CD69

Summary

CD69 (CD69 molecule, HGNC:1694) is a protein-coding gene on chromosome 12p13.31, encoding Early activation antigen CD69 (Q07108). Transmembrane protein expressed mainly on T-cells resident in mucosa that plays an essential role in immune cell homeostasis.

This gene encodes a member of the calcium dependent lectin superfamily of type II transmembrane receptors. Expression of the encoded protein is induced upon activation of T lymphocytes, and may play a role in proliferation. Furthermore, the protein may act to transmit signals in natural killer cells and platelets.

Source: NCBI Gene 969 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 21 total
• GTEx eGene: eQTL in 7 tissues, sQTL in 2 (q < 0.05)
• ChEMBL bioactivity: 7 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.42 (intermediate), LOEUF 0.86 (unconstrained)
• MANE Select transcript: NM_001781
• Interaction hub: 2,596 STRING partners (top 4% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1694
Approved symbol	CD69
Name	CD69 molecule
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	CLEC2C
Ensembl gene	ENSG00000110848
Ensembl biotype	protein_coding
OMIM	107273
Entrez	969

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

MANE Select: ENST00000228434

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 3

ENST00000228434, ENST00000416624, ENST00000536709, ENST00000543147

RefSeq mRNA: 1 — MANE Select: NM_001781 NM_001781

CCDS: CCDS8604

Canonical transcript exons

ENST00000228434 — 5 exons

Exon	Start	End
ENSE00000718659	9754587	9754690
ENSE00000718665	9755062	9755261
ENSE00000821822	9752486	9753589
ENSE00003529080	9760757	9760901
ENSE00003640877	9756297	9756419

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 95.53.

FANTOM5 (CAGE): breadth broad, TPM avg 54.5363 / max 4160.0768, expressed in 509 samples.

Highest expression (Bgee): lymph node, vermiform appendix, spleen, gall bladder, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD69 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	3.9e-06	+0.34	12:9764044:C:T
Adipose Visceral Omentum	sqtl	3.6e-03	+0.87	12:9753583:G:A
Esophagus Muscularis	eqtl	1.2e-02	-0.37	12:9673683:C:T
Brain Hippocampus	eqtl	1.6e-02	-0.28	12:8867893:A:G
Cells EBV-transformed lymphocytes	eqtl	2.1e-02	+0.15	12:9722302:T:C
Brain Putamen basal ganglia	eqtl	3.7e-02	-3.38	12:10441639:G:A
Muscle Skeletal	eqtl	4.1e-02	+0.15	12:9365626:T:C
Skin Sun Exposed Lower leg	eqtl	4.7e-02	+0.36	12:10327537:T:C
Skin Not Sun Exposed Suprapubic	sqtl	4.8e-02	+1.14	12:9058462:CAT:C

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
129431	54.4267	508
129432	0.1096	34

Top tissues by expression

showing 100 of 280 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	95.53	gold quality
vermiform appendix	UBERON:0001154	95.45	gold quality
spleen	UBERON:0002106	93.09	gold quality
gall bladder	UBERON:0002110	92.57	gold quality
rectum	UBERON:0001052	90.75	gold quality
bone marrow cell	CL:0002092	90.59	gold quality
granulocyte	CL:0000094	90.03	gold quality
caecum	UBERON:0001153	90.00	gold quality
epithelium of nasopharynx	UBERON:0001951	89.23	gold quality
nasopharynx	UBERON:0001728	89.21	gold quality
right lung	UBERON:0002167	88.33	gold quality
bone marrow	UBERON:0002371	87.95	gold quality
colonic epithelium	UBERON:0000397	87.90	gold quality
upper lobe of left lung	UBERON:0008952	87.43	gold quality
tonsil	UBERON:0002372	86.37	gold quality
upper lobe of lung	UBERON:0008948	86.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.93	gold quality
omental fat pad	UBERON:0010414	85.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.49	gold quality
peritoneum	UBERON:0002358	85.45	gold quality
amniotic fluid	UBERON:0000173	84.71	gold quality
leukocyte	CL:0000738	84.22	gold quality
upper leg skin	UBERON:0004262	83.81	gold quality
mononuclear cell	CL:0000842	83.80	gold quality
left uterine tube	UBERON:0001303	83.58	gold quality
monocyte	CL:0000576	83.44	gold quality
lung	UBERON:0002048	83.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.27	gold quality
smooth muscle tissue	UBERON:0001135	82.53	gold quality
small intestine	UBERON:0002108	82.21	gold quality
superficial temporal artery	UBERON:0001614	81.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.20	gold quality
right coronary artery	UBERON:0001625	81.00	gold quality
pylorus	UBERON:0001166	80.71	gold quality
lower lobe of lung	UBERON:0008949	80.07	gold quality
tibial nerve	UBERON:0001323	79.75	gold quality
blood	UBERON:0000178	79.70	gold quality
right uterine tube	UBERON:0001302	79.53	gold quality
thymus	UBERON:0002370	79.51	silver quality
spinal cord	UBERON:0002240	78.93	gold quality
vagina	UBERON:0000996	78.87	gold quality
mucosa of transverse colon	UBERON:0004991	78.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.40	gold quality
pleura	UBERON:0000977	78.03	gold quality
parietal pleura	UBERON:0002400	77.94	gold quality
fundus of stomach	UBERON:0001160	77.74	gold quality
transverse colon	UBERON:0001157	76.82	gold quality
ascending aorta	UBERON:0001496	76.64	gold quality
minor salivary gland	UBERON:0001830	76.50	gold quality
cardia of stomach	UBERON:0001162	76.41	gold quality
ectocervix	UBERON:0012249	76.38	gold quality
endocervix	UBERON:0000458	76.37	gold quality
right lobe of liver	UBERON:0001114	76.33	gold quality
body of stomach	UBERON:0001161	76.26	gold quality
thoracic aorta	UBERON:0001515	76.18	gold quality
thyroid gland	UBERON:0002046	76.18	gold quality
mucosa of stomach	UBERON:0001199	75.99	gold quality
right lobe of thyroid gland	UBERON:0001119	75.98	gold quality
visceral pleura	UBERON:0002401	75.94	gold quality
intestine	UBERON:0000160	75.82	gold quality
left lobe of thyroid gland	UBERON:0001120	75.75	gold quality
urethra	UBERON:0000057	75.67	gold quality
palpebral conjunctiva	UBERON:0001812	75.65	gold quality
mucosa of paranasal sinus	UBERON:0005030	75.19	gold quality
urinary bladder	UBERON:0001255	75.08	gold quality
skin of hip	UBERON:0001554	74.76	gold quality
left coronary artery	UBERON:0001626	74.51	gold quality
stomach	UBERON:0000945	74.40	gold quality
prostate gland	UBERON:0002367	74.35	gold quality
large intestine	UBERON:0000059	74.08	gold quality
skin of abdomen	UBERON:0001416	74.00	gold quality
coronary artery	UBERON:0001621	73.83	gold quality
fallopian tube	UBERON:0003889	73.67	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.64	gold quality
colon	UBERON:0001155	73.60	gold quality
lower esophagus mucosa	UBERON:0035834	73.57	gold quality
body of uterus	UBERON:0009853	73.32	gold quality
trigeminal ganglion	UBERON:0001675	73.26	silver quality
adenohypophysis	UBERON:0002196	72.69	gold quality
mouth mucosa	UBERON:0003729	72.57	gold quality
saliva-secreting gland	UBERON:0001044	72.52	gold quality
lower esophagus	UBERON:0013473	72.43	gold quality
lower esophagus muscularis layer	UBERON:0035833	72.42	gold quality
esophagus	UBERON:0001043	72.00	gold quality
penis	UBERON:0000989	71.98	gold quality
right atrium auricular region	UBERON:0006631	71.88	gold quality
skin of leg	UBERON:0001511	71.80	gold quality
muscle layer of sigmoid colon	UBERON:0035805	71.69	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.66	gold quality
esophagus mucosa	UBERON:0002469	71.52	gold quality
aorta	UBERON:0000947	71.45	gold quality
epithelial cell of pancreas	CL:0000083	71.26	silver quality
endothelial cell	CL:0000115	70.88	gold quality
uterine cervix	UBERON:0000002	70.82	gold quality
jejunal mucosa	UBERON:0000399	70.72	gold quality
oviduct epithelium	UBERON:0004804	70.65	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	70.62	gold quality
sigmoid colon	UBERON:0001159	70.38	gold quality
cardiac atrium	UBERON:0002081	70.27	gold quality
zone of skin	UBERON:0000014	69.59	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-GEOD-70580	yes	12685.29
E-CURD-126	yes	8543.91
E-MTAB-6308	yes	5737.80
E-CURD-46	yes	5680.35
E-HCAD-1	yes	3926.71
E-GEOD-130148	yes	3891.20
E-MTAB-9543	yes	3540.58
E-MTAB-6701	yes	3311.33
E-MTAB-9221	yes	3196.14
E-MTAB-10553	yes	3109.75
E-HCAD-15	yes	3061.81
E-CURD-114	yes	2946.62
E-CURD-79	yes	2800.17
E-MTAB-6678	yes	2550.21
E-MTAB-9467	yes	2539.25

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 64 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	159.6	low
Lymph node	tissue	88.3	low
Tonsil	tissue	56.3	medium
Thymus	tissue	53.2
Appendix	tissue	45.4	medium
Spleen	tissue	37.0	low
Gallbladder	tissue	25.6	not detected
Lung	tissue	21.3	not detected
Rectum	tissue	20.1	not detected
Breast	tissue	17.7	not detected
Small intestine	tissue	17.1	not detected
Urinary bladder	tissue	16.8	not detected
Smooth muscle	tissue	13.3	not detected
Liver	tissue	12.0	not detected
Esophagus	tissue	11.2	not detected
Stomach 1	tissue	11.1	not detected
Prostate	tissue	9.7	not detected
Cervix	tissue	8.7	not detected
Adipose tissue	tissue	8.5	not detected
Colon	tissue	8.4	not detected
Duodenum	tissue	7.7	not detected
Vagina	tissue	6.5	not detected
Adrenal gland	tissue	5.9	not detected
Endometrium 1	tissue	5.7	not detected
Salivary gland	tissue	4.8	not detected
Fallopian tube	tissue	4.6	not detected
Tongue	tissue	4.3
Choroid plexus	tissue	3.9
Pituitary gland	tissue	3.7
Thyroid gland	tissue	2.9	not detected
Kidney	tissue	2.9	not detected
Seminal vesicle	tissue	2.7	not detected
Epididymis	tissue	2.7	not detected
Placenta	tissue	2.4	not detected
Heart muscle	tissue	1.9	not detected
Parathyroid gland	tissue	1.9	not detected
Ovary	tissue	1.7	not detected
Pancreas	tissue	1.6	not detected
Testis	tissue	1.2	not detected
Skin 1	tissue	0.9	not detected
Locus coeruleus	tissue	0.9
Hippocampus	tissue	0.8	not detected
Spinal cord	tissue	0.6
Nucleus accumbens	tissue	0.4
Pons	tissue	0.2
Skeletal muscle	tissue	0.2	not detected
Medulla oblongata	tissue	0.2
Thalamus	tissue	0.2
Substantia nigra	tissue	0.2
Hippocampal formation	tissue	0.2
Postcentral gyrus	tissue	0.2
Periaqueductal gray	tissue	0.2
Cerebral cortex	tissue	0.1	not detected
Retina	tissue	0.1
Motor cortex	tissue	0.1
Basal ganglia	tissue	0.1	not detected
Midbrain	tissue	0.1
Hypothalamus	tissue	0.1
Superior colliculi	tissue	0.1
Corpus callosum	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 187; highest nTPM — Blood vessel (7.0), Lateral funiculus (white matter) (4.5), Cervical spinal cord, ventral horn (4.0), Nucleus raphe pallidus (3.0), Supraoptic nucleus (3.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, FOS, JUN, NFKB1, NFKB, NFKBID, PPARG, RELA, RUNX1, SLA2, STAT1, STAT5A

miRNA regulators (miRDB)

Targeting CD69 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 101 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
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-4282	99.99	75.36	6408
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814

Functional genomics

gnomAD constraint: pLI 0.418, LOEUF 0.86, missense Z 0.684 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000228434 — one region, missense o/e 0.86.

Literature-anchored findings (GeneRIF, showing 40)

• CD69 engagement initiates protein tyrosine kinase-dependent signaling pathways in IL-2-activated NK cells by inducing selective activation of Syk, but not ZAP70, kinase. (PMID:12077230)
• CD69 transduces a Bcl-2-dependent death signal when ligated by a specific antibody. As the function of CD69 appears to be restricted to activated eosinophils, making an ideal target for therapeutic intervention in asthma. (PMID:12234263)
• a higher CD69 expression when atopic neutrophils were incubated with GM-CSF compared to non-atopic neutrophils (PMID:12540017)
• GM-CSF, IFN-gamma or IFN-alpha significantly induced CD69 expression on neutrophils. We demonstrated the capacity of CD69 to act as a costimulus for TNF-alpha production by neutrophils. (PMID:12718936)
• expression of CD69 on CD3+ and CD8+ peripheral blood T cells correlates closely with the presence of acute graft rejection in renal allograft recipients (PMID:12865808)
• Increased CD69 of T lymphocytes, along with abnormally elevated immunologically active molecules play an important role in immune pathogenesis of patients with myelodysplastic syndrome(MDS). (PMID:14728878)
• Our study has identified, by immunoprecipitation and direct protein sequencing (LC/MS/MS), binding of CD69 to an N-terminal protein fragment of calreticulin expressed on the cell surface of human PBMCs. (PMID:15893733)
• The expression of CD69 in T lymphocytes from nasal polyps was abnormally high. (PMID:15952571)
• The expression of CD69 and CD154 molecules depend partially on the prolactine. (PMID:16396693)
• CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs (PMID:16525420)
• Plasmodium falciparum histidine-rich protein II reduces CD69 expression in T cells. (PMID:16788832)
• data suggest unidentified natural ligands for CD69 and/or CD69 autoantibodies possibly affect joint-composing cell types through increased production of S100A9 in neutrophils, providing insight into functions of CD69 on neutrophils in rheumatoid arthritis (PMID:17237603)
• IL-3 is a central inducer of CD69 expression. Upregulated CD69 expression on locally accumulated basophils in bronchial asthma may be partly due to a combination of local cytokines, especially IL-3, plus IgE-cross-linking allergens. (PMID:17541278)
• Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in chronic fatigue syndrome there is a disorder in the early activation of the immune system involving PKC. (PMID:17693977)
• results do not support a major role for the CD69 gene polymorphisms in RA genetic predisposition in our population. (PMID:18627570)
• the physical, biochemical and in vivo characteristics of a highly stable soluble form of CD69 obtained by bacterial expression of an appropriate extracellular segment of this protein. (PMID:18959746)
• Expression of CD69 and IL8 is upregulated upon Bcr-Abl expression (PMID:19383348)
• soluble factors in SSc plasma inhibit Treg function specifically that is associated with altered Treg CD69 and TGFbeta expression (PMID:19543397)
• analysis of CD69 molecules on human CD4+ T cell membrane (PMID:19670272)
• structure refined to 1.37 A resolution provides further details of the overall structure and the asymmetric interface between the monomers in the native dimer (PMID:20054122)
• Caffeine does not appear to depress Natural killer cell CD69 expression. (PMID:21152932)
• Studies provide a mechanistic link between CD69 and the regulation of T(H)17 responses. (PMID:21427408)
• Increased CD4(+) CD69(+) CD25(-) T cells exert a critical role in hepatocellular carcinoma progression and might represent a clinically aggressive tumor phenotype. (PMID:21557772)
• Results suggest that H. pylori induces CD69 expression through the activation of NF-kappaB, and that cagPAI might be relevant in the induction of CD69 expression in T cells. CD69 in T cells may play a role in H. pylori-induced gastritis. (PMID:21990950)
• CD69 is significantly correlated with poor clinical and biological prognostic factors and is confirmed to be an independent disease prognosticator in chronic lymphocytic leukemia. (PMID:21993667)
• T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes (PMID:22184722)
• Intron I acts as an important regulatory element of CD69 expression. (PMID:22456278)
• Priming with apoptotic debris prevented DCs from establishing cytotoxicity toward live human tumor cells by inducing a Treg-cell population, defined by coexpression of CD39 and CD69 (PMID:22678911)
• In patients with allergic rhinitis CD69 antigen is overexpressed on human peripheral blood natural killer cells reflecting their activation status. (PMID:23454781)
• CD69 overexpression is associated with the human T-cell leukemia virus type 1 infection and adult T-cell leukemia. (PMID:23507197)
• This is the first report of the regulation of CD69 expression by LMP-1, and this novel finding may, thus, represent an important link between the EBV oncoprotein LMP-1 and its critical role in the development of EBV-associated diseases. (PMID:23546309)
• CD69 is induced by integrin alpha4beta1 outside-in signalling and T-cell receptor signalling. (PMID:23758320)
• REVIEW: CD69 exerts a complex immunoregulatory role in humans, and that it could be considered as a target molecule for the therapy of immune-mediated diseases (PMID:23954168)
• Following coculture with GTKO/CD46 pig mesenchymal stromal cells, it is possible that upregulation of CD69 on human T cells initiates signaling events that would regulate CD4+ and CD8+ T cell activation and differentiation. (PMID:24044963)
• Human tumor-infiltrating CD4+CD69+ T cells suppress T cell proliferation via membarene -bound TGF-beta1. (PMID:24668348)
• these findings identify CD69 and galectin-1 to be a novel regulatory receptor-ligand pair that modulates Th17 effector cell differentiation and function. (PMID:24752896)
• Elevated expression of CD69 and CD161 on NK cells can be considered as immunological risk markers in RSA and IVF failure. (PMID:24975965)
• In vitro functional assays showed that CD69(+) Treg cells exerted an important suppressive effect on the activation of T effector cells (PMID:26100786)
• results demonstrate the functional and mechanistic interplays between CD69 and S100A8/S100A9 in supporting Treg-cell differentiation (PMID:26296369)
• Higher CD69 expression were less sensitive to bendamustine and is associated with chronic lymphocytic leukemia. (PMID:26701728)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-193e13.5	ENSDARG00000052656
danio_rerio		ENSDARG00000074732
danio_rerio	si:dkey-26c10.5	ENSDARG00000088023
danio_rerio	si:ch211-170d8.8	ENSDARG00000090945
mus_musculus	Cd69	ENSMUSG00000030156
rattus_norvegicus	Cd69	ENSRNOG00000056783
drosophila_melanogaster	rgn	FBGN0261258
caenorhabditis_elegans		WBGENE00009156
caenorhabditis_elegans		WBGENE00013008

Paralogs (24): CLEC2D (ENSG00000069493), CLEC2B (ENSG00000110852), KLRB1 (ENSG00000111796), KLRD1 (ENSG00000134539), KLRC1 (ENSG00000134545), KLRG1 (ENSG00000139187), KLRF1 (ENSG00000150045), CLEC1A (ENSG00000150048), CLEC1B (ENSG00000165682), CLEC7A (ENSG00000172243), CLEC12A (ENSG00000172322), OLR1 (ENSG00000173391), KLRC4 (ENSG00000183542), CLEC2A (ENSG00000188393), KLRG2 (ENSG00000188883), CLEC9A (ENSG00000197992), KLRC2 (ENSG00000205809), KLRC3 (ENSG00000205810), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), CLEC12B (ENSG00000256660), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227), CLECL1 (ENSG00000293488)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88343) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 15 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal humoral immune response	2
abnormal B cell differentiation	1
abnormal T cell physiology	1
increased IgM level	1
increased pre-B cell number	1
decreased susceptibility to induced arthritis	1
abnormal CD4-positive, alpha-beta T cell physiology	1
abnormal memory T cell physiology	1
decreased CD4-positive, alpha-beta T cell number	1
increased immature B cell number	1
increased IgG2a level	1
decreased tumor necrosis factor secretion	1
decreased interferon-gamma secretion	1
impaired neutrophil recruitment	1
impaired neutrophil chemotaxis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Vaccinia virus Copenhagen	P21063	97.8%	Diamond
Vaccinia virus WR	P24765	97.8%	Diamond
Fowlpox virus strain NVSL	P14371	47.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
KLRF2	protein-coding	100431172
LINC02390	ncRNA	105369652
CLECL1	protein-coding	160365
CLEC2A	protein-coding	387836
KLRF1	protein-coding	51348
CLEC2B	protein-coding	9976
CLEC2D	protein-coding	29121
LINC02470	ncRNA	100506159

Protein

Protein identifiers

Early activation antigen CD69 — Q07108 (reviewed: Q07108)

Alternative names: Activation inducer molecule, BL-AC/P26, C-type lectin domain family 2 member C, EA1, Early T-cell activation antigen p60, GP32/28, Leukocyte surface antigen Leu-23, MLR-3

All UniProt accessions (3): B4E009, Q07108, Q53ZX0

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane protein expressed mainly on T-cells resident in mucosa that plays an essential role in immune cell homeostasis. Rapidly expressed on the surface of platelets, T-lymphocytes and NK cells upon activation by various stimuli, such as antigen recognition or cytokine signaling, stimulates different signaling pathways in different cell types. Negatively regulates Th17 cell differentiation through its carbohydrate dependent interaction with galectin-1/LGALS1 present on immature dendritic cells. Association of CD69 cytoplasmic tail with the JAK3/STAT5 signaling pathway regulates the transcription of RORgamma/RORC and, consequently, differentiation toward the Th17 lineage. Also acts via the S100A8/S100A9 complex present on peripheral blood mononuclear cells to promote the conversion of naive CD4 T-cells into regulatory T-cells. Acts as an oxidized low-density lipoprotein (oxLDL) receptor in CD4 T-lymphocytes and negatively regulates the inflammatory response by inducing the expression of PDCD1 through the activation of NFAT. Participates in adipose tissue-derived mesenchymal stem cells (ASCs)-mediated protection against P.aeruginosa infection. Mechanistically, specifically recognizes P.aeruginosa to promote ERK1 activation, followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and other inflammatory cytokines secretion. In eosinophils, induces IL-10 production through the ERK1/2 pathway. Negatively regulates the chemotactic responses of effector lymphocytes and dendritic cells (DCs) to sphingosine 1 phosphate/S1P by acting as a S1PR1 receptor agonist and facilitating the internalization and degradation of the receptor.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with S100A8 and S100A9. Interacts with galactin-1/LGALS1. Interacts with S1PR1; this interaction mediates S1PR1 degradation.

Subcellular location. Cell membrane.

Tissue specificity. Expressed on the surface of activated T-cells, B-cells, natural killer cells, neutrophils, eosinophils, epidermal Langerhans cells and platelets.

Post-translational modifications. Constitutive Ser/Thr phosphorylation in both mature thymocytes and activated T-lymphocytes.

Induction. By antigens, mitogens or activators of PKC on the surface of T and B-lymphocytes. By interaction of IL-2 with the p75 IL-2R on the surface of NK cells.

RefSeq proteins (1): NP_001772* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001304	C-type_lectin-like	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR033992	NKR-like_CTLD	Domain
IPR050828	C-type_lectin/matrix_domain	Family

Pfam: PF00059

UniProt features (23 total): strand 8, disulfide bond 4, helix 3, topological domain 2, chain 1, turn 1, transmembrane region 1, domain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
3HUP	High-resolution structure of the extracellular domain of human CD69	X-RAY DIFFRACTION	1.37
1E87	Human CD69 - trigonal form	X-RAY DIFFRACTION	1.5
3CCK	Human CD69	X-RAY DIFFRACTION	1.8
1E8I	HUMAN CD69 - TETRAGONAL FORM	X-RAY DIFFRACTION	1.95
1FM5	CRYSTAL STRUCTURE OF HUMAN CD69	X-RAY DIFFRACTION	2.27
8G94	Structure of CD69-bound S1PR1 coupled to heterotrimeric Gi	ELECTRON MICROSCOPY	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07108-F1	82.84	0.66

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 8G94

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

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

Disulfide bonds (4)

Type	Positions
Disulfide bond	173–186, 85–96, 113–194
Interchain	68

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	166

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 487 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, CREL_01, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, LU_IL4_SIGNALING, GOBP_INFLAMMATORY_RESPONSE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MODULE_64, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION

GO Biological Process (4): negative regulation of inflammatory response (GO:0050728), cellular response to xenobiotic stimulus (GO:0071466), negative regulation of T-helper 17 cell lineage commitment (GO:2000329), negative regulation of T cell migration (GO:2000405)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), carbohydrate binding (GO:0030246), identical protein binding (GO:0042802), molecular sequestering activity (GO:0140313), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), protein-containing complex (GO:0032991), cell surface (GO:0009986)

GO top-level categories

24 GO namespaces:

Category	Terms
binding	2
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
negative regulation of cell fate commitment	1
T-helper 17 cell lineage commitment	1
negative regulation of T-helper 17 cell differentiation	1
regulation of T-helper 17 cell lineage commitment	1
T cell migration	1
negative regulation of lymphocyte migration	1
regulation of T cell migration	1
signaling receptor activity	1
protein binding	1
molecular_function	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular_component	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of T cell migration	BP	direct assay
negative regulation of T-helper 17 cell lineage commitment	BP	direct assay
negative regulation of inflammatory response	BP	direct assay
plasma membrane	CC	direct assay
protein-containing complex	CC	direct assay
identical protein binding	MF	direct assay
molecular sequestering activity	MF	direct assay
transmembrane signaling receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,596 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD69	CD4	P01730	930
CD69	CD8A	P01732	925
CD69	IL2	P01585	908
CD69	SELL	P14151	885
CD69	IFNG	P01579	880
CD69	CD44	P16070	863
CD69	KLRB1	Q12918	860
CD69	PTPRC	P08575	856
CD69	ITGAE	P38570	833
CD69	CD19	P15391	815
CD69	FOXP3	Q9BZS1	814
CD69	GZMB	P10144	803
CD69	CCR7	P32248	801
CD69	CD28	P10747	800
CD69	S1PR1	P21453	796

IntAct

Human interaction partners of CD69 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

17 partners by confidence:

Partner	Interaction type	MIscore	Records
TMEM190	physical association	0.720	6
NINJ2	physical association	0.600	4
ATP6V0C	physical association	0.560	3
BRICD5	physical association	0.560	3
CLDN1	physical association	0.560	3
EBP	physical association	0.560	3
MAL	physical association	0.560	3
PMP22	physical association	0.560	3
RPRM	physical association	0.560	3
SLC35B2	physical association	0.560	3
STRIT1	physical association	0.560	3
TSPO2	physical association	0.560	3
UPK1B	physical association	0.560	3
PALM3	association	0.530	2
S1PR1	physical association	0.520	2
DDAH1	physical association	0.400	1
SMARCB1	physical association	0.370	1

BioGRID (26 interactions; top human partners by supporting records): CADM4 (Affinity Capture-MS; 2 records), PALM3 (Affinity Capture-MS; 2 records), TMEM190 (Two-hybrid; 2 records), ATP6V0C (Two-hybrid), BRICD5 (Two-hybrid), CLDN1 (Two-hybrid), DDAH1 (Affinity Capture-MS), EBP (Two-hybrid), ERICH5 (Affinity Capture-MS), GNAO1 (Affinity Capture-MS), LOC100507537 (Two-hybrid), MAL (Two-hybrid), NCS1 (Affinity Capture-MS), NINJ2 (Two-hybrid), PMP22 (Two-hybrid)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
STAG2	up-regulates	CD69

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ CD69-GNAI1-GNB1-GNG2-S1PR1 complex	5	GNG2, S1PR1, CD69, GNAI1, GNB1

Disease & clinical

Genetic variants

Variant evidence for CD69: 21 ClinVar records (0 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 16 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	3
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 213):

Position(s)	Effect	Δscore	Sites
12:9755262–9755263	acceptor_loss	1.0000	6
12:9756420–9756421	acceptor_loss	1.0000	6
12:9753590–9753591	acceptor_loss	0.9900	6
12:9754692	acceptor_gain	0.9900
12:9755060–9755061	donor_loss	0.9900	6
12:9756295–9756296	donor_loss	0.9900	5
12:9760756	donor_loss	0.9900
12:9760759	donor_gain	0.9900
12:9760755–9760756	donor_loss	0.9800	2
12:9760756	donor_loss	0.9700

AlphaMissense

212 missense substitutions predicted likely pathogenic (of 1,325 scored), across 66 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
C113	7	0.972	0.985
C194	7	0.967	0.985
W142	7	0.934	0.991
W106	7	0.917	0.988
C173	7	0.912	0.964
F131	7	0.901	0.972
W155	7	0.898	0.987
C96	7	0.889	0.949
C186	7	0.874	0.924
C85	7	0.850	0.896
W89	7	0.846	0.979
Y97	5	0.891	0.969
F165	5	0.875	0.900
F161	5	0.853	0.891
W192	5	0.853	0.920
G144	5	0.851	0.939
W153	5	0.841	0.940
D128	5	0.726	0.799
A109	4	0.879	0.969
L120	4	0.863	0.954

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Rectum Adenocarcinoma (validation)	favorable	0.00019
Breast Invasive Carcinoma (TCGA)	favorable	0.000345

Disease associations

OMIM: gene MIM:107273 | disease phenotypes:

GWAS associations

16 associations:

Study	Trait	p-value
GCST90002388_321	Lymphocyte count	1e-82
GCST004627_71	Lymphocyte count	2e-75
GCST90002388_319	Lymphocyte count	1e-55
GCST004632_53	Lymphocyte percentage of white cells	9e-50
GCST004632_52	Lymphocyte percentage of white cells	3e-42
GCST90002389_456	Lymphocyte percentage of white cells	4e-30
GCST007932_9	Medication use (thyroid preparations)	1e-27
GCST004633_22	Neutrophil percentage of white cells	5e-27
GCST90002399_428	Neutrophil percentage of white cells	3e-23
GCST90002407_419	White blood cell count	4e-19
GCST90002388_320	Lymphocyte count	8e-17
GCST90002389_457	Lymphocyte percentage of white cells	3e-13
GCST005531_56	Multiple sclerosis	6e-13
GCST000392_11	Type 1 diabetes	2e-11
GCST005997_1	Lymphocyte count	6e-11
GCST005536_51	Type 1 diabetes	2e-7

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0009933	Thyroid preparation use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3308911 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 6,065 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

7 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL4072833	EVOBRUTINIB	3	1,013
CHEMBL4650323	TOLEBRUTINIB	3	390
CHEMBL5083772	BIIB-091	2	92
CHEMBL3900554	BMS-986142	2	71
CHEMBL4163691	POSELTINIB	2	1,407
CHEMBL4209441	SOFNOBRUTINIB	2	17
CHEMBL3301625	SPEBRUTINIB	2	3,075

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs11052877	Efficacy	3	tocilizumab	Rheumatoid arthritis

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11052877	CD69	3	2.75	1	tocilizumab

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs11052877	tocilizumab	Efficacy	Allele A is associated with increased response to tocilizumab in people with Arthritis, Rheumatoid as compared to allele G.	PMID:27339827

Binding affinities (BindingDB)

29 measured of 35 human assays (36 total across all organisms); most potent 29 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-(tert-butyl)-N- (2-(2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-5- yl)-1H-1,2,3-triazole-4- carboxamide	IC50	5.5 nM	US-10189829: Inhibiting agents for Bruton’s tyrosine kinase
CHEMBL5088454	IC50	40 nM
CHEMBL5206309	IC50	90 nM
(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide	IC50	100 nM
CHEMBL4066176	KD	120 nM
Tolebrutinib	IC50	200 nM
CHEMBL5094998	IC50	200 nM
CHEMBL5090290	IC50	400 nM
CHEMBL5076817	IC50	400 nM
CHEMBL5081318	IC50	400 nM
CHEMBL4744041	KD	430 nM
(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide	KD	660 nM
CHEMBL5073995	IC50	700 nM
(R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide	IC50	800 nM
HM71224	IC50	980 nM
CHEMBL4209441	IC50	1200 nM
CHEMBL5069979	IC50	1200 nM
(3R)-3-(3-chloro-5-fluoroanilino)-1-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]piperidin-2-one	IC50	1300 nM	US-9790229: Bruton’s tyrosine kinase inhibitors
CHEMBL5075191	IC50	1600 nM
CHEMBL5085931	IC50	2000 nM
CHEMBL5080861	IC50	2500 nM
AVL-292	IC50	2660 nM
(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide	IC50	4000 nM
CHEMBL5207862	KD	7200 nM
CHEMBL1210904	IC50	31600 nM
CHEBI:28009	IC50	316000 nM
CHEMBL1210903	IC50	501000 nM
CHEMBL1210905	IC50	1e+09 nM
CHEBI:41112	IC50	1e+09 nM

ChEMBL bioactivities

52 potent at pChembl≥5 of 55 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.49	Kd	0.32	nM	CHEMBL591694
9.30	IC50	0.5012	nM	CHEMBL601098
9.19	IC50	0.65	nM	CHEMBL591694
9.15	IC50	0.71	nM	CHEMBL591694
8.95	Kd	1.12	nM	CHEMBL1222111
8.52	Kd	3	nM	CHEMBL601099
8.49	Kd	3.2	nM	CHEMBL1222111
8.47	Kd	3.4	nM	CHEMBL1222111
8.43	IC50	3.7	nM	CHEMBL601099
8.37	IC50	4.3	nM	CHEMBL601099
8.00	IC50	10	nM	CHEMBL5080861
7.90	IC50	12.59	nM	CHEMBL591694
7.85	IC50	14	nM	CHEMBL601100
7.82	IC50	15	nM	CHEMBL591694
7.68	IC50	21	nM	CHEMBL601100
7.60	IC50	25.12	nM	CHEMBL601099
7.41	Kd	39	nM	CHEMBL601100
7.40	IC50	40	nM	CHEMBL4066176
7.40	IC50	40	nM	CHEMBL5088454
7.30	IC50	50.12	nM	CHEMBL601100
7.23	IC50	59	nM	CHEMBL5076817
7.20	IC50	63.1	nM	CHEMBL591636
7.16	IC50	70	nM	BIIB-091
7.15	IC50	71	nM	BIIB-091
7.10	IC50	79.43	nM	CHEMBL596977
7.05	IC50	90	nM	CHEMBL5206309
7.00	IC50	100	nM	CHEMBL5085192
6.98	IC50	104	nM	CHEMBL5085931
6.89	IC50	130	nM	CHEMBL5083323
6.82	IC50	150	nM	CHEMBL601099
6.70	IC50	200	nM	TOLEBRUTINIB
6.70	IC50	200	nM	CHEMBL5094998
6.66	IC50	220	nM	CHEMBL5084997
6.48	IC50	330	nM	CHEMBL5089327
6.41	IC50	390	nM	CHEMBL5090589
6.40	IC50	400	nM	CHEMBL5090290
6.40	IC50	400	nM	CHEMBL5081318
6.20	IC50	630	nM	CHEMBL5169765
6.16	IC50	700	nM	CHEMBL5073995
6.10	IC50	800	nM	CHEMBL5093189
6.07	IC50	860	nM	CHEMBL5087011
6.01	IC50	980	nM	POSELTINIB
5.96	IC50	1100	nM	EVOBRUTINIB
5.92	IC50	1200	nM	CHEMBL5069979
5.92	IC50	1200	nM	SOFNOBRUTINIB
5.92	IC50	1200	nM	CHEMBL5207862
5.89	IC50	1300	nM	BMS-986142
5.89	IC50	1300	nM	CHEMBL601100
5.80	IC50	1600	nM	CHEMBL5075191
5.52	IC50	3000	nM	CHEMBL4744041

PubChem BioAssay actives

52 with measured affinity, of 107 total; 37 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[26,27,28-tris(carboxymethoxy)-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3(28),4,6,9(27),10,12,15,17,19(26),21,23-dodecaen-25-yl]oxy]acetic acid	459222: Inhibition of human recombinant soluble CD69 receptor by direct binding assay	kd	0.0003	uM
N-[(2R,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-[[11,17,23-tris[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]carbamothioylamino]-25,26,27,28-tetrapropoxy-5-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]carbamothioylamino]oxan-3-yl]acetamide	459221: Inhibition of human rhodamine-labelled soluble CD69 by standard plate inhibition assay	ic50	0.0005	uM
N-[(2R,3R,4R,5S,6R)-2-[[(2R,3S,4R,5R,6R)-5-acetamido-3,4-bis[[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]-6-hydroxyoxan-2-yl]methoxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide	501258: Binding affinity to human monomeric CD69 receptor expressed in Escherichia coli by equilibrium dialysis	kd	0.0011	uM
2-[[5,11,17,23-tetratert-butyl-26,27,28-tris(carboxymethoxy)-25-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]oxy]acetic acid	459222: Inhibition of human recombinant soluble CD69 receptor by direct binding assay	kd	0.0030	uM
5-tert-butyl-N-[(5R)-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-3-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.0100	uM
2-[[17,25,27-tris(carboxymethoxy)-5-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3(28),4,6,9(27),10,12,15,17,19(26),21,23-dodecaenyl]oxy]acetic acid	459224: Inhibition of SiaTnTRI2-induced activation of CD69 high in human lymphocytes assessed as InsP2 production	ic50	0.0140	uM
(3S)-3-tert-butyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]pyrrolidine-1-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.0400	uM
10-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]-2-pyridinyl]amino]-6-oxo-3-pyridinyl]-2-pyridinyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.0400	uM
3-tert-butyl-N-[(5R)-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.0590	uM
4-[[11,17,23-tris[(4-carboxyphenyl)diazenyl]-25,26,27,28-tetrahydroxy-5-pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(24),3,5,7(28),9,11,13(27),15(26),16,18,21(25),22-dodecaenyl]diazenyl]benzoic acid	459221: Inhibition of human rhodamine-labelled soluble CD69 by standard plate inhibition assay	ic50	0.0631	uM
1-tert-butyl-N-[(5R)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(oxetan-3-yl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.0700	uM
2-[[27-(carboxymethoxy)-26,28-dihydroxy-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3(28),4,6,9(27),10,12,15,17,19(26),21,23-dodecaen-25-yl]oxy]acetic acid	459221: Inhibition of human rhodamine-labelled soluble CD69 by standard plate inhibition assay	ic50	0.0794	uM
(3R)-3-(3-chloro-5-fluoroanilino)-1-[(3R)-1-(1H-pyrazolo[5,4-d]pyrimidin-4-yl)piperidin-3-yl]piperidin-2-one	1847391: Inhibition of CD69 (unknown origin) in PBMC preincubated for 30 mins followed by IL-4 stimulation for 3 days by cell titer glo assay	ic50	0.0900	uM
1-tert-butyl-N-[(5R)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.1000	uM
1-tert-butyl-N-[(5R)-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.1040	uM
5-tert-butyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-3-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.1300	uM
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.2000	uM
1-tert-butyl-N-[(5R)-2-methyl-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.2000	uM
3-tert-butyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,2,4-oxadiazole-5-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.2200	uM
5-tert-butyl-N-[(5R)-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.3300	uM
5-tert-butyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-1,3,4-oxadiazole-2-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.3900	uM
N-[(5R)-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]-3-propan-2-yloxyazetidine-1-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.4000	uM
1-tert-butyl-N-[(5S)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.4000	uM
(3R)-3-(3-chloro-5-fluoroanilino)-1-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]piperidin-2-one	1847391: Inhibition of CD69 (unknown origin) in PBMC preincubated for 30 mins followed by IL-4 stimulation for 3 days by cell titer glo assay	ic50	0.6300	uM
1-tert-butyl-N-[(5S)-3-methyl-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1,2,4,5-tetrahydro-3-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.7000	uM
1-tert-butyl-N-[(5R)-2-(2-methoxyethyl)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.8000	uM
1-tert-butyl-N-[2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.8600	uM
N-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]furo[3,2-d]pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	0.9800	uM
1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]piperidin-1-yl]prop-2-en-1-one	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	1.1000	uM
N-[3-[6-[4-(1,4-dimethyl-6-oxopiperazin-2-yl)anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	1.2000	uM
(2R)-2-cyclopropyl-2-(3,5-dichloroanilino)-N-[(3R)-1-(1H-pyrazolo[5,4-d]pyrimidin-4-yl)piperidin-3-yl]acetamide	1847391: Inhibition of CD69 (unknown origin) in PBMC preincubated for 30 mins followed by IL-4 stimulation for 3 days by cell titer glo assay	ic50	1.2000	uM
2-[3-[4-amino-6-[(1-methylpyrazol-4-yl)amino]-1,3,5-triazin-2-yl]-2-(hydroxymethyl)phenyl]-6-cyclopropyl-8-fluoroisoquinolin-1-one	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	1.2000	uM
(7S)-3-fluoro-4-[3-(8-fluoro-1-methyl-2,4-dioxoquinazolin-3-yl)-2-methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-carbazole-1-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	1.3000	uM
1-tert-butyl-N-[(5R)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]triazole-4-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	1.6000	uM
N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]-3-propan-2-yloxyazetidine-1-carboxamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	3.0000	uM
N-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide	1820502: Inhibition of CD69 in human whole blood preincubated for 30 mins followed by anti-human IgD stimulation and measured after 18 to 22 hrs by flow cytometry	ic50	3.1000	uM
[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-(triazol-1-yl)oxan-3-yl] acetate	489739: Binding affinity to rhodamine-labeled human CD69 receptor after 2 hrs by fluorescence assay	ic50	3.9811	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases expression	6
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, increases expression, increases reaction	3
Ionomycin	increases expression, affects cotreatment	3
bis(tri-n-butyltin)oxide	increases expression	2
deoxynivalenol	increases expression	2
Calcimycin	increases expression, affects cotreatment, decreases reaction	2
Arsenic	affects expression, decreases expression	2
Benzene	decreases expression, increases expression	2
Dacarbazine	affects reaction, increases expression, affects cotreatment	2
Nickel	increases expression	2
Silicon Dioxide	decreases reaction, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
OTX015	decreases reaction, increases expression	1
fenebrutinib	decreases expression	1
evobrutinib	decreases expression	1
remibrutinib	decreases expression	1
orelabrutinib	decreases expression	1
rilzabrutinib	decreases expression	1
titanium dioxide	increases expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	decreases expression	1
zomepirac glucuronide	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, decreases expression, affects response to substance	1
tolmetin glucuronide	increases expression	1

ChEMBL screening assays

22 unique, capped per target: 22 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1068004	Binding	Inhibition of human rhodamine-labelled soluble CD69 by standard plate inhibition assay	Carboxylated calixarenes bind strongly to CD69 and protect CD69(+) killer cells from suicidal cell death induced by tumor cell surface ligands. — *Bioorg Med Chem*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8D5	Abcam HCT 116 CD69 KO	Cancer cell line	Male
CVCL_B9FC	Abcam A-549 CD69 KO	Cancer cell line	Male
CVCL_D2EA	Abcam MCF-7 CD69 KO	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CD69 across ~30M SureChEMBL compounds — explore on Sugi Predict.