CXADR

Summary

CXADR (CXADR cell adhesion molecule, HGNC:2559) is a protein-coding gene on chromosome 21q21.1, encoding Coxsackievirus and adenovirus receptor (P78310). Component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. It is a selective cancer dependency (DepMap: 10.2% of cell lines).

The protein encoded by this gene is a type I membrane receptor for group B coxsackieviruses and subgroup C adenoviruses. Several transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene are found on chromosomes 15, 18, and 21.

Source: NCBI Gene 1525 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 80 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.2% of screened cell lines
• MANE Select transcript: NM_001338

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2559
Approved symbol	CXADR
Name	CXADR cell adhesion molecule
Location	21q21.1
Locus type	gene with protein product
Status	Approved
Aliases	CAR
Ensembl gene	ENSG00000154639
Ensembl biotype	protein_coding
OMIM	602621
Entrez	1525

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000284878, ENST00000356275, ENST00000400165, ENST00000400166, ENST00000400169, ENST00000886121, ENST00000926167, ENST00000926168, ENST00000926169, ENST00000944254, ENST00000944255

RefSeq mRNA: 5 — MANE Select: NM_001338 NM_001207063, NM_001207064, NM_001207065, NM_001207066, NM_001338

CCDS: CCDS33519, CCDS56204, CCDS56205, CCDS56206, CCDS56207

Canonical transcript exons

ENST00000284878 — 7 exons

Exon	Start	End
ENSE00001016953	17560702	17560824
ENSE00001016954	17558976	17559131
ENSE00001016956	17561338	17561476
ENSE00001016957	17551749	17551953
ENSE00001356018	17513043	17513172
ENSE00001370254	17547027	17547193
ENSE00001918181	17565428	17570100

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9811 / max 637.6356, expressed in 995 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188578	14.1896	969
188577	0.4328	243
188579	0.2148	101
188576	0.0737	28
188575	0.0701	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nipple	UBERON:0002030	99.26	gold quality
palpebral conjunctiva	UBERON:0001812	99.14	gold quality
upper leg skin	UBERON:0004262	98.96	gold quality
upper arm skin	UBERON:0004263	98.96	gold quality
mammalian vulva	UBERON:0000997	98.87	gold quality
pylorus	UBERON:0001166	98.76	gold quality
skin of hip	UBERON:0001554	98.75	gold quality
jejunal mucosa	UBERON:0000399	98.62	gold quality
penis	UBERON:0000989	98.46	gold quality
gingiva	UBERON:0001828	98.37	gold quality
hair follicle	UBERON:0002073	98.29	gold quality
esophagus squamous epithelium	UBERON:0006920	98.26	gold quality
gingival epithelium	UBERON:0001949	98.23	gold quality
corpus epididymis	UBERON:0004359	98.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.11	gold quality
bronchial epithelial cell	CL:0002328	97.88	gold quality
nasal cavity epithelium	UBERON:0005384	97.87	gold quality
cortical plate	UBERON:0005343	97.84	gold quality
colonic mucosa	UBERON:0000317	97.83	gold quality
buccal mucosa cell	CL:0002336	97.82	gold quality
epithelium of bronchus	UBERON:0002031	97.82	gold quality
germinal epithelium of ovary	UBERON:0001304	97.78	gold quality
squamous epithelium	UBERON:0006914	97.77	gold quality
bronchus	UBERON:0002185	97.63	gold quality
inferior vagus X ganglion	UBERON:0005363	97.24	gold quality
cervix epithelium	UBERON:0004801	97.02	gold quality
epithelium of esophagus	UBERON:0001976	96.95	gold quality
urethra	UBERON:0000057	96.63	gold quality
tongue squamous epithelium	UBERON:0006919	96.63	gold quality
mucosa of urinary bladder	UBERON:0001259	96.62	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	2091.37
E-GEOD-75688	yes	1826.20
E-GEOD-93593	yes	1636.11
E-MTAB-8142	yes	650.35
E-MTAB-8271	yes	219.96
E-MTAB-10287	yes	49.68
E-HCAD-10	yes	32.46
E-MTAB-5061	yes	26.85
E-GEOD-81547	yes	22.12
E-MTAB-10553	yes	19.92
E-HCAD-5	yes	16.38
E-MTAB-9388	yes	11.87
E-GEOD-81608	yes	5.15
E-GEOD-75140	no	2351.97
E-GEOD-83139	no	3.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, SNAI1, SNAI2, SP1, TP53, ZEB1, ZEB2

miRNA regulators (miRDB)

210 targeting CXADR, 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-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AN	99.97	70.91	2817

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Review: Receptor for the group B coxsackieviruses and adenoviruses, CAR (PMID:11479928)
• Additional splice variants discovered; possible result of splicing variants is to influence the efficacy of an adenovirus subgroup C-mediated gene therapy (PMID:11549277)
• adenovirus serotype 30 fiber does not mediate transduction via the coxsackie-adenovirus receptor (PMID:11752156)
• palmitylation is important for stable plasma membrane expression and biological activity of CAR but is not critical for adenovirus receptor performance. (PMID:12021372)
• Since DAF is abundantly expressed in epithelial and endothelial cells, interaction of cardiotropic Coxsackie Virus B with the DAF coreceptor protein, in addition to CAR, could therefore be advantageous to the virus by enhancing viral entry into the heart. (PMID:12920584)
• identified 3 CAR isoforms lacking the transmembrane domain and are the result of alternative RNA splicing events between exons IV and VII (CAR4/7), exons III and VII (CAR3/7), and exons II and VII (CAR2/7); CAR4/7 but not CAR2/7 binds to coxsackievirus B3 (PMID:14978041)
• expression levels of CAR mRNA varies markedly between different tumor types (PMID:15173092)
• CAR interacts with several distinct PDZ-domain-containing proteins and may exert its biological function through these interactions (PMID:15304526)
• Results indicate that the coxsackievirus and adenovirus receptor interacts with multi-PDZ domain protein 1 (MUPP1) and is involved in MUPP1 recruitment to the tight junction. (PMID:15364909)
• Data suggest that modulating the expression of integrin subunits beta3/5 in human neurons may enhance adenoviral infectivity via the coxsackie-adenovirus receptor. (PMID:15456946)
• interacts with a DAF binding Coxsackievirus B3 to induce A-particle formation (PMID:15596863)
• the entire extracellular domain of CAR is of vital importance to the biology of this highly conserved and important protein (PMID:15778494)
• swine vesicular disease virus isolates from early and recent outbreaks have been compared for their capacity to utilize the progenitor virus receptors coxsackie-adenovirus receptor and decay-accelerating factor (PMID:15831949)
• Because the CVB3-specific siRNA is effective against other enteroviruses, siRNAs have potential for a universal anti-enterovirus strategy. (PMID:15956603)
• Enhanced CAR expression can promote cancer cell survival and data suggest differential expression of CAR as a new factor in tumorigenesis. (PMID:15958612)
• NMR analysis and secondary structure of domain 2 (PMID:16101391)
• data show that CAR expression is significantly increased in breast tumor tissue and increased with increasing grade of tumor (PMID:16284735)
• molecular model of ligand-binding domain (PMID:16831563)
• determined the crystal structures of canine adenovirus serotype 2 (CAV-2) and the human adenovirus serotype 37 (HAd37) in complex with human CAR D1 at 2.3 and 1.5A resolution, respectively (PMID:16923808)
• Coxsackievirus-adenovirus receptor does not have a role in 5-FU-related enhancement of adenoviral infection (PMID:16937527)
• Genistein combined wwith a histone deacetylase inhibitor can inhibit cancer by altering the transcriptional regulation of CXADR. (PMID:16951199)
• results identify the binding of adenovirus type 5 (Ad5) fiber with the cellular CAR as a key proinflammatory activation event in epithelial respiratory cells that is independent of the transcription of Ad5 genes (PMID:16956941)
• levels of CAR expression observed in cases of squamous cell carcinoma lung cancers, and in cases of small cell lung cancers, and in adenocarcinoma lung cancers (PMID:17031523)
• Compared with Whites, Hispanic donor livers have increased expression of many genes that are transcriptionally regulated by CAR. (PMID:17118917)
• CAR may affect cell migration through its interaction with microtubules. (PMID:17210569)
• Soluble CAR isoforms 3/7 and 4/7 may play a pivotal role in ovarian cancer biology. (PMID:17278108)
• Data show that human pancreatic islet endothelial cells express coxsackievirus and adenovirus receptor and are activated by coxsackie B virus infection. (PMID:17494992)
• Data show that the overexpression of coxsackie and the adenovirus receptor in T24 bladder cancer cells can inhibit cell growth both in vitro and in vivo. (PMID:17506949)
• The prevalence of CAR expression was significantly higher in viral myocarditis and dilated cardiomyopathy patients than in controls. (PMID:17896511)
• The data indicated that the five colon cancer cell lines tested expressed CAR and could be efficiently infected by adenoviral vectors. (PMID:18081225)
• The coactivator NCOA6 mediates the mechanism of the synergistic activation of the CYP2C9 gene by CAR and HNF4alpha. (PMID:18552123)
• Overexpressiom of coxsackievirus and adenovirus receptor is associted with Endometrial Neoplasms (PMID:18558015)
• the association between estrogen receptivity and the expression of hCAR in breast cancer seems to not only reflect a phenotype of low malignancy, but expression of hCAR may also be directly influenced by ER-specific ligands. (PMID:18618240)
• The genes in GENESET 11 together with CAR may play a pathogenic role in the development of dilated cardiomyopathy. (PMID:18959124)
• CAR stabilizes lymphatic endothelial cell interactions in the skin and may contribute to lymphatic vessel integrity. (PMID:19007771)
• Complement protein C1q and anti-hexon antibodies together can mediate efficient adenovirus infection in coxsackie and adenovirus receptor-negative cell types. (PMID:19115936)
• presence of CAR on erythrocytes leads to prolonged in vivo blood half-life and significantly reduced liver infection when a CAR-tropic adenoviruse is injected intravenously. (PMID:19119424)
• Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1. (PMID:19131551)
• These data do also suggest that CAR does not contribute substantially to carcinogenesis in Barrett’s esophagus, however, it may be speculated that loss of CAR promotes tumor progression in advanced stages of Barrett’s carcinomas. (PMID:19132065)
• Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression. (PMID:19142187)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cxadr	ENSDARG00000043658
danio_rerio	si:dkey-65b12.10	ENSDARG00000092311
danio_rerio	si:dkey-65b12.12	ENSDARG00000094458
mus_musculus	Cxadr	ENSMUSG00000022865
mus_musculus	Gm1123	ENSMUSG00000044860
rattus_norvegicus	Cxadr	ENSRNOG00000001557
rattus_norvegicus	Cxadrl1	ENSRNOG00000029029

Paralogs (14): VSIG2 (ENSG00000019102), VSIG1 (ENSG00000101842), VSIR (ENSG00000107738), GPA33 (ENSG00000143167), IGSF11 (ENSG00000144847), ESAM (ENSG00000149564), JAM2 (ENSG00000154721), F11R (ENSG00000158769), MXRA8 (ENSG00000162576), JAM3 (ENSG00000166086), CLMP (ENSG00000166250), MUC15 (ENSG00000169550), VSTM2B (ENSG00000187135), VSIG8 (ENSG00000243284)

Protein

Protein identifiers

Coxsackievirus and adenovirus receptor — P78310 (reviewed: P78310)

Alternative names: CVB3-binding protein, Coxsackievirus B-adenovirus receptor, HCVADR

All UniProt accessions (1): P78310

UniProt curated annotations — full annotation on UniProt →

Function. Component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. Also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair. (Microbial infection) Acts as a receptor for adenovirus type C. (Microbial infection) Acts as a receptor for Coxsackievirus B1 to B6.

Subunit / interactions. Monomer. May form homodimer. Interacts with LNX, MAGI1, DLG4, PRKCABP, TJP1 and CTNNB1. Interacts with MPDZ; recruits MPDZ to intercellular contact sites. Interacts with JAML (homodimeric form). Secreted isoform 3, isoform 4 and isoform 5 can interact with the extracellular domain of the receptor. (Microbial infection) Interacts with adenovirus subgroups A, C, D, E and F fiber proteins as well as coxsackievirus B1, B2, B3, B4, B5 and B6 capsid proteins.

Subcellular location. Cell membrane. Basolateral cell membrane. Cell junction. Tight junction. Adherens junction Secreted Secreted Secreted.

Tissue specificity. Expressed in pancreas, brain, heart, small intestine, testis, prostate and at a lower level in liver and lung. Isoform 5 is ubiquitously expressed. Isoform 3 is expressed in heart, lung and pancreas. In skeletal muscle, isoform 1 is found at the neuromuscular junction and isoform 2 is found in blood vessels. In cardiac muscle, isoform 1 and isoform 2 are found at intercalated disks. In heart expressed in subendothelial layers of the vessel wall but not in the luminal endothelial surface. Expression is elevated in hearts with dilated cardiomyopathy.

Post-translational modifications. N-glycosylated. Palmitoylated on Cys-259 and/or Cys-260; required for proper localization to the plasma membrane.

Domain organisation. The Ig-like C2-type 1 domain mediates homodimerization and interaction with JAML. The PDZ-binding motif mediates interaction with MPDZ and MAGI1.

Isoforms (7)

UniProt ID	Names	Canonical?
P78310-1	1, SIV	yes
P78310-2	2, CAR2, HCAR2, TVV
P78310-3	3, CAR2/7, Gamma
P78310-4	4, CAR3/7
P78310-5	5, CAR4/7, Beta
P78310-6	6
P78310-7	7, CAR 4/6

RefSeq proteins (5): NP_001193992, NP_001193993, NP_001193994, NP_001193995, NP_001329* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR052307	EJ_Adhesion_Regulator	Family

Pfam: PF07686, PF13927

UniProt features (61 total): strand 18, splice variant 10, modified residue 6, mutagenesis site 4, helix 3, compositionally biased region 2, lipid moiety-binding region 2, glycosylation site 2, topological domain 2, disulfide bond 2, domain 2, signal peptide 1, chain 1, transmembrane region 1, sequence variant 1, turn 1, sequence conflict 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
1EAJ	X-RAY DIFFRACTION	1.35
2J12	X-RAY DIFFRACTION	1.5
2WBW	X-RAY DIFFRACTION	1.55
1F5W	X-RAY DIFFRACTION	1.7
7W14	ELECTRON MICROSCOPY	2.2
2J1K	X-RAY DIFFRACTION	2.3
1KAC	X-RAY DIFFRACTION	2.6
7VYK	ELECTRON MICROSCOPY	2.79
7VYL	ELECTRON MICROSCOPY	2.79
1P6A	X-RAY DIFFRACTION	2.9
2W9L	X-RAY DIFFRACTION	2.91
1P69	X-RAY DIFFRACTION	3.1
7VXZ	ELECTRON MICROSCOPY	3.19
7DQ1	ELECTRON MICROSCOPY	3.6
7VYM	ELECTRON MICROSCOPY	3.68
7DPZ	ELECTRON MICROSCOPY	3.8
3J6L	ELECTRON MICROSCOPY	9
3J6M	ELECTRON MICROSCOPY	9
3J6N	ELECTRON MICROSCOPY	9
3J6O	ELECTRON MICROSCOPY	9
1JEW	ELECTRON MICROSCOPY	22
1RSF	SOLUTION NMR
2NPL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78310-F1	79.51	0.58

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 (8): 297, 304, 306, 323, 332, 363, 259, 260

Disulfide bonds (2): 41–120, 162–212

Glycosylation sites (2): 106, 201

Mutagenesis-validated functional residues (4):

Position	Phenotype
70–72	abolishes binding to adenovirus type 5.
259–260	loss of palmitoylation and altered localization.
318	affects basolateral localization in airway epithelial cells.
345–348	affects basolateral localization in airway epithelial cells.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-202733	Cell surface interactions at the vascular wall

MSigDB gene sets: 382 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, HORIUCHI_WTAP_TARGETS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, BECKER_TAMOXIFEN_RESISTANCE_UP, LI_PROSTATE_CANCER_EPIGENETIC, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (18): mitochondrion organization (GO:0007005), heterophilic cell-cell adhesion (GO:0007157), heart development (GO:0007507), primordial germ cell migration (GO:0008354), epithelial structure maintenance (GO:0010669), actin cytoskeleton organization (GO:0030036), neutrophil chemotaxis (GO:0030593), homotypic cell-cell adhesion (GO:0034109), cell-cell junction organization (GO:0045216), gamma-delta T cell activation (GO:0046629), defense response to virus (GO:0051607), cardiac muscle cell development (GO:0055013), transepithelial transport (GO:0070633), AV node cell to bundle of His cell communication (GO:0086067), AV node cell-bundle of His cell adhesion involved in cell communication (GO:0086072), regulation of AV node cell action potential (GO:0098904), cell adhesion (GO:0007155), symbiont entry into host cell (GO:0046718)

GO Molecular Function (10): virus receptor activity (GO:0001618), signaling receptor binding (GO:0005102), integrin binding (GO:0005178), beta-catenin binding (GO:0008013), PDZ domain binding (GO:0030165), identical protein binding (GO:0042802), cell adhesion molecule binding (GO:0050839), connexin binding (GO:0071253), cell adhesive protein binding involved in AV node cell-bundle of His cell communication (GO:0086082), protein binding (GO:0005515)

GO Cellular Component (22): acrosomal vesicle (GO:0001669), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), intercalated disc (GO:0014704), basolateral plasma membrane (GO:0016323), apicolateral plasma membrane (GO:0016327), cell junction (GO:0030054), filopodium (GO:0030175), growth cone (GO:0030426), neuromuscular junction (GO:0031594), protein-containing complex (GO:0032991), neuron projection (GO:0043005), cell body (GO:0044297), membrane raft (GO:0045121), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	5
cellular anatomical structure	5
cell-cell adhesion	2
plasma membrane region	2
organelle organization	1
animal organ development	1
circulatory system development	1
gamete generation	1
cell migration	1
tissue homeostasis	1
cytoskeleton organization	1
actin filament-based process	1
granulocyte chemotaxis	1
neutrophil migration	1
cell junction organization	1
T cell activation	1
defense response	1
response to virus	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
transport	1
cell communication involved in cardiac conduction	1
heterotypic cell-cell adhesion	1
cardiac muscle cell-cardiac muscle cell adhesion	1
AV node cell to bundle of His cell communication	1
regulation of cell communication	1
AV node cell action potential	1
regulation of cardiac muscle cell action potential	1
cellular process	1
viral life cycle	1
symbiont entry into host	1
symbiont entry into host cell	1
exogenous protein binding	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
protein domain specific binding	1
AV node cell-bundle of His cell adhesion involved in cell communication	1
protein binding involved in heterotypic cell-cell adhesion	1

Protein interactions and networks

STRING

1164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CXADR	JAML	Q86YT9	902
CXADR	LNX1	Q8TBB1	881
CXADR	CD55	P08174	859
CXADR	CD46	P15529	857
CXADR	TJP1	Q07157	791
CXADR	OCLN	Q16625	790
CXADR	CYP2B6	P20813	733
CXADR	DSG2	Q14126	653
CXADR	NR1I3	Q14994	651
CXADR	AGBL3	Q8NEM8	650
CXADR	CYP3A4	P05184	646
CXADR	CD59	P13987	645
CXADR	ADGRE5	P48960	636
CXADR	SLAMF1	Q13291	625
CXADR	IGSF5	Q9NSI5	596

IntAct

64 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
JAML	CXADR	psi-mi:“MI:0915”(physical association)	0.590
CXADR	JAML	psi-mi:“MI:0915”(physical association)	0.590
CXADR	ANKRD46	psi-mi:“MI:0915”(physical association)	0.560
MAL	CXADR	psi-mi:“MI:0915”(physical association)	0.560
CXADR	FAM3C	psi-mi:“MI:0915”(physical association)	0.560
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	CXADR	psi-mi:“MI:0407”(direct interaction)	0.440
CXADR	H1-5	psi-mi:“MI:0915”(physical association)	0.400
CXADR	CXADR	psi-mi:“MI:0915”(physical association)	0.400
CXADR	EWSR1	psi-mi:“MI:0915”(physical association)	0.370
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
CACYBP	VPS37C	psi-mi:“MI:0914”(association)	0.350
CACYBP	PSMD11	psi-mi:“MI:0914”(association)	0.350
CAPRIN1	VPS37C	psi-mi:“MI:0914”(association)	0.350
CAPRIN1	SDCBP	psi-mi:“MI:0914”(association)	0.350
CFL2	VPS37C	psi-mi:“MI:0914”(association)	0.350
CFL2	PSMD11	psi-mi:“MI:0914”(association)	0.350
EIF4A1	SNAP23	psi-mi:“MI:0914”(association)	0.350
FNTA	SDCBP	psi-mi:“MI:0914”(association)	0.350
TSC22D3	VPS37C	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SLC12A5	KIF2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (397): CXADR (Affinity Capture-MS), CXADR (Affinity Capture-MS), EWSR1 (Two-hybrid), CXADR (Proximity Label-MS), CXADR (Proximity Label-MS), CXADR (Proximity Label-MS), CXADR (Proximity Label-MS), CXADR (Affinity Capture-MS), CXADR (Affinity Capture-MS), CXADR (Affinity Capture-MS), CXADR (Proximity Label-MS), CXADR (Proximity Label-MS), CXADR (Proximity Label-MS), CXADR (Proximity Label-MS), CXADR (Affinity Capture-MS)

ESM2 similar proteins: A0A8M2B818, A3KPA0, A5D7C3, B0JYH6, O35112, O46634, O46651, O88792, P17790, P18461, P18572, P21802, P21803, P26453, P35613, P42292, P57087, P78310, P97792, Q01638, Q13740, Q15198, Q1WIM2, Q2PFX1, Q2WGK2, Q3V3F6, Q5R764, Q5RJP7, Q61490, Q66KX2, Q68FQ2, Q6DJ83, Q6PE55, Q6UWV2, Q7ZXX1, Q8BLQ9, Q8N3J6, Q8WMV3, Q90Y50, Q99795

Diamond homologs: A0JM41, A2VD98, A5D7C3, O60487, O60939, O70255, O95297, P06907, P10522, P20938, P25189, P27573, P37301, P54900, P78310, P97792, Q08E08, Q32PI9, Q3TEW6, Q3V3F6, Q4KLY3, Q56A07, Q5EAB0, Q5R764, Q5R804, Q6AYT8, Q6UWV2, Q6WEB5, Q864L3, Q86YT9, Q8AVM3, Q8IWT1, Q8WMV3, Q91664, Q96IQ7, Q9PWR4, Q9R066, Q86XK7, A2AJ76, D3YXG0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	5	22.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	46
Likely benign	10
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
395680	GRCh37/hg19 21q11.2-21.1(chr21:15442582-20723130)	Pathogenic

SpliceAI

1529 predictions. Top by Δscore:

Variant	Effect	Δscore
21:17547025:A:AG	acceptor_gain	1.0000
21:17547025:AGAT:A	acceptor_loss	1.0000
21:17547026:G:GT	acceptor_gain	1.0000
21:17547026:GA:G	acceptor_gain	1.0000
21:17547026:GAT:G	acceptor_gain	1.0000
21:17547026:GATT:G	acceptor_gain	1.0000
21:17547026:GATTT:G	acceptor_gain	1.0000
21:17547191:GTG:G	donor_gain	1.0000
21:17547194:G:GG	donor_gain	1.0000
21:17547194:GTA:G	donor_loss	1.0000
21:17547195:T:A	donor_loss	1.0000
21:17551748:GATT:G	acceptor_gain	1.0000
21:17551951:TTGGT:T	donor_loss	1.0000
21:17551952:TGGT:T	donor_loss	1.0000
21:17551954:G:GA	donor_loss	1.0000
21:17551954:G:GG	donor_gain	1.0000
21:17551955:TAAGT:T	donor_loss	1.0000
21:17558974:A:AG	acceptor_gain	1.0000
21:17558975:G:GG	acceptor_gain	1.0000
21:17558975:GTT:G	acceptor_gain	1.0000
21:17558975:GTTA:G	acceptor_gain	1.0000
21:17558975:GTTAA:G	acceptor_gain	1.0000
21:17559076:G:GG	donor_gain	1.0000
21:17560700:A:AG	acceptor_gain	1.0000
21:17560701:G:GG	acceptor_gain	1.0000
21:17560825:G:GG	donor_gain	1.0000
21:17561333:TTTA:T	acceptor_loss	1.0000
21:17561334:TTA:T	acceptor_loss	1.0000
21:17561335:TA:T	acceptor_loss	1.0000
21:17561336:A:AG	acceptor_gain	1.0000

AlphaMissense

2369 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:17547152:T:A	W57R	0.999
21:17547152:T:C	W57R	0.999
21:17547154:G:C	W57C	0.999
21:17547154:G:T	W57C	0.999
21:17551896:T:A	C120S	0.999
21:17551897:G:C	C120S	0.999
21:17559083:T:A	W175R	0.999
21:17559083:T:C	W175R	0.999
21:17559085:G:C	W175C	0.999
21:17559085:G:T	W175C	0.999
21:17551807:G:C	R90P	0.998
21:17551896:T:C	C120R	0.998
21:17560758:T:G	Y210D	0.998
21:17560764:T:A	C212S	0.998
21:17560765:G:C	C212S	0.998
21:17560766:T:G	C212W	0.998
21:17560778:C:A	N216K	0.998
21:17560778:C:G	N216K	0.998
21:17558996:T:C	C146R	0.997
21:17559044:T:A	C162S	0.997
21:17559044:T:C	C162R	0.997
21:17559045:G:C	C162S	0.997
21:17560764:T:C	C212R	0.997
21:17560765:G:A	C212Y	0.997
21:17560777:A:T	N216I	0.997
21:17547153:G:C	W57S	0.996
21:17551898:C:G	C120W	0.996
21:17551942:T:C	L135P	0.996
21:17558996:T:A	C146S	0.996
21:17558997:G:C	C146S	0.996

dbSNP variants (sampled 300 via entrez): RS1000020256 (21:17610560 T>A,C), RS1000022334 (21:17562134 C>A), RS1000033307 (21:17530843 A>G), RS1000102016 (21:17604461 A>G), RS1000125191 (21:17603767 T>C), RS1000190493 (21:17560144 A>T), RS1000191305 (21:17602234 G>T), RS1000218209 (21:17573247 A>G), RS1000236710 (21:17521675 A>C), RS1000246814 (21:17533090 G>A,C), RS1000272677 (21:17554065 T>C), RS1000291979 (21:17535491 T>C), RS1000326837 (21:17616338 T>C), RS1000334121 (21:17597513 G>A,C), RS1000407420 (21:17633724 A>G)

Disease associations

OMIM: gene MIM:602621 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002398_62	Neutrophil count	7.000000e-11
GCST90011900_14	Serum alkaline phosphatase levels	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879448 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	increases expression, increases reaction, affects cotreatment, decreases expression	4
Benzo(a)pyrene	decreases expression, increases methylation	3
Estradiol	affects cotreatment, decreases expression, increases expression, affects expression	3
Valproic Acid	increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression, decreases expression	3
Cyclosporine	decreases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Calcitriol	increases expression, affects cotreatment	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
lead acetate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
nickel chloride	decreases expression	1
cupric chloride	decreases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, decreases expression, affects response to substance	1
pentabromodiphenyl ether	increases expression	1
BQ 788	decreases expression	1
2-palmitoylglycerol	increases expression	1
clothianidin	increases expression	1
torcetrapib	increases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Valsartan	decreases expression	1
Decitabine	increases expression, increases reaction	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4834547	Binding	Agonist activity at human CAR by luciferase reporter assay	Building a Chemical Toolbox for Human Pregnane X Receptor Research: Discovery of Agonists, Inverse Agonists, and Antagonists Among Analogs Based on the Unique Chemical Scaffold of SPA70. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SK21	HAP1 CXADR (-) 1	Cancer cell line	Male
CVCL_XN04	HAP1 CXADR (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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