CDX2

Summary

CDX2 (caudal type homeobox 2, HGNC:1806) is a protein-coding gene on chromosome 13q12.2, encoding Homeobox protein CDX-2 (Q99626). Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium.

This gene is a member of the caudal-related homeobox transcription factor gene family. The encoded protein is a major regulator of intestine-specific genes involved in cell growth an differentiation. This protein also plays a role in early embryonic development of the intestinal tract. Aberrant expression of this gene is associated with intestinal inflammation and tumorigenesis.

Source: NCBI Gene 1045 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 54 total — 2 likely-pathogenic
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Transcription factor: yes — 86 downstream targets (CollecTRI)
• MANE Select transcript: NM_001265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1806
Approved symbol	CDX2
Name	caudal type homeobox 2
Location	13q12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000165556
Ensembl biotype	protein_coding
OMIM	600297
Entrez	1045

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000381020, ENST00000548877, ENST00000891171, ENST00000947371

RefSeq mRNA: 2 — MANE Select: NM_001265 NM_001265, NM_001354700

CCDS: CCDS9328

Canonical transcript exons

ENST00000381020 — 3 exons

Exon	Start	End
ENSE00001323854	27960918	27963369
ENSE00001487241	27968466	27969315
ENSE00003600647	27964870	27965015

Expression profiles

Bgee: expression breadth broad, 64 present calls, max score 98.57.

FANTOM5 (CAGE): breadth broad, TPM avg 3.9065 / max 3282.3832, expressed in 191 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136513	1.4403	129
136509	1.0684	142
136511	0.4097	88
136510	0.2743	77
136508	0.2403	72
136506	0.2049	6
136505	0.1085	3
136512	0.0961	39
136504	0.0252	3
136507	0.0171	4

Top tissues by expression

262 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.57	gold quality
rectum	UBERON:0001052	96.28	gold quality
transverse colon	UBERON:0001157	87.82	gold quality
cervix squamous epithelium	UBERON:0006922	87.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.36	gold quality
duodenum	UBERON:0002114	85.46	gold quality
small intestine	UBERON:0002108	84.86	gold quality
colonic epithelium	UBERON:0000397	83.65	gold quality
colonic mucosa	UBERON:0000317	81.02	gold quality
ileal mucosa	UBERON:0000331	80.01	gold quality
cervix epithelium	UBERON:0004801	79.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	78.88	gold quality
heart right ventricle	UBERON:0002080	78.58	gold quality
vermiform appendix	UBERON:0001154	78.12	gold quality
jejunal mucosa	UBERON:0000399	77.51	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	76.90	gold quality
inferior olivary complex	UBERON:0002127	76.65	gold quality
intestine	UBERON:0000160	76.46	gold quality
caecum	UBERON:0001153	76.39	gold quality
parotid gland	UBERON:0001831	75.81	gold quality
frontal pole	UBERON:0002795	75.56	gold quality
paraflocculus	UBERON:0005351	75.07	gold quality
middle frontal gyrus	UBERON:0002702	74.40	gold quality
endometrium epithelium	UBERON:0004811	74.18	gold quality
large intestine	UBERON:0000059	73.70	gold quality
colon	UBERON:0001155	73.29	gold quality
body of pancreas	UBERON:0001150	71.59	gold quality
islet of Langerhans	UBERON:0000006	70.60	gold quality
pancreas	UBERON:0001264	70.01	gold quality
tongue squamous epithelium	UBERON:0006919	69.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	13.63
E-ANND-3	yes	8.24

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

86 targets.

Target	Regulation
ABCB1	Unknown
ACAT2	Activation
ADAM2
ALPI	Repression
APC	Activation
ATOH1	Activation
ATRX
AXIN2	Activation
B3GALT5	Activation
BCL2	Activation
BMP4	Unknown
CA1	Unknown
CCL25	Activation
CCND1	Repression
CDH17	Activation
CDKN1A	Activation
CDKN2A
CDX1	Unknown
CDX2	Unknown
CDX4	Unknown
CEL
CFTR	Activation
CLDN1	Unknown
CLDN2	Activation
DPP4	Activation
DSC2	Unknown
ELMO3	Activation
FURIN	Unknown
FUT2	Activation
GCG	Unknown

JASPAR motifs

Motif	Name	Family
MA0465.1	CDX2	HOX
MA0465.2	CDX2	HOX
MA0465.3	CDX2	HOX

JASPAR matrix evidence (PMIDs): PMID:20696899

Upstream regulators (CollecTRI, top): AGR2, AHR, AP1, CDX1, CDX2, CTNNB1, FOS, FOXM1, GATA2, GATA3, GATA6, H19, HNF4A, JUN, KLF4, NANOG, NFKB1, NFKB, NR1H4, POU2F1, POU5F1, RELA, SMAD1, SMAD2, SMAD4, SOX2, SOX9, STAT3, TCF4, TCF7L2, TEAD4

miRNA regulators (miRDB)

86 targeting CDX2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• Markedly reduced or absent CDX2 expression was noted by immunohistochemistry in 13 of 15 (87%) large cell minimally differentiated carcinomas (LCMDCs), whereas only 1 of the 25 (4%) differentiated adenocarcinomas (DACs)showed reduced CDX2 expression. (PMID:11733373)
• Increased CDX2 mRNA is associated with chronic atrophic gastritis (PMID:11846061)
• expression of CDX2 precedes expression of CDX1 during the progression of intestinal metaplasia;expression of CDX2 may trigger the initiation and development of intestinal metaplasia (PMID:11871772)
• The homeobox gene belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells (PMID:12270138)
• These results suggest that CDX2, but not CDX1, interacts with the MUC2 promoter and activates MUC2 transcription, and plays an important role in the differentiation of goblet cells. (PMID:12559945)
• findings suggest caudal type homeo box transcription factor 2(CDX2) inactivation in colon cancer results from defects in trans-acting pathways regulating CDX2 transcription, and CDX2 silencing contributes to altered phenotype of some colorectal cancers (PMID:12947088)
• A Cdx-2 binding site polymorphism (G to A) in the promoter region of the vitamin D receptor gene was reported. investigated the relationship between the VDR Cdx-2 genotype and risk of fracture (PMID:12968672)
• p21 is a transcriptional target of CDX2. Our results may thus provide a new mechanism underlying the functions of CDX2. (PMID:12970742)
• Cdx-2 activates the expression of MUC2 mucin gene in gastric cells, inducing an intestinal transdifferentiation phenotype that parallels what is observed both in intestinal metaplasia and some gastric carcinomas (PMID:14525978)
• results suggest that Cdx2 is a useful prognostic marker for gastric cancer; advanced gastric cancers with both intestinal and gastric phenotypic expression have a relatively good prognosis (PMID:14557879)
• Cdx2 protein is a sensitive marker of intestinal metaplasia in the upper gastrointestinal tract and may be useful in detecting histologically equivocal cases of Barrett’s esophagus. (PMID:14576477)
• These results show that Cdx1 and Cdx2 might be indispensable for intestinal phenotypic expression even in gastric cancer cells (PMID:14615935)
• Aberrant expression of CDX2 is closely related to the overexpression of MUC2 in mucinous intrahepatic cholangiocarcinoma and intraductal papillary neoplasia of the liver associated with hepatolithiasis. (PMID:15048136)
• Cdx2 is a highly sensitive marker for Barrett’s esophagus. (PMID:15167938)
• APC and CDX2 have roles in controlling retinoic acid biosynthesis and in promoting a retinoid-induced program of colonocyte differentiation (PMID:15190067)
• CDX2 is a sensitive and specific marker for colorectal adenocarcinoma. (PMID:15205684)
• Cdx1 and Cdx2 inhibit colon cancer cell proliferation by blocking beta-catenin/TCF transcriptional activity (PMID:15215241)
• Cdx-2 is a permissive factor that influences basal CaBP expression in enterocytes and that HNF-1alpha modulates CaBP gene expression during cellular differentiation. (PMID:15217781)
• CDX2 and MUC2 genes are repressed by SOX9 in intestinal epithelium (PMID:15240568)
• identification of MOK, a member of the mitogen-activated protein kinase superfamily, as one of the genes induced by a caudal-related homeobox transcription factor, Cdx2 (PMID:15327990)
• a sensitive and specific marker for differentiating metastatic colorectal adenocarcinoma from mucinous bronchioloalveolar adenocarcinoma. (PMID:15362373)
• There is a transient loss of Cdx2 in budding tumor cells at the tumor host interface in colorectal cancer, and reexpression of Cdx2 in metastases. (PMID:15466189)
• CDX2 may be considered a sensitive and specific marker of midgut serotonin-producing /EC/-cells and EC-cell tumors, and its expression may be useful in the diagnosis of metastases from occult ETs (PMID:15517368)
• Cdx2 expression in invasive ductal carcinomas may be a novel prognostic marker for patient survival. (PMID:15547744)
• the major factors determining the presence of CDX-2 in colorectal carcinomas at the protein product level may include cancer location and the solid phenotype of the tumor. (PMID:15619975)
• CDX2 plays an important role in gallbladder carcinogenesis with intestinal differentiation. (PMID:15645288)
• Study suggests that CDX2 is a relatively specific marker for tumors with intestinal differentiation; it can be seen in large cell and adenocarcinomas of the lung. (PMID:15722794)
• Cdx1 activates the IAP gene via a novel cis element, whereas Cdx2 inhibits the Cdx1 effects (PMID:15774940)
• Aberrant expression of cdx2 homeobox gene was detected in pancreatic intraductal papillary mucinous neoplasm but not in ductal adenocarcinoma (PMID:15782100)
• marker for cellular phenotype in sinonasal intestinal-type adenocarcinoma (PMID:15894926)
• CDX2 expression levels were strongly associated with microsatellite instability and tumor location in the gastrointestinal tract, consistent with a possible role in the specification of gastrointestinal epithelial cell fate in humans. (PMID:15994917)
• Phosphorylation of CDX2 mediates its ubiquitin-dependent proteasome degradation. (PMID:16027724)
• Higher expression of Cdx2 is associated with intestinal-type carcinomas (PMID:16144916)
• CDX2 mRNA and CDX2 protein expression are upregulated in Barrett’s IM tissues, compared with normal squamous esophagus, and remain elevated in dysplasia and adenocarcinoma tissues (PMID:16291394)
• disruption of CDX2 in MKN45 cells does not significantly affect their tumorigenic potential (PMID:16331267)
• The loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors. (PMID:16361536)
• Cdx2 requires additional factors to activate the enterocyte differentiation program in normal undifferentiated cells (PMID:16480684)
• CDX-2 expression in stomach cancer may be a marker of the progression of gastric carcinogenesis, and that its activation may represent an early event. (PMID:16509871)
• Transformation associated with reflux at the gastroesophageal junction reflects activation by bile acid and acid of a transcriptional program involving NF-kappaB and Cdx2, which mediate intestinal metaplasia and ectopic expression of GC-C. (PMID:16618413)
• Cdx2 was shown to cooperatively activate the UGT2B7 promoter in conjunction with hepatocyte nuclear factor 1alpha (HNF1alpha), a mechanism previously observed to regulate other intestine-specific genes. (PMID:16788384)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cdx2	ENSMUSG00000029646
rattus_norvegicus	Cdx2	ENSRNOG00000032759

Paralogs (2): CDX1 (ENSG00000113722), CDX4 (ENSG00000131264)

Protein

Protein identifiers

Homeobox protein CDX-2 — Q99626 (reviewed: Q99626)

Alternative names: CDX-3, Caudal-type homeobox protein 2

All UniProt accessions (1): Q99626

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium. Binds to the promoter of the intestinal sucrase-isomaltase SI and activates SI transcription. Binds to the DNA sequence 5’-ATAAAAACTTAT-3’ in the promoter region of VDR and activates VDR transcription. Binds to and activates transcription of LPH. Activates transcription of CLDN2 and intestinal mucin MUC2. Binds to the 5’-AATTTTTTACAACACCT-3’ DNA sequence in the promoter region of CA1 and activates CA1 transcription. Important in broad range of functions from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine. Binds preferentially to methylated DNA.

Subunit / interactions. Can bind DNA as a monomer or homodimer.

Subcellular location. Nucleus.

Tissue specificity. Detected in small intestine, colon and pancreas.

Post-translational modifications. Ubiquitinated, leading to its degradation by the proteasome. Phosphorylation at Ser-60 reduces transactivation capacity. Phosphorylation at Ser-283 reduces transactivation capacity and also increases ubiquitin-dependent proteasome degradation.

Similarity. Belongs to the Caudal homeobox family.

RefSeq proteins (2): NP_001256, NP_001341629 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR006820	Caudal_activation_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR047152	Caudal_homeobox	Family

Pfam: PF00046, PF04731

UniProt features (18 total): sequence conflict 3, helix 3, region of interest 3, compositionally biased region 2, modified residue 2, chain 1, DNA-binding region 1, sequence variant 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6ES3	X-RAY DIFFRACTION	2.57
5LTY	X-RAY DIFFRACTION	2.66
6ES2	X-RAY DIFFRACTION	2.95
7Q4N	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99626-F1	63.77	0.22

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 60, 283

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-381771	Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
R-HSA-2892245	POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-400508	Incretin synthesis, secretion, and inactivation

MSigDB gene sets: 175 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_VACUOLAR_TRANSPORT, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (26): negative regulation of transcription by RNA polymerase II (GO:0000122), blood vessel development (GO:0001568), trophectodermal cell differentiation (GO:0001829), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell population proliferation (GO:0008284), endosome to lysosome transport (GO:0008333), embryonic pattern specification (GO:0009880), animal organ morphogenesis (GO:0009887), anterior/posterior axis specification (GO:0009948), regulation of somitogenesis (GO:0014807), cell differentiation (GO:0030154), somatic stem cell population maintenance (GO:0035019), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), positive regulation of cell differentiation (GO:0045597), positive regulation of transcription by RNA polymerase II (GO:0045944), digestive tract development (GO:0048565), stem cell differentiation (GO:0048863), intestinal epithelial cell differentiation (GO:0060575), labyrinthine layer development (GO:0060711), blastocyst development (GO:0001824), placenta development (GO:0001890), regulation of DNA-templated transcription (GO:0006355), multicellular organism development (GO:0007275), pattern specification process (GO:0007389), anterior/posterior pattern specification (GO:0009952), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (11): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), methyl-CpG binding (GO:0008327), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), condensed nuclear chromosome (GO:0000794), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription repressor complex (GO:0017053), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Incretin synthesis, secretion, and inactivation	1
Transcriptional regulation of pluripotent stem cells	1
Metabolism of proteins	1
Peptide hormone metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
anatomical structure development	3
cell differentiation	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
positive regulation of cellular process	2
transcription cis-regulatory region binding	2
sequence-specific DNA binding	2
DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
vasculature development	1
blastocyst formation	1
cell population proliferation	1
regulation of cell population proliferation	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
pattern specification process	1
embryo development	1
anatomical structure morphogenesis	1
animal organ development	1
axis specification	1
anterior/posterior pattern specification	1
somitogenesis	1
regulation of anatomical structure morphogenesis	1
regulation of multicellular organismal process	1
cellular developmental process	1
stem cell population maintenance	1
establishment or maintenance of apical/basal cell polarity	1
regulation of cell differentiation	1
positive regulation of developmental process	1
positive regulation of DNA-templated transcription	1
tube development	1
digestive system development	1
columnar/cuboidal epithelial cell differentiation	1
digestive tract development	1
embryonic placenta development	1
in utero embryonic development	1

Protein interactions and networks

STRING

2102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDX2	POU5F1	P31359	921
CDX2	KRT20	P35900	909
CDX2	LIAT1	Q6ZQX7	904
CDX2	GATA6	P78327	889
CDX2	KRT7	P08729	886
CDX2	SOX2	P48431	866
CDX2	MUC2	Q02817	863
CDX2	FOXA2	Q9Y261	802
CDX2	TEAD4	Q15561	799
CDX2	SOX17	Q9H6I2	794
CDX2	GATA3	P23771	793
CDX2	EOMES	O95936	791
CDX2	ELF5	Q9UKW6	787
CDX2	MUC6	Q6W4X9	770
CDX2	HNF1A	P20823	765

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CFAP206	CDX2	psi-mi:“MI:0915”(physical association)	0.560
CDX2	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.560
CDX2	H1-5	psi-mi:“MI:0915”(physical association)	0.400
CDX2		psi-mi:“MI:0914”(association)	0.350
CDX2	MEP1A	psi-mi:“MI:0914”(association)	0.350
FOXE1	DDX39A	psi-mi:“MI:0914”(association)	0.350
CDX2	IPO8	psi-mi:“MI:0914”(association)	0.350
CFAP206	CDX2	psi-mi:“MI:0915”(physical association)	0.000
KRTAP4-12	CDX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (43): CDX2 (Affinity Capture-Western), CDX2 (Affinity Capture-MS), CDX2 (Reconstituted Complex), CDX2 (Affinity Capture-Western), CDX2 (Affinity Capture-Western), CDX2 (Affinity Capture-Western), RELA (Affinity Capture-Western), FBXW7 (Affinity Capture-Western), GSK3B (Affinity Capture-Western), CDX2 (Affinity Capture-MS), CDX2 (Affinity Capture-MS), CDX2 (Reconstituted Complex), EP300 (Reconstituted Complex), PAX6 (Reconstituted Complex), PAX6 (Affinity Capture-Western)

ESM2 similar proteins: A1YER7, A1YFD8, A1YFY3, A2D4P8, A2D4R4, A2D5I1, A2D5K9, A2D5Y4, A2D649, A2T6H5, A2T6X6, A2T748, B5DFK3, P06798, P09016, P09017, P09021, P09024, P09027, P09629, P09631, P10284, P10628, P13378, P17277, P17483, P18864, P23463, P28356, P28357, P31249, P31259, P31269, P31277, P31311, P31313, P31315, P43241, P43345, P52946

Diamond homologs: A1YFA5, A2D5K9, A2D5Y4, A2T7F3, A2T7H5, A8XSQ8, O13074, O14627, O42504, P02830, P02832, P02833, P04476, P06798, P07548, P09013, P09014, P09017, P09019, P09021, P09023, P09024, P09067, P09070, P09071, P09077, P09079, P09080, P09085, P09092, P09629, P09630, P10038, P10178, P10284, P10629, P13545, P14838, P14839, P14840

SIGNOR signaling

28 interactions.

A	Effect	B	Mechanism
CDK2	“down-regulates quantity by destabilization”	CDX2	phosphorylation
CDX2	“up-regulates quantity by expression”	VIL1	“transcriptional regulation”
MAPK14	“down-regulates quantity by destabilization”	CDX2	phosphorylation
GATA6	“up-regulates quantity by expression”	CDX2
SOX9	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	CDH17	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	MEP1A	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	UGT1A10	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	UGT1A8	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	FUT2	“transcriptional regulation”
NANOG	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
PDHX	“down-regulates activity”	CDX2	binding
CDX2	“up-regulates quantity by expression”	INS	“transcriptional regulation”
POU5F1	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
CDX2	“form complex”	CDX2/PAX6/P300	binding
GSK3B	unknown	CDX2	phosphorylation
CDX2	“up-regulates quantity by expression”	LCT	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	MUC2	“transcriptional regulation”
CDX2	“up-regulates quantity by expression”	TFF3	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — ESCA.

Clinical variants and AI predictions

ClinVar

54 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	49
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
145957	GRCh38/hg38 13q12.13-12.3(chr13:26965244-30097858)x3	Likely pathogenic
812557	NM_001265.6(CDX2):c.940T>C (p.Ter314Arg)	Likely pathogenic

SpliceAI

662 predictions. Top by Δscore:

Variant	Effect	Δscore
13:27963365:TTAAC:T	acceptor_gain	1.0000
13:27963366:TAAC:T	acceptor_gain	1.0000
13:27963370:C:CG	acceptor_loss	1.0000
13:27963376:A:C	acceptor_gain	1.0000
13:27964911:T:A	donor_gain	1.0000
13:27964914:T:TA	donor_gain	1.0000
13:27965011:TTTCA:T	acceptor_gain	1.0000
13:27965012:TTCA:T	acceptor_gain	1.0000
13:27965013:TCA:T	acceptor_gain	1.0000
13:27965014:CA:C	acceptor_gain	1.0000
13:27965014:CACTG:C	acceptor_gain	1.0000
13:27965016:C:CC	acceptor_gain	1.0000
13:27965016:CTGTG:C	acceptor_loss	1.0000
13:27965017:T:G	acceptor_loss	1.0000
13:27965018:G:C	acceptor_gain	1.0000
13:27965018:G:GC	acceptor_gain	1.0000
13:27963367:AAC:A	acceptor_gain	0.9900
13:27963368:AC:A	acceptor_gain	0.9900
13:27963369:CC:C	acceptor_gain	0.9900
13:27963370:C:CC	acceptor_gain	0.9900
13:27963376:A:AC	acceptor_gain	0.9900
13:27964902:G:C	donor_gain	0.9900
13:27964864:CCCCA:C	donor_loss	0.9800
13:27964865:CCCA:C	donor_loss	0.9800
13:27964866:CCACC:C	donor_loss	0.9800
13:27964867:CA:C	donor_loss	0.9800
13:27964868:AC:A	donor_loss	0.9800
13:27964869:C:CT	donor_loss	0.9800
13:27965012:TTCAC:T	acceptor_gain	0.9800
13:27965013:TCACT:T	acceptor_gain	0.9800

AlphaMissense

2012 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:27963328:T:A	K243N	1.000
13:27963328:T:G	K243N	1.000
13:27963329:T:A	K243I	1.000
13:27963330:T:C	K243E	1.000
13:27963331:C:A	R242S	1.000
13:27963331:C:G	R242S	1.000
13:27963332:C:A	R242M	1.000
13:27963332:C:G	R242T	1.000
13:27963333:T:A	R242W	1.000
13:27963336:C:T	E241K	1.000
13:27963337:C:A	K240N	1.000
13:27963337:C:G	K240N	1.000
13:27963338:T:A	K240M	1.000
13:27963338:T:G	K240T	1.000
13:27963339:T:C	K240E	1.000
13:27963339:T:G	K240Q	1.000
13:27963341:G:A	A239V	1.000
13:27963342:C:G	A239P	1.000
13:27963342:C:T	A239T	1.000
13:27963343:T:A	R238S	1.000
13:27963343:T:G	R238S	1.000
13:27963344:C:A	R238I	1.000
13:27963344:C:G	R238T	1.000
13:27963345:T:C	R238G	1.000
13:27963347:C:A	R237L	1.000
13:27963347:C:G	R237P	1.000
13:27963347:C:T	R237H	1.000
13:27963348:G:A	R237C	1.000
13:27963348:G:C	R237G	1.000
13:27963348:G:T	R237S	1.000

dbSNP variants (sampled 300 via entrez): RS1000356367 (13:27960670 T>C), RS1000662860 (13:27965609 C>T), RS1000803534 (13:27965524 G>A), RS1000886841 (13:27960640 G>A,C,T), RS1001730699 (13:27961114 C>A), RS1002078151 (13:27961435 C>G), RS1002166891 (13:27965832 C>T), RS1002219435 (13:27965650 G>A), RS1002673154 (13:27962817 G>C), RS1002874072 (13:27968499 G>A,T), RS1002880766 (13:27968204 G>A), RS1003206491 (13:27967290 C>G), RS1003701561 (13:27967722 G>C), RS1003768321 (13:27961324 C>T), RS1004229482 (13:27966236 C>A)

Disease associations

OMIM: gene MIM:600297 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): anorectal malformation (MONDO:0019938), sirenomelia (MONDO:0017850)

Orphanet (2): Anorectal malformation (Orphanet:96346), Sirenomelia (Orphanet:3169)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002553_1	Pancreatic cancer	2.000000e-09
GCST004625_129	Monocyte count	1.000000e-27
GCST005951_4	Body mass index	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3812863	CDX2		0.00	0

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects reaction, decreases reaction, increases expression, affects cotreatment, increases reaction	3
6-formylindolo(3,2-b)carbazole	increases reaction, affects cotreatment, decreases reaction, increases expression	2
Decitabine	affects cotreatment, increases expression, decreases methylation, decreases reaction, increases reaction	2
3,19-(2-bromobenzylidene)andrographolide	increases expression, decreases response to substance	1
trichostatin A	increases expression, increases reaction	1
indole-3-carbinol	increases expression, increases reaction	1
2-ethylhexyldiphenylphosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
puag-haad	decreases reaction, increases expression	1
nitazoxanide	increases expression	1
santicizer 148	decreases expression	1
bisindolylmaleimide I	decreases reaction, increases expression	1
CGP 52608	increases reaction, affects binding	1
tizoxanide	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects expression	1
bisphenol S	decreases methylation	1
CL 075	increases expression, increases reaction	1
(+)-JQ1 compound	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Acids	decreases methylation, increases expression	1
Benzo(a)pyrene	increases methylation	1
Bile Acids and Salts	increases expression	1
Chenodeoxycholic Acid	increases expression	1
Cholic Acids	decreases methylation, increases expression	1
Fluorouracil	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lipopolysaccharides	affects reaction, decreases reaction, increases expression, affects cotreatment	1
Methapyrilene	decreases methylation	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0N1	SEES3-1V human CDX2, clone1	Embryonic stem cell	Male
CVCL_A0N2	SEES3-1V human CDX2, clone2	Embryonic stem cell	Male
CVCL_A0N3	SEES3-1V human CDX2, clone3	Embryonic stem cell	Male
CVCL_B8DJ	Abcam HCT 116 CDX2 KO	Cancer cell line	Male
CVCL_B8U1	Abcam MCF-7 CDX2 KO	Cancer cell line	Female
CVCL_B9FS	Abcam A-549 CDX2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

9 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03746834	PHASE4	COMPLETED	NASHA/Dx as a Perianal Implant for the Treatment of Persistent Fecal Incontience After Anorectal Malformation
NCT07392203	EARLY_PHASE1	NOT_YET_RECRUITING	Role of (Saline- Glycerin) Rectal Enema in Treatment of Fecal Incontinence in Children
NCT00909415	Not specified	COMPLETED	Urodynamic Evaluation in Patients With Anorectal Malformation According to Spinal Cord Abnormalities
NCT02029248	Not specified	COMPLETED	National Study on the Quality of Life of Patients With Anorectal Malformation
NCT02624232	Not specified	UNKNOWN	Long-term Outcome in Patients With Anorectal Malformations
NCT03174028	Not specified	UNKNOWN	Laparoscopically Assisted Anorectal Pull-through Versus Posterior Sagittal Anorectoplasty
NCT03185637	Not specified	COMPLETED	Children’s Surgery in Sub-Saharan Africa
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT07603232	Not specified	ENROLLING_BY_INVITATION	Long-Term Health Outcomes in Children Born With Hirschsprung’s Disease and Anorectal Malformations at the Colorectal Centre of Excellence in Quebec