ID CDX2_HUMAN Reviewed; 313 AA. AC Q99626; O00503; Q5VTU7; Q969L8; Q9UD92; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 3. DT 27-MAR-2024, entry version 205. DE RecName: Full=Homeobox protein CDX-2; DE AltName: Full=CDX-3; DE AltName: Full=Caudal-type homeobox protein 2; GN Name=CDX2; Synonyms=CDX3; 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], AND VARIANT SER-293. RX PubMed=9459001; DOI=10.1046/j.1469-1809.1997.6150393.x; RA Drummond F.J., Putt W., Fox M., Edwards Y.H.; RT "Cloning and chromosome assignment of the human CDX2 gene."; RL Ann. Hum. Genet. 61:393-400(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT SER-293. RC TISSUE=Colon carcinoma; RX PubMed=9036867; RX DOI=10.1002/(sici)1097-0215(19970220)74:1<35::aid-ijc7>3.0.co;2-1; RA Mallo G.V., Rechreche H., Frigerio J.-M., Rocha D., Zweibaum A., Lacasa M., RA Jordan B.R., Dusetti N.J., Dagorn J.-C., Iovanna J.L.; RT "Molecular cloning, sequencing and expression of the mRNA encoding human RT Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression RT during colorectal carcinogenesis."; RL Int. J. Cancer 74:35-44(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-293. RX PubMed=11161380; DOI=10.1054/bjoc.2000.1544; RA Sivagnanasundaram S., Islam I., Talbot I., Drummond F., Walters J.R., RA Edwards Y.H.; RT "The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis."; RL Br. J. Cancer 84:218-225(2001). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-293. RA Tanizawa Y., Ueda K., Inoue H., Ayame H., Aoki M., Kuwano A., German M.S., RA Liu L., Donis-Keller H., Permutt M.A., Oka Y.; RT "Isolation, characterization, and linkage mapping of the human caudal-type RT homeobox gene, CDX2/3."; RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-293. RC TISSUE=Colon; 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 NUCLEOTIDE SEQUENCE [MRNA] OF 205-232. RC TISSUE=T-cell; RX PubMed=8105782; DOI=10.1006/bbrc.1993.2235; RA Inamori K., Takeshita K., Chiba S., Yazaki Y., Hirai H.; RT "Identification of homeobox genes expressed in human T-lymphocytes."; RL Biochem. Biophys. Res. Commun. 196:203-208(1993). RN [8] RP TISSUE SPECIFICITY. RX PubMed=9933478; DOI=10.1359/jbmr.1999.14.2.240; RA Yamamoto H., Miyamoto K., Li B., Taketani Y., Kitano M., Inoue Y., RA Morita K., Pike J.W., Takeda E.; RT "The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor RT gene expression in the small intestine."; RL J. Bone Miner. Res. 14:240-247(1999). RN [9] {ECO:0007744|PDB:5LTY} RP X-RAY CRYSTALLOGRAPHY (2.66 ANGSTROMS) OF 185-255 IN COMPLEX WITH RP METHYLATED DNA, AND DNA-BINDING. RX PubMed=28473536; DOI=10.1126/science.aaj2239; RA Yin Y., Morgunova E., Jolma A., Kaasinen E., Sahu B., Khund-Sayeed S., RA Das P.K., Kivioja T., Dave K., Zhong F., Nitta K.R., Taipale M., Popov A., RA Ginno P.A., Domcke S., Yan J., Schubeler D., Vinson C., Taipale J.; RT "Impact of cytosine methylation on DNA binding specificities of human RT transcription factors."; RL Science 356:0-0(2017). CC -!- FUNCTION: Transcription factor which regulates the transcription of CC multiple genes expressed in the intestinal epithelium (By similarity). CC Binds to the promoter of the intestinal sucrase-isomaltase SI and CC activates SI transcription (By similarity). Binds to the DNA sequence CC 5'-ATAAAAACTTAT-3' in the promoter region of VDR and activates VDR CC transcription (By similarity). Binds to and activates transcription of CC LPH (By similarity). Activates transcription of CLDN2 and intestinal CC mucin MUC2 (By similarity). Binds to the 5'-AATTTTTTACAACACCT-3' DNA CC sequence in the promoter region of CA1 and activates CA1 transcription CC (By similarity). Important in broad range of functions from early CC differentiation to maintenance of the intestinal epithelial lining of CC both the small and large intestine. Binds preferentially to methylated CC DNA (PubMed:28473536). {ECO:0000250|UniProtKB:P43241, CC ECO:0000250|UniProtKB:Q04649, ECO:0000269|PubMed:28473536}. CC -!- SUBUNIT: Can bind DNA as a monomer or homodimer. CC {ECO:0000250|UniProtKB:P43241}. CC -!- INTERACTION: CC Q99626; Q8IYR0: CFAP206; NbExp=3; IntAct=EBI-10899513, EBI-749051; CC Q99626; Q9BQ66: KRTAP4-12; NbExp=3; IntAct=EBI-10899513, EBI-739863; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P43241}. CC -!- TISSUE SPECIFICITY: Detected in small intestine, colon and pancreas. CC {ECO:0000269|PubMed:9933478}. CC -!- PTM: Ubiquitinated, leading to its degradation by the proteasome. CC {ECO:0000250|UniProtKB:P43241}. CC -!- PTM: Phosphorylation at Ser-60 reduces transactivation capacity. CC Phosphorylation at Ser-283 reduces transactivation capacity and also CC increases ubiquitin-dependent proteasome degradation. CC {ECO:0000250|UniProtKB:P43241}. CC -!- SIMILARITY: Belongs to the Caudal homeobox family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/326/CDX2"; 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; Y13709; CAA74038.1; -; mRNA. DR EMBL; U51096; AAB40603.1; -; mRNA. DR EMBL; AJ278431; CAB94779.1; -; Genomic_DNA. DR EMBL; AJ278432; CAB94779.1; JOINED; Genomic_DNA. DR EMBL; AJ278434; CAB94779.1; JOINED; Genomic_DNA. DR EMBL; AF007886; AAD05200.1; -; Genomic_DNA. DR EMBL; AF007884; AAD05200.1; JOINED; Genomic_DNA. DR EMBL; AF007885; AAD05200.1; JOINED; Genomic_DNA. DR EMBL; AL591024; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC014461; AAH14461.1; -; mRNA. DR CCDS; CCDS9328.1; -. DR PIR; PN0625; PN0625. DR RefSeq; NP_001256.3; NM_001265.4. DR PDB; 5LTY; X-ray; 2.66 A; K/M=185-255. DR PDB; 6ES2; X-ray; 2.95 A; K/L=186-256. DR PDB; 6ES3; X-ray; 2.57 A; K/M=184-255. DR PDB; 7Q4N; X-ray; 3.20 A; C/K=187-253. DR PDBsum; 5LTY; -. DR PDBsum; 6ES2; -. DR PDBsum; 6ES3; -. DR PDBsum; 7Q4N; -. DR AlphaFoldDB; Q99626; -. DR SMR; Q99626; -. DR BioGRID; 107475; 30. DR CORUM; Q99626; -. DR IntAct; Q99626; 4. DR MINT; Q99626; -. DR STRING; 9606.ENSP00000370408; -. DR iPTMnet; Q99626; -. DR PhosphoSitePlus; Q99626; -. DR BioMuta; CDX2; -. DR DMDM; 311033469; -. DR jPOST; Q99626; -. DR MassIVE; Q99626; -. DR MaxQB; Q99626; -. DR PaxDb; 9606-ENSP00000370408; -. DR PeptideAtlas; Q99626; -. DR ProteomicsDB; 78366; -. DR Pumba; Q99626; -. DR Antibodypedia; 3700; 1421 antibodies from 49 providers. DR DNASU; 1045; -. DR Ensembl; ENST00000381020.8; ENSP00000370408.6; ENSG00000165556.10. DR GeneID; 1045; -. DR KEGG; hsa:1045; -. DR MANE-Select; ENST00000381020.8; ENSP00000370408.6; NM_001265.6; NP_001256.4. DR UCSC; uc001urv.5; human. DR AGR; HGNC:1806; -. DR CTD; 1045; -. DR DisGeNET; 1045; -. DR GeneCards; CDX2; -. DR HGNC; HGNC:1806; CDX2. DR HPA; ENSG00000165556; Tissue enriched (intestine). DR MIM; 600297; gene. DR neXtProt; NX_Q99626; -. DR OpenTargets; ENSG00000165556; -. DR PharmGKB; PA26352; -. DR VEuPathDB; HostDB:ENSG00000165556; -. DR eggNOG; KOG0848; Eukaryota. DR GeneTree; ENSGT00940000161261; -. DR HOGENOM; CLU_073177_1_0_1; -. DR InParanoid; Q99626; -. DR OMA; CSAGVMQ; -. DR OrthoDB; 728401at2759; -. DR PhylomeDB; Q99626; -. DR TreeFam; TF351605; -. DR PathwayCommons; Q99626; -. DR Reactome; R-HSA-381771; Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1). DR SignaLink; Q99626; -. DR SIGNOR; Q99626; -. DR BioGRID-ORCS; 1045; 49 hits in 1172 CRISPR screens. DR ChiTaRS; CDX2; human. DR GeneWiki; CDX2; -. DR GenomeRNAi; 1045; -. DR Pharos; Q99626; Tbio. DR PRO; PR:Q99626; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; Q99626; Protein. DR Bgee; ENSG00000165556; Expressed in mucosa of transverse colon and 48 other cell types or tissues. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0000794; C:condensed nuclear chromosome; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0017053; C:transcription repressor complex; IEA:Ensembl. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IBA:GO_Central. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB. DR GO; GO:0008327; F:methyl-CpG binding; IDA:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central. DR GO; GO:0009948; P:anterior/posterior axis specification; IBA:GO_Central. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0008333; P:endosome to lysosome transport; IEA:Ensembl. DR GO; GO:0045197; P:establishment or maintenance of epithelial cell apical/basal polarity; IEA:Ensembl. DR GO; GO:0060575; P:intestinal epithelial cell differentiation; ISS:UniProtKB. DR GO; GO:0060711; P:labyrinthine layer development; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:NTNU_SB. DR GO; GO:0045597; P:positive regulation of cell differentiation; IEA:Ensembl. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB. DR GO; GO:0014807; P:regulation of somitogenesis; ISS:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl. DR GO; GO:0048863; P:stem cell differentiation; IEA:Ensembl. DR GO; GO:0001829; P:trophectodermal cell differentiation; IEA:Ensembl. DR CDD; cd00086; homeodomain; 1. DR Gene3D; 1.10.10.60; Homeodomain-like; 1. DR InterPro; IPR006820; Caudal_activation_dom. DR InterPro; IPR047152; Caudal_homeobox. DR InterPro; IPR009057; Homeobox-like_sf. DR InterPro; IPR017970; Homeobox_CS. DR InterPro; IPR001356; Homeobox_dom. DR InterPro; IPR020479; Homeobox_metazoa. DR InterPro; IPR000047; HTH_motif. DR PANTHER; PTHR24332; HOMEOBOX PROTEIN CDX; 1. DR PANTHER; PTHR24332:SF27; HOMEOBOX PROTEIN CDX-2; 1. DR Pfam; PF04731; Caudal_act; 1. DR Pfam; PF00046; Homeodomain; 1. DR PRINTS; PR00024; HOMEOBOX. DR PRINTS; PR00031; HTHREPRESSR. DR SMART; SM00389; HOX; 1. DR SUPFAM; SSF46689; Homeodomain-like; 1. DR PROSITE; PS00027; HOMEOBOX_1; 1. DR PROSITE; PS50071; HOMEOBOX_2; 1. DR Genevisible; Q99626; HS. PE 1: Evidence at protein level; KW 3D-structure; Activator; Developmental protein; DNA-binding; Homeobox; KW Nucleus; Phosphoprotein; Reference proteome; Transcription; KW Transcription regulation; Ubl conjugation. FT CHAIN 1..313 FT /note="Homeobox protein CDX-2" FT /id="PRO_0000048849" FT DNA_BIND 186..245 FT /note="Homeobox" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108" FT REGION 186..216 FT /note="Interaction with DNA" FT /evidence="ECO:0000305|PubMed:28473536" FT REGION 228..242 FT /note="Interaction with 5-mCpG DNA" FT /evidence="ECO:0000305|PubMed:28473536" FT REGION 242..313 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 283..295 FT /note="4S motif; modulates transactivation activity and FT protein stability" FT /evidence="ECO:0000250|UniProtKB:P43241" FT COMPBIAS 255..279 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 60 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P43241" FT MOD_RES 283 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P43241" FT VARIANT 293 FT /note="P -> S (in dbSNP:rs1805107)" FT /evidence="ECO:0000269|PubMed:11161380, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9036867, FT ECO:0000269|PubMed:9459001, ECO:0000269|Ref.4" FT /id="VAR_014530" FT CONFLICT 52..53 FT /note="AA -> Q (in Ref. 2; AAB40603)" FT /evidence="ECO:0000305" FT CONFLICT 89 FT /note="Missing (in Ref. 2; AAB40603)" FT /evidence="ECO:0000305" FT CONFLICT 95 FT /note="G -> A (in Ref. 2; AAB40603)" FT /evidence="ECO:0000305" FT STRAND 187..189 FT /evidence="ECO:0007829|PDB:6ES3" FT HELIX 195..207 FT /evidence="ECO:0007829|PDB:6ES3" FT HELIX 213..223 FT /evidence="ECO:0007829|PDB:6ES3" FT HELIX 227..254 FT /evidence="ECO:0007829|PDB:6ES3" SQ SEQUENCE 313 AA; 33520 MW; B5724F1F7CA569AF CRC64; MYVSYLLDKD VSMYPSSVRH SGGLNLAPQN FVSPPQYPDY GGYHVAAAAA AAANLDSAQS PGPSWPAAYG APLREDWNGY APGGAAAAAN AVAHGLNGGS PAAAMGYSSP ADYHPHHHPH HHPHHPAAAP SCASGLLQTL NPGPPGPAAT AAAEQLSPGG QRRNLCEWMR KPAQQSLGSQ VKTRTKDKYR VVYTDHQRLE LEKEFHYSRY ITIRRKAELA ATLGLSERQV KIWFQNRRAK ERKINKKKLQ QQQQQQPPQP PPPPPQPPQP QPGPLRSVPE PLSPVSSLQA SVPGSVPGVL GPTGGVLNPT VTQ //