Orphanet85193. Idiopathic juvenile osteoporosis.
PharmGKBPA27345.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG289067.
HOGENOMHOG000246998.
HOVERGENHBG000441.
InParanoidO94907.
KOK02165.
OMAGQEGSVC.
OrthoDBEOG7K3TMT.
PhylomeDBO94907.
TreeFamTF330916.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
SignaLinkO94907.

Gene expression databases

ArrayExpressO94907.
BgeeO94907.
CleanExHS_DKK1.
GenevestigatorO94907.

Family and domain databases

InterProIPR006796. Dickkopf_N.
[Graphical view]
PfamPF04706. Dickkopf_N. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSDKK1. human.
GeneWikiDKK1.
GenomeRNAi22943.
NextBio43697.
PMAP-CutDBO94907.
PROO94907.
SOURCESearch...

Entry information

Entry nameDKK1_HUMAN
AccessionPrimary (citable) accession number: O94907
Secondary accession number(s): B2RC19
Entry history
Integrated into UniProtKB/Swiss-Prot: February 21, 2001
Last sequence update: May 1, 1999
Last modified: July 9, 2014
This is version 127 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 10

Human chromosome 10: entries, gene names and cross-references to MIM