KREM2_HUMAN
ID KREM2_HUMAN Reviewed; 462 AA.
AC Q8NCW0; B4DXF6; I3L2S2; Q8N2J4; Q8NCW1; Q96GL8; Q9BTP9;
DT 23-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=Kremen protein 2;
DE AltName: Full=Dickkopf receptor 2;
DE AltName: Full=Kringle domain-containing transmembrane protein 2;
DE AltName: Full=Kringle-containing protein marking the eye and the nose;
DE Flags: Precursor;
GN Name=KREMEN2; Synonyms=KRM2;
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 {ECO:0000312|EMBL:BAC00872.1};
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RA Tanaka S., Sugimachi K.;
RT "Human Kremen2 and Wnt signaling.";
RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3; 4 AND 5).
RC TISSUE=Ovarian carcinoma, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [4] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
RC TISSUE=Brain, and Uterus;
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).
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. Plays a role in limb development; attenuates
CC Wnt signaling in the developing limb to allow normal limb patterning
CC and can also negatively regulate bone formation.
CC {ECO:0000250|UniProtKB:Q8K1S7}.
CC -!- SUBUNIT: Interacts with ERLEC1. Forms a ternary complex with DKK1 and
CC LRP6. {ECO:0000250|UniProtKB:Q8K1S7}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1 {ECO:0000305};
CC IsoId=Q8NCW0-1; Sequence=Displayed;
CC Name=2 {ECO:0000305}; Synonyms=Kremen2a;
CC IsoId=Q8NCW0-2; Sequence=VSP_050509, VSP_050510;
CC Name=3 {ECO:0000305}; Synonyms=Kremen2b;
CC IsoId=Q8NCW0-3; Sequence=VSP_050511, VSP_050512;
CC Name=4 {ECO:0000305}; Synonyms=Kremen2c;
CC IsoId=Q8NCW0-4; Sequence=VSP_050513, VSP_050514;
CC Name=5;
CC IsoId=Q8NCW0-5; Sequence=VSP_046399;
CC Name=6;
CC IsoId=Q8NCW0-6; Sequence=VSP_046399, VSP_047386;
CC -!- DOMAIN: Binding to ERLEC1 is mediated by the oligosaccharides linked to
CC the kringle domain. {ECO:0000250|UniProtKB:Q8K1S7}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB086405; BAC00872.1; -; mRNA.
DR EMBL; AB086355; BAC00823.1; -; mRNA.
DR EMBL; AB086356; BAC00824.1; -; mRNA.
DR EMBL; AB086357; BAC00825.1; -; mRNA.
DR EMBL; AK027669; BAB55281.1; -; mRNA.
DR EMBL; AK075033; BAC11365.1; -; mRNA.
DR EMBL; AK301953; BAG63368.1; -; mRNA.
DR EMBL; AC004235; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471112; EAW85449.1; -; Genomic_DNA.
DR EMBL; BC003533; AAH03533.1; -; mRNA.
DR EMBL; BC009383; AAH09383.1; -; mRNA.
DR CCDS; CCDS10483.1; -. [Q8NCW0-1]
DR CCDS; CCDS10484.1; -. [Q8NCW0-3]
DR CCDS; CCDS58412.1; -. [Q8NCW0-5]
DR CCDS; CCDS58413.1; -. [Q8NCW0-6]
DR RefSeq; NP_001240654.1; NM_001253725.1. [Q8NCW0-6]
DR RefSeq; NP_001240655.1; NM_001253726.1. [Q8NCW0-5]
DR RefSeq; NP_078783.1; NM_024507.3. [Q8NCW0-3]
DR RefSeq; NP_757384.1; NM_172229.2. [Q8NCW0-1]
DR AlphaFoldDB; Q8NCW0; -.
DR SMR; Q8NCW0; -.
DR BioGRID; 122662; 31.
DR IntAct; Q8NCW0; 1.
DR STRING; 9606.ENSP00000304422; -.
DR GlyGen; Q8NCW0; 5 sites.
DR iPTMnet; Q8NCW0; -.
DR PhosphoSitePlus; Q8NCW0; -.
DR BioMuta; KREMEN2; -.
DR DMDM; 30173086; -.
DR EPD; Q8NCW0; -.
DR MassIVE; Q8NCW0; -.
DR PaxDb; Q8NCW0; -.
DR PeptideAtlas; Q8NCW0; -.
DR PRIDE; Q8NCW0; -.
DR ProteomicsDB; 47024; -.
DR ProteomicsDB; 5431; -.
DR ProteomicsDB; 72953; -. [Q8NCW0-1]
DR ProteomicsDB; 72954; -. [Q8NCW0-2]
DR ProteomicsDB; 72955; -. [Q8NCW0-3]
DR ProteomicsDB; 72956; -. [Q8NCW0-4]
DR Antibodypedia; 1159; 118 antibodies from 26 providers.
DR DNASU; 79412; -.
DR Ensembl; ENST00000303746.10; ENSP00000304422.5; ENSG00000131650.14. [Q8NCW0-1]
DR Ensembl; ENST00000319500.10; ENSP00000322079.6; ENSG00000131650.14. [Q8NCW0-3]
DR Ensembl; ENST00000571007.5; ENSP00000461860.1; ENSG00000131650.14. [Q8NCW0-5]
DR Ensembl; ENST00000572045.5; ENSP00000460578.1; ENSG00000131650.14. [Q8NCW0-4]
DR Ensembl; ENST00000575769.1; ENSP00000460917.1; ENSG00000131650.14. [Q8NCW0-2]
DR Ensembl; ENST00000575885.5; ENSP00000459878.1; ENSG00000131650.14. [Q8NCW0-6]
DR GeneID; 79412; -.
DR KEGG; hsa:79412; -.
DR MANE-Select; ENST00000303746.10; ENSP00000304422.5; NM_172229.3; NP_757384.1.
DR UCSC; uc002csg.4; human. [Q8NCW0-1]
DR CTD; 79412; -.
DR DisGeNET; 79412; -.
DR GeneCards; KREMEN2; -.
DR HGNC; HGNC:18797; KREMEN2.
DR HPA; ENSG00000131650; Tissue enhanced (retina, skin).
DR MIM; 609899; gene.
DR neXtProt; NX_Q8NCW0; -.
DR OpenTargets; ENSG00000131650; -.
DR PharmGKB; PA38683; -.
DR VEuPathDB; HostDB:ENSG00000131650; -.
DR eggNOG; KOG4157; Eukaryota.
DR GeneTree; ENSGT00940000162126; -.
DR HOGENOM; CLU_047976_0_0_1; -.
DR InParanoid; Q8NCW0; -.
DR OMA; RNCSWVV; -.
DR PhylomeDB; Q8NCW0; -.
DR TreeFam; TF331319; -.
DR PathwayCommons; Q8NCW0; -.
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; Q8NCW0; -.
DR SIGNOR; Q8NCW0; -.
DR BioGRID-ORCS; 79412; 18 hits in 1075 CRISPR screens.
DR GenomeRNAi; 79412; -.
DR Pharos; Q8NCW0; Tbio.
DR PRO; PR:Q8NCW0; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q8NCW0; protein.
DR Bgee; ENSG00000131650; Expressed in skin of abdomen and 96 other tissues.
DR Genevisible; Q8NCW0; HS.
DR GO; GO:0031901; C:early endosome membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0060173; P:limb development; ISS:UniProtKB.
DR GO; GO:0030279; P:negative regulation of ossification; ISS: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 2: Evidence at transcript level;
KW Alternative splicing; Disulfide bond; Glycoprotein; Kringle; Membrane;
KW Reference proteome; Signal; Transmembrane; Transmembrane helix;
KW Wnt signaling pathway.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..462
FT /note="Kremen protein 2"
FT /id="PRO_0000021568"
FT TOPO_DOM 26..364
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 365..387
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 388..462
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 35..119
FT /note="Kringle"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00121"
FT DOMAIN 121..215
FT /note="WSC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00558,
FT ECO:0000305"
FT DOMAIN 219..326
FT /note="CUB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00059,
FT ECO:0000305"
FT REGION 328..352
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 49
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 222
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 244
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 351
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 36..119
FT /evidence="ECO:0000250"
FT DISULFID 60..100
FT /evidence="ECO:0000250"
FT DISULFID 89..114
FT /evidence="ECO:0000250"
FT DISULFID 219..245
FT /evidence="ECO:0000250"
FT VAR_SEQ 162..200
FT /note="Missing (in isoform 5 and isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046399"
FT VAR_SEQ 367..462
FT /note="ARVFSTVTAVSVLLLLLLGLLRPLRRRSCLLAPGKGPPALGASRGPRRSWAV
FT WYQQPRGVALPCSPGDPQAEGSAAGYRPLSASSQSSLRSLISAL -> GAVCWLREKGP
FT RRWGLPGAPGEAGLCGTNSPEGWPCPAPPGTPRLRVLPRATGL (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_047386"
FT VAR_SEQ 367..420
FT /note="ARVFSTVTAVSVLLLLLLGLLRPLRRRSCLLAPGKGPPALGASRGPRRSWAV
FT WY -> GAVCWLREKGPRRWGLPGAPGEAGLCGTNSPEGWPCPAPPGTPRLRVLPRATG
FT L (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_050511"
FT VAR_SEQ 367..399
FT /note="ARVFSTVTAVSVLLLLLLGLLRPLRRRSCLLAP -> GEAGARDGSESGSRP
FT LAPILTAAVCPQPGSSRR (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_050513"
FT VAR_SEQ 394..424
FT /note="SCLLAPGKGPPALGASRGPRRSWAVWYQQPR -> CGALGQGLRADRWWGAG
FT APEGNRARKELLGS (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_050509"
FT VAR_SEQ 400..462
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_050514"
FT VAR_SEQ 421..462
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_050512"
FT VAR_SEQ 425..462
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_050510"
FT VARIANT 408
FT /note="A -> P (in dbSNP:rs11866302)"
FT /id="VAR_059691"
FT CONFLICT 164..202
FT /note="Missing (in Ref. 2; BAC11365)"
FT /evidence="ECO:0000305"
FT CONFLICT 285
FT /note="A -> D (in Ref. 2; BAC11365)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 462 AA; 48849 MW; CE33015917A9AA68 CRC64;
MGTQALQGFL FLLFLPLLQP RGASAGSLHS PGLSECFQVN GADYRGHQNR TGPRGAGRPC
LFWDQTQQHS YSSASDPHGR WGLGAHNFCR NPDGDVQPWC YVAETEEGIY WRYCDIPSCH
MPGYLGCFVD SGAPPALSGP SGTSTKLTVQ VCLRFCRMKG YQLAGVEAGY ACFCGSESDL
ARGRLAPATD CDQICFGHPG QLCGGDGRLG VYEVSVGSCQ GNWTAPQGVI YSPDFPDEYG
PDRNCSWALG PPGAALELTF RLFELADPRD RLELRDAASG SLLRAFDGAR PPPSGPLRLG
TAALLLTFRS DARGHAQGFA LTYRGLQDAA EDPEAPEGSA QTPAAPLDGA NVSCSPRPGA
PPAAIGARVF STVTAVSVLL LLLLGLLRPL RRRSCLLAPG KGPPALGASR GPRRSWAVWY
QQPRGVALPC SPGDPQAEGS AAGYRPLSAS SQSSLRSLIS AL
