DKK1_MOUSE
ID DKK1_MOUSE Reviewed; 272 AA.
AC O54908; Q80UL5;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 2.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Dickkopf-related protein 1;
DE Short=Dickkopf-1;
DE Short=Dkk-1;
DE Short=mDkk-1;
DE Flags: Precursor;
GN Name=Dkk1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9450748; DOI=10.1038/34848;
RA Glinka A., Wu W., Delius H., Monaghan A.P., Blumenstock C., Niehrs C.;
RT "Dickkopf-1 is a member of a new family of secreted proteins and functions
RT in head induction.";
RL Nature 391:357-362(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Hu L., Jiang G., Yang J., Liu S.;
RT "Molecular cloning and bioinformatic analysis of DKK1.";
RL Submitted (OCT-2011) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Trophoblast stem cell;
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 [7]
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 [8]
RP FUNCTION, SUBUNIT, INTERACTION WITH LRP5 AND LRP6, AND MUTAGENESIS OF
RP HIS-210; LYS-217; ARG-242 AND HIS-267.
RX PubMed=18524778; DOI=10.1074/jbc.m802375200;
RA Chen L., Wang K., Shao Y., Huang J., Li X., Shan J., Wu D., Zheng J.J.;
RT "Structural insight into the mechanisms of Wnt signaling antagonism by
RT Dkk.";
RL J. Biol. Chem. 283:23364-23370(2008).
RN [9]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=18505822; DOI=10.1128/mcb.00222-08;
RA Ellwanger K., Saito H., Clement-Lacroix P., Maltry N., Niedermeyer J.,
RA Lee W.K., Baron R., Rawadi G., Westphal H., Niehrs C.;
RT "Targeted disruption of the Wnt regulator Kremen induces limb defects and
RT high bone density.";
RL Mol. Cell. Biol. 28:4875-4882(2008).
RN [10]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=26206087; DOI=10.1038/cdd.2015.100;
RA Causeret F., Sumia I., Pierani A.;
RT "Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner.";
RL Cell Death Differ. 23:323-332(2016).
RN [11]
RP DEVELOPMENTAL STAGE.
RX PubMed=27550540; DOI=10.1038/srep31668;
RA Mulvaney J.F., Thompkins C., Noda T., Nishimura K., Sun W.W., Lin S.Y.,
RA Coffin A., Dabdoub A.;
RT "Kremen1 regulates mechanosensory hair cell development in the mammalian
RT cochlea and the zebrafish lateral line.";
RL Sci. Rep. 6:31668-31668(2016).
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 (PubMed:18524778). Inhibits the pro-apoptotic function of KREMEN1 in a
CC Wnt-independent manner, and has anti-apoptotic activity
CC (PubMed:26206087). Plays a role in limb development; attenuates Wnt
CC signaling in the developing limb to allow normal limb patterning
CC (PubMed:18505822). {ECO:0000269|PubMed:18505822,
CC ECO:0000269|PubMed:18524778, ECO:0000269|PubMed:26206087}.
CC -!- SUBUNIT: Interacts (via the C-termianl Cys-rich domain) with LRP5 (via
CC beta-propeller regions 3 and 4); the interaction, enhanced by MESD and
CC or KREMEN, antagonizes Wnt-mediated signaling. Interacts with LRP6
CC (PubMed:18524778). Forms a ternary complex with LRP6 and KREM1.
CC Interacts with KREM1 (By similarity). {ECO:0000250|UniProtKB:O94907,
CC ECO:0000269|PubMed:18524778}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- DEVELOPMENTAL STAGE: Expressed in the developing brain, cochlea and
CC limb buds. {ECO:0000269|PubMed:26206087, ECO:0000269|PubMed:27550540}.
CC -!- DOMAIN: The C-terminal cysteine-rich domain mediates interaction with
CC LRP5 and LRP6.
CC -!- DISRUPTION PHENOTYPE: Triple knockout mice KREM1/KREM2/DKK1 exhibit
CC enhanced growth of ectopic digits. {ECO:0000269|PubMed:18505822}.
CC -!- SIMILARITY: Belongs to the dickkopf family. {ECO:0000305}.
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DR EMBL; AF030433; AAC02426.1; -; mRNA.
DR EMBL; JN966751; AFI61654.1; -; mRNA.
DR EMBL; AK141693; BAE24802.1; -; mRNA.
DR EMBL; AK144119; BAE25711.1; -; mRNA.
DR EMBL; AC103405; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466534; EDL41707.1; -; Genomic_DNA.
DR EMBL; BC050189; AAH50189.1; -; mRNA.
DR CCDS; CCDS29744.1; -.
DR RefSeq; NP_034181.2; NM_010051.3.
DR AlphaFoldDB; O54908; -.
DR SMR; O54908; -.
DR BioGRID; 199226; 9.
DR CORUM; O54908; -.
DR STRING; 10090.ENSMUSP00000025803; -.
DR BindingDB; O54908; -.
DR ChEMBL; CHEMBL3745589; -.
DR GlyGen; O54908; 2 sites.
DR PhosphoSitePlus; O54908; -.
DR PaxDb; O54908; -.
DR PRIDE; O54908; -.
DR ProteomicsDB; 279674; -.
DR ABCD; O54908; 15 sequenced antibodies.
DR Antibodypedia; 4049; 971 antibodies from 47 providers.
DR DNASU; 13380; -.
DR Ensembl; ENSMUST00000025803; ENSMUSP00000025803; ENSMUSG00000024868.
DR GeneID; 13380; -.
DR KEGG; mmu:13380; -.
DR UCSC; uc008hen.2; mouse.
DR CTD; 22943; -.
DR MGI; MGI:1329040; Dkk1.
DR VEuPathDB; HostDB:ENSMUSG00000024868; -.
DR eggNOG; KOG1218; Eukaryota.
DR GeneTree; ENSGT00940000161319; -.
DR HOGENOM; CLU_080459_0_0_1; -.
DR InParanoid; O54908; -.
DR OMA; LDNYQPY; -.
DR OrthoDB; 1139517at2759; -.
DR PhylomeDB; O54908; -.
DR TreeFam; TF330916; -.
DR Reactome; R-MMU-3772470; Negative regulation of TCF-dependent signaling by WNT ligand antagonists.
DR BioGRID-ORCS; 13380; 6 hits in 75 CRISPR screens.
DR PRO; PR:O54908; -.
DR Proteomes; UP000000589; Chromosome 19.
DR RNAct; O54908; protein.
DR Bgee; ENSMUSG00000024868; Expressed in dermal bone and 214 other tissues.
DR Genevisible; O54908; MM.
DR GO; GO:0005576; C:extracellular region; ISS:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0039706; F:co-receptor binding; ISO:MGI.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISO:MGI.
DR GO; GO:0048019; F:receptor antagonist activity; ISO:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IMP:MGI.
DR GO; GO:0000904; P:cell morphogenesis involved in differentiation; IMP:MGI.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IGI:MGI.
DR GO; GO:0007492; P:endoderm development; IMP:MGI.
DR GO; GO:0001706; P:endoderm formation; IDA:MGI.
DR GO; GO:0060325; P:face morphogenesis; IMP:MGI.
DR GO; GO:0030900; P:forebrain development; IGI:MGI.
DR GO; GO:0001942; P:hair follicle development; IDA:MGI.
DR GO; GO:0060323; P:head morphogenesis; IGI:MGI.
DR GO; GO:0007611; P:learning or memory; IDA:ARUK-UCL.
DR GO; GO:0060173; P:limb development; IMP:UniProtKB.
DR GO; GO:0001707; P:mesoderm formation; IDA:MGI.
DR GO; GO:0061743; P:motor learning; IDA:ParkinsonsUK-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:ParkinsonsUK-UCL.
DR GO; GO:1901296; P:negative regulation of canonical Wnt signaling pathway involved in cardiac muscle cell fate commitment; ISO:MGI.
DR GO; GO:2000726; P:negative regulation of cardiac muscle cell differentiation; ISO:MGI.
DR GO; GO:0042662; P:negative regulation of mesodermal cell fate specification; ISO:MGI.
DR GO; GO:0010977; P:negative regulation of neuron projection development; IDA:ARUK-UCL.
DR GO; GO:0030279; P:negative regulation of ossification; IMP:UniProtKB.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; ISO:MGI.
DR GO; GO:1905607; P:negative regulation of presynapse assembly; IDA:ARUK-UCL.
DR GO; GO:0032091; P:negative regulation of protein binding; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IDA:MGI.
DR GO; GO:1904723; P:negative regulation of Wnt-Frizzled-LRP5/6 complex assembly; ISO:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ARUK-UCL.
DR GO; GO:0090082; P:positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISO:MGI.
DR GO; GO:1904958; P:positive regulation of midbrain dopaminergic neuron differentiation; IMP:ParkinsonsUK-UCL.
DR GO; GO:1901216; P:positive regulation of neuron death; ISO:MGI.
DR GO; GO:1902949; P:positive regulation of tau-protein kinase activity; IDA:ARUK-UCL.
DR GO; GO:0042663; P:regulation of endodermal cell fate specification; ISO:MGI.
DR GO; GO:0002090; P:regulation of receptor internalization; ISO:MGI.
DR GO; GO:0050807; P:regulation of synapse organization; IDA:ParkinsonsUK-UCL.
DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IDA:ParkinsonsUK-UCL.
DR GO; GO:0030111; P:regulation of Wnt signaling pathway; IMP:MGI.
DR GO; GO:0032526; P:response to retinoic acid; IDA:MGI.
DR GO; GO:0016055; P:Wnt signaling pathway; IDA:MGI.
DR GO; GO:0090244; P:Wnt signaling pathway involved in somitogenesis; IGI:MGI.
DR InterPro; IPR006796; Dickkopf_N.
DR InterPro; IPR039863; DKK-like.
DR PANTHER; PTHR12113; PTHR12113; 1.
DR Pfam; PF04706; Dickkopf_N; 1.
PE 1: Evidence at protein level;
KW Developmental protein; Disulfide bond; Glycoprotein; Reference proteome;
KW Secreted; Signal; Wnt signaling pathway.
FT SIGNAL 1..31
FT /evidence="ECO:0000255"
FT CHAIN 32..272
FT /note="Dickkopf-related protein 1"
FT /id="PRO_0000007219"
FT REGION 86..141
FT /note="DKK-type Cys-1"
FT REGION 195..269
FT /note="DKK-type Cys-2"
FT CARBOHYD 62
FT /note="O-linked (GalNAc...) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 262
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 86..98
FT /evidence="ECO:0000250"
FT DISULFID 92..114
FT /evidence="ECO:0000250"
FT DISULFID 117..131
FT /evidence="ECO:0000250"
FT DISULFID 124..136
FT /evidence="ECO:0000250"
FT DISULFID 130..141
FT /evidence="ECO:0000250"
FT DISULFID 195..207
FT /evidence="ECO:0000250"
FT DISULFID 201..216
FT /evidence="ECO:0000250"
FT DISULFID 206..243
FT /evidence="ECO:0000250"
FT DISULFID 226..251
FT /evidence="ECO:0000250"
FT DISULFID 245..269
FT /evidence="ECO:0000250"
FT MUTAGEN 210
FT /note="H->E: 50% reduced binding to LRP6."
FT /evidence="ECO:0000269|PubMed:18524778"
FT MUTAGEN 217
FT /note="K->E: 50% reduced binding to LRP6."
FT /evidence="ECO:0000269|PubMed:18524778"
FT MUTAGEN 242
FT /note="R->E: 50% reduced binding to LRP6."
FT /evidence="ECO:0000269|PubMed:18524778"
FT MUTAGEN 267
FT /note="H->E: 43% reduced binding to LRP6."
FT /evidence="ECO:0000269|PubMed:18524778"
FT CONFLICT 7
FT /note="A -> P (in Ref. 1; AAC02426)"
FT /evidence="ECO:0000305"
FT CONFLICT 126
FT /note="R -> T (in Ref. 1; AAC02426)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 272 AA; 29298 MW; ADFAC3E7B8858A9E CRC64;
MMVVCAAAAV RFLAVFTMMA LCSLPLLGAS ATLNSVLINS NAIKNLPPPL GGAGGQPGSA
VSVAPGVLYE GGNKYQTLDN YQPYPCAEDE ECGSDEYCSS PSRGAAGVGG VQICLACRKR
RKRCMRHAMC CPGNYCKNGI CMPSDHSHFP RGEIEESIIE NLGNDHNAAA GDGYPRRTTL
TSKIYHTKGQ EGSVCLRSSD CAAGLCCARH FWSKICKPVL KEGQVCTKHK RKGSHGLEIF
QRCYCGEGLA CRIQKDHHQA SNSSRLHTCQ RH
