DKK4_HUMAN
ID DKK4_HUMAN Reviewed; 224 AA.
AC Q9UBT3; Q3KNX0; Q9Y4C3;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Dickkopf-related protein 4;
DE Short=Dickkopf-4;
DE Short=Dkk-4;
DE Short=hDkk-4;
DE Contains:
DE RecName: Full=Dickkopf-related protein 4 short form;
DE Flags: Precursor;
GN Name=DKK4;
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], PROTEIN SEQUENCE OF 19-28 AND 134-144, AND
RP PROTEOLYTIC PROCESSING.
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 [GENOMIC DNA / MRNA].
RA Tate G., Mitsuya T.;
RT "Human Dickkopf as well as DAN family members, Cerberus and Gremlin, are
RT preferentially expressed in the epithelial malignant cell lines.";
RL J. Biochem. Mol. Biol. Biophys. 3:239-242(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP PROTEIN SEQUENCE OF 19-33.
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 [5]
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).
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 Q9UBT3; Q96F15: GIMAP5; NbExp=3; IntAct=EBI-18030204, EBI-6166686;
CC Q9UBT3; P11215: ITGAM; NbExp=3; IntAct=EBI-18030204, EBI-2568251;
CC Q9UBT3; Q96CV9: OPTN; NbExp=3; IntAct=EBI-18030204, EBI-748974;
CC Q9UBT3; Q5TGU0: TSPO2; NbExp=3; IntAct=EBI-18030204, EBI-12195249;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed in cerebellum, T-cells, esophagus and
CC lung.
CC -!- DOMAIN: The C-terminal cysteine-rich domain mediates interaction with
CC LRP5 and LRP6. {ECO:0000250}.
CC -!- PTM: Appears to be not glycosylated.
CC -!- PTM: Can be proteolytically processed by a furin-like protease.
CC {ECO:0000269|PubMed:10570958}.
CC -!- SIMILARITY: Belongs to the dickkopf family. {ECO:0000305}.
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DR EMBL; AF177397; AAF02677.1; -; mRNA.
DR EMBL; AB018005; BAA33475.1; -; Genomic_DNA.
DR EMBL; AB017788; BAA33438.1; -; mRNA.
DR EMBL; BC107046; AAI07047.1; -; mRNA.
DR EMBL; BC107047; AAI07048.1; -; mRNA.
DR CCDS; CCDS6130.1; -.
DR RefSeq; NP_055235.1; NM_014420.2.
DR RefSeq; XP_011542790.1; XM_011544488.2.
DR RefSeq; XP_016868805.1; XM_017013316.1.
DR PDB; 5O57; NMR; -; A=19-97.
DR PDBsum; 5O57; -.
DR AlphaFoldDB; Q9UBT3; -.
DR SMR; Q9UBT3; -.
DR BioGRID; 118012; 8.
DR IntAct; Q9UBT3; 8.
DR STRING; 9606.ENSP00000220812; -.
DR GlyGen; Q9UBT3; 1 site, 1 O-linked glycan (1 site).
DR PhosphoSitePlus; Q9UBT3; -.
DR BioMuta; DKK4; -.
DR DMDM; 13124092; -.
DR MassIVE; Q9UBT3; -.
DR PaxDb; Q9UBT3; -.
DR PeptideAtlas; Q9UBT3; -.
DR PRIDE; Q9UBT3; -.
DR ProteomicsDB; 84056; -.
DR Antibodypedia; 24127; 414 antibodies from 33 providers.
DR DNASU; 27121; -.
DR Ensembl; ENST00000220812.3; ENSP00000220812.2; ENSG00000104371.5.
DR GeneID; 27121; -.
DR KEGG; hsa:27121; -.
DR MANE-Select; ENST00000220812.3; ENSP00000220812.2; NM_014420.3; NP_055235.1.
DR UCSC; uc003xpb.4; human.
DR CTD; 27121; -.
DR DisGeNET; 27121; -.
DR GeneCards; DKK4; -.
DR HGNC; HGNC:2894; DKK4.
DR HPA; ENSG00000104371; Tissue enhanced (brain, esophagus).
DR MIM; 605417; gene.
DR neXtProt; NX_Q9UBT3; -.
DR OpenTargets; ENSG00000104371; -.
DR PharmGKB; PA27348; -.
DR VEuPathDB; HostDB:ENSG00000104371; -.
DR eggNOG; KOG1218; Eukaryota.
DR GeneTree; ENSGT00940000161614; -.
DR HOGENOM; CLU_080459_1_0_1; -.
DR InParanoid; Q9UBT3; -.
DR OMA; RKFCLQP; -.
DR OrthoDB; 1139517at2759; -.
DR PhylomeDB; Q9UBT3; -.
DR TreeFam; TF330916; -.
DR PathwayCommons; Q9UBT3; -.
DR Reactome; R-HSA-201681; TCF dependent signaling in response to WNT.
DR Reactome; R-HSA-3772470; Negative regulation of TCF-dependent signaling by WNT ligand antagonists.
DR Reactome; R-HSA-5339717; Signaling by LRP5 mutants.
DR SignaLink; Q9UBT3; -.
DR BioGRID-ORCS; 27121; 9 hits in 1067 CRISPR screens.
DR GenomeRNAi; 27121; -.
DR Pharos; Q9UBT3; Tbio.
DR PRO; PR:Q9UBT3; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q9UBT3; protein.
DR Bgee; ENSG00000104371; Expressed in endometrium epithelium and 85 other tissues.
DR Genevisible; Q9UBT3; 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:0090090; P:negative regulation of canonical Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0061170; P:negative regulation of hair follicle placode formation; IEA:Ensembl.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; NAS:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR006796; Dickkopf_N.
DR InterPro; IPR039863; DKK-like.
DR InterPro; IPR023569; Prokineticin_domain.
DR PANTHER; PTHR12113; PTHR12113; 1.
DR Pfam; PF04706; Dickkopf_N; 1.
DR Pfam; PF06607; Prokineticin; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cleavage on pair of basic residues; Developmental protein;
KW Direct protein sequencing; Disulfide bond; Reference proteome; Secreted;
KW Signal; Wnt signaling pathway.
FT SIGNAL 1..18
FT /evidence="ECO:0000269|PubMed:10570958,
FT ECO:0000269|PubMed:15340161"
FT CHAIN 19..224
FT /note="Dickkopf-related protein 4"
FT /id="PRO_0000007225"
FT CHAIN 134..224
FT /note="Dickkopf-related protein 4 short form"
FT /id="PRO_0000007226"
FT REGION 41..90
FT /note="DKK-type Cys-1"
FT REGION 109..139
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 145..218
FT /note="DKK-type Cys-2"
FT COMPBIAS 125..139
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT DISULFID 145..157
FT /evidence="ECO:0000250"
FT DISULFID 151..166
FT /evidence="ECO:0000250"
FT DISULFID 156..194
FT /evidence="ECO:0000250"
FT DISULFID 176..202
FT /evidence="ECO:0000250"
FT DISULFID 196..218
FT /evidence="ECO:0000250"
FT CONFLICT 93
FT /note="M -> L (in Ref. 2; BAA33438)"
FT /evidence="ECO:0000305"
FT STRAND 38..40
FT /evidence="ECO:0007829|PDB:5O57"
FT HELIX 44..46
FT /evidence="ECO:0007829|PDB:5O57"
FT STRAND 47..50
FT /evidence="ECO:0007829|PDB:5O57"
FT STRAND 57..59
FT /evidence="ECO:0007829|PDB:5O57"
FT STRAND 69..72
FT /evidence="ECO:0007829|PDB:5O57"
FT TURN 76..78
FT /evidence="ECO:0007829|PDB:5O57"
FT STRAND 83..86
FT /evidence="ECO:0007829|PDB:5O57"
FT STRAND 89..92
FT /evidence="ECO:0007829|PDB:5O57"
FT TURN 93..95
FT /evidence="ECO:0007829|PDB:5O57"
SQ SEQUENCE 224 AA; 24876 MW; 45F8EBC476961357 CRC64;
MVAAVLLGLS WLCSPLGALV LDFNNIRSSA DLHGARKGSQ CLSDTDCNTR KFCLQPRDEK
PFCATCRGLR RRCQRDAMCC PGTLCVNDVC TTMEDATPIL ERQLDEQDGT HAEGTTGHPV
QENQPKRKPS IKKSQGRKGQ EGESCLRTFD CGPGLCCARH FWTKICKPVL LEGQVCSRRG
HKDTAQAPEI FQRCDCGPGL LCRSQLTSNR QHARLRVCQK IEKL