KREM1_MOUSE
ID KREM1_MOUSE Reviewed; 473 AA.
AC Q99N43; Q640Q6;
DT 15-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Kremen protein 1;
DE AltName: Full=Dickkopf receptor;
DE AltName: Full=Kringle domain-containing transmembrane protein 1;
DE AltName: Full=Kringle-containing protein marking the eye and the nose;
DE Flags: Precursor;
GN Name=Kremen1; Synonyms=Kremen;
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], DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY.
RC TISSUE=Brain, and Kidney;
RX PubMed=11267660; DOI=10.1016/s0167-4781(01)00168-3;
RA Nakamura T., Aoki S., Kitajima K., Takahashi T., Matsumoto K., Nakamura T.;
RT "Molecular cloning and characterization of Kremen, a novel kringle-
RT containing transmembrane protein.";
RL Biochim. Biophys. Acta 1518:63-72(2001).
RN [2]
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 [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
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 [5]
RP FUNCTION, AND IDENTIFICATION IN A TERNARY COMPLEX WITH DKK1 AND LRP6.
RX PubMed=12050670; DOI=10.1038/nature756;
RA Mao B., Wu W., Davidson G., Marhold J., Li M., Mechler B.M., Delius H.,
RA Hoppe D., Stannek P., Walter C., Glinka A., Niehrs C.;
RT "Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin
RT signalling.";
RL Nature 417:664-667(2002).
RN [6]
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 [7]
RP FUNCTION, DEVELOPMENTAL STAGE, AND MUTAGENESIS OF SER-419; SER-437;
RP ILE-453; SER-472 AND ASP-473.
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 [8]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP 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: Receptor for Dickkopf proteins. Cooperates with DKK1/2 to
CC inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt
CC receptors LRP5 and LRP6 (PubMed:12050670). In the absence of DKK1,
CC potentiates Wnt-beta-catenin signaling by maintaining LRP5 or LRP6 at
CC the cell membrane (By similarity). Can trigger apoptosis in a Wnt-
CC independent manner and this apoptotic activity is inhibited upon
CC binding of the ligand DKK1 (PubMed:26206087). Plays a role in limb
CC development; attenuates Wnt signaling in the developing limb to allow
CC normal limb patterning and can also negatively regulate bone formation
CC (PubMed:18505822). Modulates cell fate decisions in the developing
CC cochlea with an inhibitory role in hair cell fate specification
CC (PubMed:27550540). {ECO:0000250|UniProtKB:Q90Y90,
CC ECO:0000269|PubMed:12050670, ECO:0000269|PubMed:18505822,
CC ECO:0000269|PubMed:26206087, ECO:0000269|PubMed:27550540}.
CC -!- SUBUNIT: Forms a ternary complex with DKK1 and LRP6 (PubMed:12050670).
CC Interacts with LRP6 in a DKK1-dependent manner. Interacts with DKK1 and
CC RSPO1 (via FU repeats) (By similarity). {ECO:0000250|UniProtKB:Q96MU8,
CC ECO:0000269|PubMed:12050670}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:27550540};
CC Single-pass type I membrane protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: In the adult, widely expressed with high levels in
CC heart, lung, kidney, skeletal muscle and testis.
CC {ECO:0000269|PubMed:11267660}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the developing cochlea. Expressed
CC first in the prosensory domain and the expression is restricted to
CC supporting cells as development proceeds (at protein level). In the
CC embryo, expression is first detected on day 9 and increases up to day
CC 18. Lower levels are found in adult. At 9.5 dpc, expression is
CC localized to the apical ectodermal ridge (AER) of the developing
CC fore- and hindlimb buds, the telencephalon and the first brachial arch.
CC At 10.5 dpc, expression is also observed in the myotome and in sensory
CC tissues such as the nasal pit and optic vesicle. Expressed in the
CC developing brain and developing limb buds.
CC {ECO:0000269|PubMed:11267660, ECO:0000269|PubMed:18505822,
CC ECO:0000269|PubMed:26206087, ECO:0000269|PubMed:27550540}.
CC -!- DISRUPTION PHENOTYPE: Animals with a double knockout of KREM1 and KREM2
CC exhibit enhanced Wnt signaling accompanied by ectopic postaxial
CC forelimb digits and expanded apical ectodermal ridges. They also
CC exhibit increased bone volume and bone formation rates. Triple knockout
CC mice KREM1/KREM2/DKK1 exhibit enhanced growth of ectopic digits.
CC {ECO:0000269|PubMed:18505822}.
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DR EMBL; AB059617; BAB40968.1; -; mRNA.
DR EMBL; AK141321; BAE24649.1; -; mRNA.
DR EMBL; AL662853; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC082546; AAH82546.1; -; mRNA.
DR EMBL; BC138465; AAI38466.1; -; mRNA.
DR EMBL; BC138464; AAI38465.1; -; mRNA.
DR CCDS; CCDS24399.1; -.
DR RefSeq; NP_115772.2; NM_032396.3.
DR AlphaFoldDB; Q99N43; -.
DR SMR; Q99N43; -.
DR CORUM; Q99N43; -.
DR STRING; 10090.ENSMUSP00000020662; -.
DR GlyGen; Q99N43; 6 sites.
DR PhosphoSitePlus; Q99N43; -.
DR PaxDb; Q99N43; -.
DR PeptideAtlas; Q99N43; -.
DR PRIDE; Q99N43; -.
DR ProteomicsDB; 263462; -.
DR Antibodypedia; 24417; 323 antibodies from 28 providers.
DR DNASU; 84035; -.
DR Ensembl; ENSMUST00000020662; ENSMUSP00000020662; ENSMUSG00000020393.
DR GeneID; 84035; -.
DR KEGG; mmu:84035; -.
DR UCSC; uc007hwh.1; mouse.
DR CTD; 83999; -.
DR MGI; MGI:1933988; Kremen1.
DR VEuPathDB; HostDB:ENSMUSG00000020393; -.
DR eggNOG; KOG4157; Eukaryota.
DR GeneTree; ENSGT00940000158390; -.
DR HOGENOM; CLU_043485_0_0_1; -.
DR InParanoid; Q99N43; -.
DR OMA; DNVHQNK; -.
DR OrthoDB; 516719at2759; -.
DR PhylomeDB; Q99N43; -.
DR TreeFam; TF331319; -.
DR Reactome; R-MMU-3772470; Negative regulation of TCF-dependent signaling by WNT ligand antagonists.
DR BioGRID-ORCS; 84035; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Kremen1; mouse.
DR PRO; PR:Q99N43; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q99N43; protein.
DR Bgee; ENSMUSG00000020393; Expressed in interventricular septum and 246 other tissues.
DR ExpressionAtlas; Q99N43; baseline and differential.
DR Genevisible; Q99N43; MM.
DR GO; GO:0016021; C:integral component of membrane; NAS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:MGI.
DR GO; GO:0043025; C:neuronal cell body; IDA:ARUK-UCL.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:0060173; P:limb development; IMP:UniProtKB.
DR GO; GO:0048681; P:negative regulation of axon regeneration; IMP:ARUK-UCL.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:UniProtKB.
DR GO; GO:0030279; P:negative regulation of ossification; IMP:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd00041; CUB; 1.
DR CDD; cd00108; KR; 1.
DR Gene3D; 2.40.20.10; -; 1.
DR Gene3D; 2.60.120.290; -; 1.
DR InterPro; IPR000859; CUB_dom.
DR InterPro; IPR017076; Kremen.
DR InterPro; IPR000001; Kringle.
DR InterPro; IPR013806; Kringle-like.
DR InterPro; IPR018056; Kringle_CS.
DR InterPro; IPR038178; Kringle_sf.
DR InterPro; IPR035914; Sperma_CUB_dom_sf.
DR InterPro; IPR002889; WSC_carb-bd.
DR Pfam; PF00431; CUB; 1.
DR Pfam; PF00051; Kringle; 1.
DR Pfam; PF01822; WSC; 1.
DR PIRSF; PIRSF036961; Kremen; 1.
DR SMART; SM00042; CUB; 1.
DR SMART; SM00130; KR; 1.
DR SMART; SM00321; WSC; 1.
DR SUPFAM; SSF49854; SSF49854; 1.
DR SUPFAM; SSF57440; SSF57440; 1.
DR PROSITE; PS01180; CUB; 1.
DR PROSITE; PS00021; KRINGLE_1; 1.
DR PROSITE; PS50070; KRINGLE_2; 1.
DR PROSITE; PS51212; WSC; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; Glycoprotein; Kringle; Membrane;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix;
KW Wnt signaling pathway.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..473
FT /note="Kremen protein 1"
FT /id="PRO_0000021565"
FT TOPO_DOM 21..392
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 393..413
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 414..473
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 31..114
FT /note="Kringle"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00121"
FT DOMAIN 116..210
FT /note="WSC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00558"
FT DOMAIN 214..321
FT /note="CUB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059"
FT REGION 414..473
FT /note="Essential for apoptotic activity"
FT /evidence="ECO:0000269|PubMed:26206087"
FT CARBOHYD 59
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 217
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 255
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 293
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 333
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 345
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 32..114
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 55..95
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 84..109
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 122..186
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 147..167
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 151..169
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 190..198
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT DISULFID 214..240
FT /evidence="ECO:0000250|UniProtKB:Q96MU8"
FT MUTAGEN 419
FT /note="S->F: Significant reduction of apoptotic activity."
FT /evidence="ECO:0000269|PubMed:26206087"
FT MUTAGEN 437
FT /note="S->L: Significant reduction of apoptotic activity."
FT /evidence="ECO:0000269|PubMed:26206087"
FT MUTAGEN 453
FT /note="I->V: Significant reduction of apoptotic activity."
FT /evidence="ECO:0000269|PubMed:26206087"
FT MUTAGEN 472
FT /note="S->G: Complete loss of apoptotic activity."
FT /evidence="ECO:0000269|PubMed:26206087"
FT MUTAGEN 473
FT /note="D->N: Complete loss of apoptotic activity."
FT /evidence="ECO:0000269|PubMed:26206087"
FT CONFLICT 238
FT /note="R -> K (in Ref. 1; BAB40968)"
FT /evidence="ECO:0000305"
FT CONFLICT 248
FT /note="G -> E (in Ref. 1; BAB40968)"
FT /evidence="ECO:0000305"
FT CONFLICT 266
FT /note="D -> N (in Ref. 1; BAB40968)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 473 AA; 51673 MW; 5E7A906662B80F7D CRC64;
MAPPAARLAL LSAAALTLAA RPAPGPRSGP ECFTANGADY RGTQSWTALQ GGKPCLFWNE
TFQHPYNTLK YPNGEGGLGE HNYCRNPDGD VSPWCYVAEH EDGVYWKYCE IPACQMPGNL
GCYKDHGNPP PLTGTSKTSN KLTIQTCISF CRSQRFKFAG MESGYACFCG NNPDYWKHGE
AASTECNSVC FGDHTQPCGG DGRIILFDTL VGACGGNYSA MAAVVYSPDF PDTYATGRVC
YWTIRVPGAS RIHFNFTLFD IRDSADMVEL LDGYTHRVLV RLSGRSRPPL SFNVSLDFVI
LYFFSDRINQ AQGFAVLYQA TKEEPPQERP AVNQTLAEVI TEQANLSVSA AHSSKVLYVI
TPSPSHPPQT APGSHSWAPS VGANSHRVEG WTVYGLATLL ILTVTAVVAK ILLHVTFKSH
RVPASGDLRD CRQPGASGDI WTIFYEPSTT ISIFKKKLKG QSQQDDRNPL VSD
