CASP8AP2

Summary

CASP8AP2 (caspase 8 associated protein 2, HGNC:1510) is a protein-coding gene on chromosome 6q15, encoding CASP8-associated protein 2 (Q9UKL3). Participates in TNF-induced blockade of glucocorticoid receptor (GR) transactivation at the nuclear receptor coactivator level, upstream and independently of NF-kappa-B.

This protein is highly similar to FLASH, a mouse apoptotic protein identified by its interaction with the death-effector domain (DED) of caspase 8. Studies of FLASH protein suggested that this protein may be a component of the death-inducing signaling complex that includes Fas receptor, Fas-binding adapter FADD, and caspase 8, and plays a regulatory role in Fas-mediated apoptosis. Alternative splicing results in multiple transcript variants encoding the same protein.

Source: NCBI Gene 9994 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 272 total
• GTEx eGene: eQTL in 21 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.21 (highly constrained)
• MANE Select transcript: NM_001137667
• Notable: 272 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1510
Approved symbol	CASP8AP2
Name	caspase 8 associated protein 2
Location	6q15
Locus type	gene with protein product
Status	Approved
Aliases	FLASH, CED-4, RIP25, FLJ11208, KIAA1315
Ensembl gene	ENSG00000118412
Ensembl biotype	protein_coding
OMIM	606880
Entrez	9994

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 5: 3

ENST00000237177, ENST00000419040, ENST00000547893, ENST00000548224, ENST00000551025, ENST00000552401

RefSeq mRNA: 3 — MANE Select: NM_001137667 NM_001137667, NM_001137668, NM_012115

Canonical transcript exons

ENST00000551025 — 9 exons

Exon	Start	End
ENSE00001549290	89829939	89830106
ENSE00002429684	89871289	89871388
ENSE00003525343	89846562	89846644
ENSE00003577625	89854817	89854917
ENSE00003584787	89857084	89857199
ENSE00003591009	89855470	89855544
ENSE00003617458	89853166	89853234
ENSE00003627505	89865953	89869082
ENSE00003630495	89862126	89864371

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 92.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.1041 / max 172.2434, expressed in 1693 samples.

Highest expression (Bgee): calcaneal tendon, corpus callosum, colonic epithelium, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CASP8AP2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 21 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 21 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Pituitary	eqtl	7.4e-11	-0.29	6:89837939:G:A
Nerve Tibial	eqtl	2.8e-07	+0.18	6:89805569:G:A
Thyroid	eqtl	9.3e-06	-0.15	6:89804803:A:G
Skin Sun Exposed Lower leg	eqtl	4.8e-04	+0.10	6:89797109:C:T
Testis	eqtl	5.5e-04	-0.14	6:89815230:A:G
Adipose Visceral Omentum	eqtl	9.6e-04	-0.11	6:89829363:G:C
Esophagus Muscularis	eqtl	4.5e-03	+0.10	6:89627914:C:T
Artery Aorta	eqtl	1.4e-02	+0.12	6:89917834:A:G
Brain Spinal cord cervical c-1	eqtl	1.9e-02	-0.66	6:88867264:C:T
Brain Cerebellum	eqtl	2.0e-02	+0.19	6:89837475:G:A
Muscle Skeletal	eqtl	2.1e-02	-0.22	6:90299096:G:A
Lung	eqtl	2.1e-02	-0.08	6:89859353:A:G
Artery Tibial	eqtl	2.5e-02	+0.35	6:89359482:A:G
Heart Atrial Appendage	eqtl	2.5e-02	-0.14	6:89629144:C:T
Brain Cortex	eqtl	2.6e-02	-0.20	6:89825748:A:G
Brain Frontal Cortex BA9	eqtl	2.6e-02	-0.21	6:89815888:T:C
Brain Nucleus accumbens basal ganglia	eqtl	2.8e-02	-0.20	6:89825748:A:G
Stomach	eqtl	3.2e-02	+0.17	6:89899614:G:A
Vagina	eqtl	3.2e-02	+0.27	6:89917834:A:G
Adipose Subcutaneous	eqtl	4.9e-02	+0.07	6:89765286:A:C

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
68889	8.4265	1670
68890	0.6776	380

Top tissues by expression

showing 100 of 139 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	92.18	gold quality
corpus callosum	UBERON:0002336	92.09	gold quality
colonic epithelium	UBERON:0000397	90.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.11	gold quality
ventricular zone	UBERON:0003053	86.88	gold quality
ganglionic eminence	UBERON:0004023	85.23	gold quality
tonsil	UBERON:0002372	83.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.67	gold quality
cortical plate	UBERON:0005343	83.42	gold quality
endometrium	UBERON:0001295	83.28	gold quality
lymph node	UBERON:0000029	82.33	gold quality
bone marrow cell	CL:0002092	81.71	gold quality
adrenal tissue	UBERON:0018303	80.83	gold quality
smooth muscle tissue	UBERON:0001135	80.16	gold quality
leukocyte	CL:0000738	80.08	gold quality
monocyte	CL:0000576	80.03	gold quality
skeletal muscle tissue	UBERON:0001134	79.92	gold quality
urinary bladder	UBERON:0001255	79.81	gold quality
bone marrow	UBERON:0002371	79.63	gold quality
vermiform appendix	UBERON:0001154	79.26	gold quality
gastrocnemius	UBERON:0001388	79.00	gold quality
rectum	UBERON:0001052	78.94	gold quality
muscle tissue	UBERON:0002385	78.79	gold quality
skeletal muscle organ	UBERON:0014892	78.77	gold quality
muscle of leg	UBERON:0001383	78.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	78.64	gold quality
placenta	UBERON:0001987	78.59	gold quality
popliteal artery	UBERON:0002250	78.55	gold quality
tibial artery	UBERON:0007610	78.53	gold quality
cerebellar hemisphere	UBERON:0002245	78.22	gold quality
cerebellar cortex	UBERON:0002129	78.19	gold quality
islet of Langerhans	UBERON:0000006	78.16	gold quality
granulocyte	CL:0000094	78.13	gold quality
cerebellum	UBERON:0002037	78.04	gold quality
mucosa of transverse colon	UBERON:0004991	78.01	gold quality
stromal cell of endometrium	CL:0002255	77.97	gold quality
lower esophagus	UBERON:0013473	77.89	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.89	gold quality
aorta	UBERON:0000947	77.71	gold quality
sural nerve	UBERON:0015488	77.67	gold quality
descending thoracic aorta	UBERON:0002345	77.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	77.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.28	gold quality
tibial nerve	UBERON:0001323	77.21	gold quality
colon	UBERON:0001155	77.06	gold quality
myometrium	UBERON:0001296	77.04	gold quality
intestine	UBERON:0000160	76.80	gold quality
left coronary artery	UBERON:0001626	76.79	gold quality
body of uterus	UBERON:0009853	76.78	gold quality
uterine cervix	UBERON:0000002	76.75	gold quality
thoracic aorta	UBERON:0001515	76.60	gold quality
thoracic mammary gland	UBERON:0005200	76.56	gold quality
right coronary artery	UBERON:0001625	76.55	gold quality
esophagus	UBERON:0001043	76.53	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.48	gold quality
ascending aorta	UBERON:0001496	76.46	gold quality
spleen	UBERON:0002106	76.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	76.39	gold quality
lung	UBERON:0002048	76.33	gold quality
spinal cord	UBERON:0002240	76.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.27	gold quality
pancreas	UBERON:0001264	76.22	gold quality
heart	UBERON:0000948	76.15	gold quality
adipose tissue	UBERON:0001013	75.99	gold quality
ectocervix	UBERON:0012249	75.95	gold quality
lower esophagus mucosa	UBERON:0035834	75.95	gold quality
ovary	UBERON:0000992	75.85	gold quality
heart left ventricle	UBERON:0002084	75.85	gold quality
right lung	UBERON:0002167	75.60	gold quality
gall bladder	UBERON:0002110	75.58	gold quality
material anatomical entity	UBERON:0000465	75.57	gold quality
multicellular organism	UBERON:0000468	75.57	gold quality
anatomical system	UBERON:0000467	75.56	gold quality
right ovary	UBERON:0002118	75.48	gold quality
small intestine	UBERON:0002108	75.34	gold quality
duodenum	UBERON:0002114	75.30	gold quality
omental fat pad	UBERON:0010414	75.30	gold quality
vagina	UBERON:0000996	75.20	gold quality
Ammon’s horn	UBERON:0001954	75.19	gold quality
right lobe of liver	UBERON:0001114	75.16	gold quality
substantia nigra	UBERON:0002038	75.16	gold quality
adrenal gland	UBERON:0002369	75.15	gold quality
left ovary	UBERON:0002119	74.94	gold quality
brain	UBERON:0000955	74.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.91	gold quality
primary visual cortex	UBERON:0002436	74.90	gold quality
esophagus mucosa	UBERON:0002469	74.89	gold quality
stomach	UBERON:0000945	74.82	gold quality
body of pancreas	UBERON:0001150	74.82	gold quality
right atrium auricular region	UBERON:0006631	74.82	gold quality
prostate gland	UBERON:0002367	74.81	gold quality
liver	UBERON:0002107	74.71	gold quality
endocervix	UBERON:0000458	74.66	gold quality
amygdala	UBERON:0001876	74.65	gold quality
small intestine Peyer’s patch	UBERON:0003454	74.65	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.65	gold quality
fundus of stomach	UBERON:0001160	74.62	gold quality
transverse colon	UBERON:0001157	74.61	gold quality
right adrenal gland cortex	UBERON:0035827	74.54	gold quality
hypothalamus	UBERON:0001898	74.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.67

HPA expression

RNA tissue specificity: Not detected

showing 60 of 66 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Corpus callosum	tissue	10.8
Cerebellum	tissue	10.4
Olfactory bulb	tissue	9.7
Midbrain	tissue	9.2
Putamen	tissue	8.9
Thalamus	tissue	8.9
Pons	tissue	8.8
Hippocampal formation	tissue	8.8
Amygdala	tissue	8.6
Ventral forebrain	tissue	8.6
Spinal cord	tissue	8.5
Septum	tissue	8.5
Superior colliculi	tissue	8.4
Medulla oblongata	tissue	8.3
Substantia nigra	tissue	8.2
Basal ganglia	tissue	8.1
Cerebral cortex	tissue	8.0
Entorhinal cortex	tissue	8.0
Somatosensory cortex	tissue	8.0
Occipital cortex	tissue	8.0
Periaqueductal gray	tissue	7.9
Hypothalamus	tissue	7.8
Retrosplenial and cingulate cortex	tissue	7.8
Motor cortex	tissue	7.7
Retrosplenial cortex	tissue	7.5
Temporal cortex	tissue	7.5
Prefrontal cortex	tissue	7.4
Insular cortex	tissue	7.2
Caudate putamen	tissue	4.4
Frontal cortex	tissue	3.7
Postcentral gyrus	tissue	2.9
Hippocampus	tissue	1.8
Choroid plexus	tissue	1.6
Locus coeruleus	tissue	1.3
Nucleus accumbens	tissue	1.2
Tongue	tissue	0.6
Pancreas	tissue	0.5
Thymus	tissue	0.5
Lymph node	tissue	0.3
Urinary bladder	tissue	0.3
Appendix	tissue	0.3
Stomach 1	tissue	0.2
Ovary	tissue	0.2
Adipose tissue	tissue	0.2
Esophagus	tissue	0.2
Smooth muscle	tissue	0.2
Endometrium 1	tissue	0.2
Thyroid gland	tissue	0.2
Tonsil	tissue	0.2
Cervix	tissue	0.1
Breast	tissue	0.1
Testis	tissue	0.1
Heart muscle	tissue	0.1
Rectum	tissue	0.1
Parathyroid gland	tissue	0.1
Colon	tissue	0.1
Placenta	tissue	0.1
Lung	tissue	0.1
Liver	tissue	0.1
Small intestine	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — White matter (10.8), Dorsal hippocampus (8.8), Subiculum (8.7), Dorsal spinal cord (8.5), Ventral spinal cord (8.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, HOXB4, HOXD13, MYB, MYC, NCOA2, NFAT5, TP73

miRNA regulators (miRDB)

Targeting CASP8AP2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 52 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-548O-3P	99.74	69.30	2228

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.209, missense Z 3.33 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000551025 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
6:89,846,590–89,869,022	1778 / 2336.0	0.76	no
6:89,869,023–89,871,388	26 / 64.6	0.40	no

Literature-anchored findings (GeneRIF, showing 39)

• endogenous caspase-8 mediates tumor necrosis factor-alpha-induced activation of NF-kappaB via FLASH (PMID:15592525)
• FLASH differentially suppresses steroid hormone receptor-induced transcriptional activity by interfering with their association with steroid hormone receptor coactivator 2 (SRC2)/N-CoA2 and SRC3/N-CoA3 (PMID:15698540)
• High levels of CASP8AP2 expression were associated with a greater propensity of leukemic lymphoblasts to undergo apoptosis (PMID:16627760)
• These results identify FLASH as an important component of the machinery required for histone precursor mRNA expression and cell-cycle progression. (PMID:17003125)
• FLICE-associated huge protein (FLASH), originally described as a component of the apoptosis signaling pathway, is mainly localized in Cajal bodies and is essential for their structure. (PMID:17003126)
• CD95 signals are mediated by nucleo-cytoplasmic translocation of FLASH. (PMID:17245429)
• increased expression of FLASH in malignant gastric epithelial cells compared to the normal cells suggests that FLASH expression may play a role in gastric tumorigenesis; data suggest that somatic mutation of FLASH is a rare event in gastric carcinomas (PMID:17696945)
• Frameshift mutation in the polyadenine tracts in both FLASH and PTPN13 genes is rare in colorectal carcinomas. Both FLASH and PTPN13 mutations in the polyadenine tracts may not have a crucial role in the pathogenesis of colorectal carcinomas. (PMID:18038312)
• c-Myb cooperates with FLASH in foci associated with active RNA polymerase II, leading to enhancement of Myb-dependent gene activation. (PMID:18408764)
• Only the number of FLASH/NPAT histone gene locus bodies correlates with ploidy and only these organelles appear to be regulated during the cell cycle. (PMID:18677100)
• a deletion at 6q15-16.1 in 9 of 73 (12%) of the childhood T-ALL patients predicts poor early treatment response. This deletion includes the CASP8AP2 gene, whose expression is shown to be down-regulated. (PMID:19406988)
• Results suggest that FLASH functions in S phase progression through interaction with ARS2. (PMID:19546234)
• these results point to a complex involvement of sumoylation in modulating the function of FLASH. (PMID:19615980)
• Human FLASH interacts with Lsm11 in vitro and stimulates 3’ end processing of histone pre-mRNA in mammalian nuclear extracts. (PMID:19854135)
• investigated the expression of three apoptosis related genes, BCL2L13, CASP8AP2, and Livin, as well as their prognostic significance, in a retrospective study of 90 pediatric ALL patients diagnosed between 1996 and 2007 in Taiwan (PMID:20109966)
• Critical residues in human FLASH and Lsm11 that are involved in the interaction between these two proteins, are identified. (PMID:21245389)
• PIAS1 is a common partner for two cancer-related nuclear factors, c-Myb and FLASH. (PMID:21338522)
• CASP8AP2 is a promising prognostic indicator in pediatric acute lymphoblastic leukemia. (PMID:21696825)
• Data show that show that the transcription factor p73 binds to Flice-Associated Huge Protein (FLASH) and is part of the complex that regulates histone gene transcription. (PMID:21725362)
• This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells (PMID:22216762)
• FLASH knockdown in HT1080 mutant cells defective in p53 did not significantly accelerate Fas mediated apoptosis indicating that the effect was dependent on functional p53. (PMID:22427918)
• These data demonstrate that methylation within the Casp8AP2 promoter correlates with the development of drug resistance and might serve as a biomarker and treatment target for drug resistance in cancer cells. (PMID:22595458)
• FLASH/Lsm11 complex bind a unique combination of polyadenylation factors (PMID:23071092)
• Data suggest that SUMO targets FLASH for proteasome-dependent degradation, which is associated with recruitment of FLASH to PML bodies. (PMID:23673342)
• Hypermethylation of two CpG sites upstream of CASP8AP2 promoter influences gene expression and treatment outcome in childhood acute lymphoblastic leukemia. (PMID:23953914)
• the predictive values regarding low expressions of H2AFZ and CASP8AP2 and high white blood cell count suggest that these features could help to identify more accurately patients at greater risk of relapse. (PMID:24397596)
• High-quality solution NMR structures of three homeodomains from human proteins ALX4, ZHX1 and CASP8AP2 were solved. (PMID:24941917)
• FLASH is required for embryogenesis, but not for cell proliferation or differentiation in embryonic stem cells. (PMID:25238250)
• The conserved C-terminal domain shared by FLASH, YARP, and Mute recognizes the C-terminal sequence of NPAT orthologues, thus acting as a signal targeting proteins to histone locus bodies. (PMID:25339177)
• ARS2 and CASP8AP2 expressions can precisely predict high-risk of relapse and ALL prognosis. (PMID:25530566)
• Our results indicate that the APAF1, BAX, and FLASH genes not only harbor frameshift mutations but also demonstrate mutational ITH, which together might play a role in the tumorigenesis of CRC with MSI-H by affecting the apoptosis of cancer cells. (PMID:25599959)
• FLASH plays two roles in 3’ end processing of histone pre-mRNAs: It interacts with Lsm11 to form a docking platform for the polyadenylation factors, and it cooperates with SLBP to recruit U7 snRNP to histone pre-mRNA. (PMID:28289156)
• Here, we assembled core U7 snRNP bound to FLASH from recombinant components and analyzed its appearance by electron microscopy and ability to support histone pre-mRNA processing in the presence of polyadenylation factors from nuclear extracts (PMID:31819999)
• Structural Analysis of the SANT/Myb Domain of FLASH and YARP Proteins and Their Complex with the C-Terminal Fragment of NPAT by NMR Spectroscopy and Computer Simulations. (PMID:32722282)
• Low expression of CTBP2 and CASP8AP2 predicts risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a retrospective cohort study. (PMID:32804017)
• Knockout of the caspase 8-associated protein 2 gene improves recombinant protein expression in HEK293 cells through up-regulation of the cyclin-dependent kinase inhibitor 2A gene. (PMID:32910455)
• Interaction between CASP8AP2 and ZEB2-CtBP2 Regulates the Expression of LEF1. (PMID:35139734)
• Interaction of E2F3a and CASP8AP2 Regulates Histone Expression and Chemosensitivity of Leukemic Cells. (PMID:36162009)
• CRISPRi screening identifies CASP8AP2 as an essential viability factor in lung cancer controlling tumor cell death via the AP-1 pathway. (PMID:36252816)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp8ap2	ENSDARG00000022718
mus_musculus	Casp8ap2	ENSMUSG00000028282
rattus_norvegicus	Casp8ap2	ENSRNOG00000006487
drosophila_melanogaster	FLASH	FBGN0033806

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1349399) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
embryonic lethality before implantation, complete penetrance	1

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
MDN1-AS1	ncRNA	101929057
MDN1	protein-coding	23195
LYRM2	protein-coding	57226
GJA10	protein-coding	84694
BACH2	protein-coding	60468
ANKRD6	protein-coding	22881

Protein

Protein identifiers

CASP8-associated protein 2 — Q9UKL3 (reviewed: Q9UKL3)

Alternative names: FLICE-associated huge protein

All UniProt accessions (2): A0A087WTW5, A0A096LP21

UniProt curated annotations — full annotation on UniProt →

Function. Participates in TNF-induced blockade of glucocorticoid receptor (GR) transactivation at the nuclear receptor coactivator level, upstream and independently of NF-kappa-B. Suppresses both NCOA2- and NCOA3-induced enhancement of GR transactivation. Involved in TNF-induced activation of NF-kappa-B via a TRAF2-dependent pathway. Acts as a downstream mediator for CASP8-induced activation of NF-kappa-B. Required for the activation of CASP8 in FAS-mediated apoptosis. Involved for histone gene transcription and progression through S phase: required for the generation of mature histone mRNAs following the 3’ end cleavage of histone pre-mRNAs.

Subunit / interactions. Self-associates. Component of the death-inducing signaling complex (DISC) with CASP8, FADD and FAS. Interacts with NCOA2 and NCOA3. Interacts with SRRT. Interacts with TRAF2. Interacts with NPAT. Interacts (via SIM domains) with SUMO1 and SUMO2. Interacts with SP100; may negatively regulate CASP8AP2 export from the nucleus to the cytoplasm. Interacts with CDK11 (CDK11A or CDK11B).

Subcellular location. Cytoplasm. Nucleus. PML body. Mitochondrion.

Induction. By TNF which induces strong nuclear localization.

RefSeq proteins (3): NP_001131139, NP_001131140, NP_036247 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR039674	FLASH	Family
IPR049257	Gon4l/CASP8AP2_myb-like	Domain

Pfam: PF21227

UniProt features (52 total): compositionally biased region 16, modified residue 10, sequence conflict 8, region of interest 7, helix 4, short sequence motif 3, initiator methionine 1, chain 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
6AOZ	Crystal structure of human FLASH N-terminal domain C54S/C83A (Crystal form 1)	X-RAY DIFFRACTION	2.1
6AP0	Crystal structure of human FLASH N-terminal domain C54S/C83A (Crystal form 2)	X-RAY DIFFRACTION	2.58
6ANO	Crystal structure of human FLASH N-terminal domain	X-RAY DIFFRACTION	2.61
2LR8	Solution NMR Structure of CASP8-associated protein 2 from Homo sapiens, Northeast …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKL3-F1	44.28	0.09

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at transcript level

Subcellular location (HPA, imaging): nuclear bodies; nucleoli

Antibody reliability (HPA): IF approved

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 (10)

Type	Positions
N-acetylalanine	2
Phosphoserine	20, 194, 567, 658, 815, 875, 940, 1161
N6-acetyllysine	1343

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 1; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

1 pathways:

ID	Pathway	Evidence
R-HSA-3899300	SUMOylation of transcription cofactors	curated

MSigDB gene sets: 169 (showing top): chr6q15, E2F_Q4, E2F_Q4_01, E2F4DP1_01, PAL_PRMT5_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, TTTGTAG_MIR520D, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, E2F1DP1_01, MODULE_205, ONKEN_UVEAL_MELANOMA_UP, E2F_Q3, E2F1DP2_01, GOBP_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (7): DNA-templated transcription (GO:0006351), signal transduction (GO:0007165), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), Fas signaling pathway (GO:0036337), cellular response to mechanical stimulus (GO:0071260), apoptotic signaling pathway (GO:0097190), apoptotic process (GO:0006915)

GO Molecular Function (7): transcription corepressor activity (GO:0003714), death receptor binding (GO:0005123), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), peptidase activator activity involved in apoptotic process (GO:0016505), SUMO polymer binding (GO:0032184), protease binding (GO:0002020), identical protein binding (GO:0042802)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), PML body (GO:0016605)

Reactome top-level categories

1 top-level categories:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

32 GO namespaces:

Category	Terms
apoptotic process	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
gene expression	1
RNA biosynthetic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
extrinsic apoptotic signaling pathway	1
cell surface receptor signaling pathway	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
signal transduction	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
tumor necrosis factor receptor superfamily binding	1
peptidase activator activity involved in apoptotic process	1
cysteine-type endopeptidase regulator activity involved in apoptotic process	1
peptidase activator activity	1
SUMO binding	1
enzyme binding	1
protein binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
Fas signaling pathway	BP	mutant phenotype
cellular response to mechanical stimulus	BP	expression pattern
extrinsic apoptotic signaling pathway via death domain receptors	BP	mutant phenotype
PML body	CC	direct assay
cytoplasm	CC	direct assay
mitochondrion	CC	direct assay
nucleus	CC	direct assay
SUMO polymer binding	MF	direct assay
transcription corepressor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 858 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP8AP2	LSM11	P83369	871
CASP8AP2	NPAT	Q14207	806
CASP8AP2	CPSF3	Q9UKF6	799
CASP8AP2	COIL	P38432	605
CASP8AP2	WDR76	Q9H967	551
CASP8AP2	GAS2L3	Q86XJ1	550
CASP8AP2	CASP8	Q14790	541
CASP8AP2	DSCC1	Q9BVC3	537
CASP8AP2	UBR7	Q8N806	534
CASP8AP2	G2E3	Q7L622	507
CASP8AP2	CHAF1B	Q13112	502
CASP8AP2	GINS2	Q9Y248	497
CASP8AP2	LSM2	Q9Y333	496
CASP8AP2	FADD	Q13158	482
CASP8AP2	NASP	P49321	479

IntAct

Human interaction partners of CASP8AP2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
CASP8	physical association	0.700	5
SP100	physical association	0.600	5
UBE2I	physical association	0.550	2
PIAS1	physical association	0.510	4
TP73	physical association	0.400	3
FADD	physical association	0.400	1
NPAT	physical association	0.400	1
CASP10	physical association	0.370	1
CFAP418	physical association	0.370	1
CREM	physical association	0.370	1
CTBP2	physical association	0.370	1
PML	physical association	0.370	1
GLUL	physical association	0.000	1
SREBF2	physical association	0.000	1

BioGRID (67 interactions; top human partners by supporting records): PIAS1 (Two-hybrid; 4 records), HDAC1 (Affinity Capture-MS; 3 records), RCOR1 (Affinity Capture-MS; 2 records), SCOC (Affinity Capture-MS; 2 records), SUMO2 (Reconstituted Complex; 2 records), TRAF2 (Reconstituted Complex; 2 records), UBE2I (Biochemical Activity; 2 records), ASF1A (Proximity Label-MS), BCL2L1 (Affinity Capture-Western), BRD4 (Affinity Capture-MS), C16orf72 (Affinity Capture-MS), CALM1 (Reconstituted Complex), CASP10 (Two-hybrid), CASP8 (Affinity Capture-Western), COIL (Proximity Label-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
CASP8	up-regulates	CASP8AP2	binding
CASP8AP2	up-regulates	NFKB1	binding
CASP8AP2	up-regulates	NfKb-p65/p50	binding

Protein complexes (CORUM) (2)

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

2 complexes by size:

Complex	Subunits	Members
★ CASP8AP2-NR3C1 complex	2	CASP8AP2, NR3C1
★ CASP8AP2-NR3C2 complex	2	CASP8AP2, NR3C2

Disease & clinical

Genetic variants

Variant evidence for CASP8AP2: 272 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	254
Likely benign	18
Benign	0

HPA cancer prognostics

RNA cancer specificity: Not detected

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (validation)	unfavorable	0.000714
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000921

Disease associations

OMIM: gene MIM:606880 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST009798_44	Asthma	5e-27
GCST012490_452	Femur bone mineral density x serum urate levels interaction	4e-8
GCST008745_48	Estimated glomerular filtration rate in non-diabetics	5e-8
GCST005231_3	Major depressive disorder	4e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
perfluorooctane sulfonic acid	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Genistein	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
daidzein	affects cotreatment, increases expression	1
apocarotenal	increases expression	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
daidzin	affects cotreatment, increases expression	1
zinc chromate	increases abundance, increases expression	1
coumarin	decreases phosphorylation	1
genistin	affects cotreatment, increases expression	1
usnic acid	increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
glycitein	affects cotreatment, increases expression	1
glycitin	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
jinfukang	decreases expression	1
5-OH-BDE-47	decreases expression	1
6-OH-BDE-47	affects expression	1
Resveratrol	increases expression, affects cotreatment	1
Arsenic Trioxide	increases degradation, increases localization, affects cotreatment	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benztropine	decreases expression, affects cotreatment	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9ZH	Ubigene HeLa CASP8AP2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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