ALYREF

Summary

ALYREF (Aly/REF export factor, HGNC:19071) is a protein-coding gene on chromosome 17q25.3, encoding THO complex subunit 4 (Q86V81). Functions as an mRNA export adapter; component of the transcription/export (TREX) complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. It is a common-essential gene (DepMap: required in 98.1% of cancer cell lines).

The protein encoded by this gene is a heat stable, nuclear protein and functions as a molecular chaperone. It is thought to regulate dimerization, DNA binding, and transcriptional activity of basic region-leucine zipper (bZIP) proteins.

Source: NCBI Gene 10189 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 15 total — 1 pathogenic
• GTEx eGene: eQTL in 9 tissues, sQTL in 3 (q < 0.05)
• Cancer dependency (DepMap): dependent in 98.1% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.23 (highly constrained)
• MANE Select transcript: NM_005782
• Interaction hub: 2,702 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19071
Approved symbol	ALYREF
Name	Aly/REF export factor
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	ALY, BEF, ALY/REF, REF
Ensembl gene	ENSG00000183684
Ensembl biotype	protein_coding
OMIM	604171
Entrez	10189

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000505490

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

ENST00000505490, ENST00000504015, ENST00000511412, ENST00000512673, ENST00000864755, ENST00001019936, ENST00001089160, ENST00001135084

RefSeq mRNA: 1 — MANE Select: NM_005782 NM_005782

CCDS: CCDS32768

Canonical transcript exons

ENST00000505490 — 6 exons

Exon	Start	End
ENSE00001294955	81888241	81888418
ENSE00001298141	81891323	81891586
ENSE00002022356	81887835	81888145
ENSE00003572266	81888520	81888583
ENSE00003601841	81889182	81889329
ENSE00003658206	81890689	81890820

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 97.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 157.8760 / max 838.8614, expressed in 1828 samples.

Highest expression (Bgee): ganglionic eminence, ventricular zone, stromal cell of endometrium, testis, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ALYREF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Anterior cingulate cortex BA24	sqtl	2.7e-04	-2.67	17:82586794:G:A
Esophagus Mucosa	eqtl	6.4e-03	+0.32	17:81007887:G:C
Artery Tibial	eqtl	7.4e-03	-0.38	17:82398936:G:A
Brain Cerebellum	eqtl	8.7e-03	+0.19	17:81053072:A:G
Stomach	eqtl	2.1e-02	-0.10	17:82234042:GTGTTAGCCAGGA:G
Cells Cultured fibroblasts	eqtl	2.7e-02	-0.04	17:81652378:A:G
Muscle Skeletal	eqtl	4.0e-02	+0.10	17:81979110:T:C
Muscle Skeletal	sqtl	4.0e-02	+0.24	17:82020805:AT:A
Testis	eqtl	4.3e-02	-0.12	17:81538742:A:G
Colon Transverse	sqtl	4.3e-02	+0.99	17:81861697:G:T
Nerve Tibial	eqtl	4.4e-02	+0.09	17:82126553:T:C
Breast Mammary Tissue	eqtl	4.5e-02	+0.31	17:81418945:C:T

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
168845	154.6004	1828
168846	2.9144	799
168847	0.3611	160

Top tissues by expression

showing 100 of 256 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.12	gold quality
ventricular zone	UBERON:0003053	96.87	gold quality
stromal cell of endometrium	CL:0002255	96.68	gold quality
left testis	UBERON:0004533	96.67	gold quality
mucosa of transverse colon	UBERON:0004991	96.64	gold quality
right testis	UBERON:0004534	96.55	gold quality
monocyte	CL:0000576	96.46	gold quality
leukocyte	CL:0000738	96.24	gold quality
granulocyte	CL:0000094	95.61	gold quality
vermiform appendix	UBERON:0001154	95.53	gold quality
skin of abdomen	UBERON:0001416	95.46	gold quality
bone marrow cell	CL:0002092	95.20	gold quality
tendon of biceps brachii	UBERON:0008188	95.15	gold quality
calcaneal tendon	UBERON:0003701	95.07	gold quality
skin of leg	UBERON:0001511	94.86	gold quality
esophagus mucosa	UBERON:0002469	94.84	gold quality
testis	UBERON:0000473	94.81	gold quality
left uterine tube	UBERON:0001303	94.71	gold quality
thymus	UBERON:0002370	94.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.06	gold quality
tendon	UBERON:0000043	93.97	gold quality
spleen	UBERON:0002106	93.88	gold quality
transverse colon	UBERON:0001157	93.65	gold quality
ectocervix	UBERON:0012249	93.60	gold quality
upper lobe of left lung	UBERON:0008952	93.53	gold quality
zone of skin	UBERON:0000014	93.52	gold quality
esophagus	UBERON:0001043	93.49	gold quality
omental fat pad	UBERON:0010414	93.35	gold quality
peritoneum	UBERON:0002358	93.32	gold quality
adenohypophysis	UBERON:0002196	93.26	gold quality
cortical plate	UBERON:0005343	93.25	gold quality
upper lobe of lung	UBERON:0008948	93.21	gold quality
right ovary	UBERON:0002118	93.19	gold quality
lymph node	UBERON:0000029	93.12	gold quality
left ovary	UBERON:0002119	93.01	gold quality
left lobe of thyroid gland	UBERON:0001120	92.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.94	gold quality
lower esophagus mucosa	UBERON:0035834	92.93	gold quality
right lobe of thyroid gland	UBERON:0001119	92.91	gold quality
body of stomach	UBERON:0001161	92.89	gold quality
gastrocnemius	UBERON:0001388	92.82	gold quality
minor salivary gland	UBERON:0001830	92.78	gold quality
left coronary artery	UBERON:0001626	92.76	gold quality
tibial nerve	UBERON:0001323	92.75	gold quality
body of uterus	UBERON:0009853	92.61	gold quality
metanephros cortex	UBERON:0010533	92.60	gold quality
muscle of leg	UBERON:0001383	92.57	gold quality
colon	UBERON:0001155	92.56	gold quality
ascending aorta	UBERON:0001496	92.56	gold quality
thoracic aorta	UBERON:0001515	92.56	gold quality
right atrium auricular region	UBERON:0006631	92.49	gold quality
tibial artery	UBERON:0007610	92.47	gold quality
popliteal artery	UBERON:0002250	92.46	gold quality
aorta	UBERON:0000947	92.42	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.37	gold quality
small intestine	UBERON:0002108	92.28	gold quality
gall bladder	UBERON:0002110	92.26	gold quality
thyroid gland	UBERON:0002046	92.18	gold quality
apex of heart	UBERON:0002098	92.17	gold quality
mucosa of stomach	UBERON:0001199	92.13	gold quality
right coronary artery	UBERON:0001625	92.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.08	gold quality
lower esophagus	UBERON:0013473	92.07	gold quality
large intestine	UBERON:0000059	92.04	gold quality
pituitary gland	UBERON:0000007	92.01	gold quality
intestine	UBERON:0000160	91.99	gold quality
right lung	UBERON:0002167	91.99	gold quality
rectum	UBERON:0001052	91.98	gold quality
endocervix	UBERON:0000458	91.80	gold quality
coronary artery	UBERON:0001621	91.73	gold quality
mouth mucosa	UBERON:0003729	91.73	gold quality
left adrenal gland cortex	UBERON:0035825	91.69	gold quality
cardiac atrium	UBERON:0002081	91.66	gold quality
caecum	UBERON:0001153	91.65	gold quality
left adrenal gland	UBERON:0001234	91.64	gold quality
descending thoracic aorta	UBERON:0002345	91.55	gold quality
right adrenal gland	UBERON:0001233	91.54	gold quality
stomach	UBERON:0000945	91.51	gold quality
heart left ventricle	UBERON:0002084	91.46	gold quality
right lobe of liver	UBERON:0001114	91.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.38	gold quality
colonic epithelium	UBERON:0000397	91.35	gold quality
right uterine tube	UBERON:0001302	91.29	gold quality
cardiac ventricle	UBERON:0002082	91.13	gold quality
duodenum	UBERON:0002114	90.99	gold quality
body of pancreas	UBERON:0001150	90.98	gold quality
colonic mucosa	UBERON:0000317	90.97	gold quality
right adrenal gland cortex	UBERON:0035827	90.97	gold quality
heart	UBERON:0000948	90.93	gold quality
adrenal gland	UBERON:0002369	90.81	gold quality
islet of Langerhans	UBERON:0000006	90.80	gold quality
bone marrow	UBERON:0002371	90.60	gold quality
prefrontal cortex	UBERON:0000451	90.53	gold quality
pancreas	UBERON:0001264	90.49	gold quality
cartilage tissue	UBERON:0002418	90.48	gold quality
saliva-secreting gland	UBERON:0001044	90.38	gold quality
smooth muscle tissue	UBERON:0001135	90.33	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-79	yes	234.34
E-HCAD-13	yes	174.05
E-ANND-3	yes	6.09
E-MTAB-6379	no	35.78
E-GEOD-124858	no	23.79

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	140.5	high
Thymus	tissue	61.3
Lymph node	tissue	58.3	high
Skeletal muscle	tissue	57.6	high
Appendix	tissue	47.4	high
Testis	tissue	46.4	high
Tonsil	tissue	45.7	high
Vagina	tissue	34.2	high
Urinary bladder	tissue	33.3	high
Esophagus	tissue	32.4	high
Spleen	tissue	31.3	high
Duodenum	tissue	30.9	high
Colon	tissue	30.7	high
Small intestine	tissue	30.2	high
Placenta	tissue	30.1	high
Spinal cord	tissue	29.8
Pons	tissue	29.0
Medulla oblongata	tissue	28.6
Midbrain	tissue	28.5
Corpus callosum	tissue	28.0
Skin 1	tissue	27.9	high
Postcentral gyrus	tissue	27.5
Pituitary gland	tissue	27.3
Superior colliculi	tissue	27.0
Heart muscle	tissue	26.8	high
Thalamus	tissue	26.8
Hypothalamus	tissue	26.7
Stomach 1	tissue	25.9	high
Adipose tissue	tissue	25.9	high
Substantia nigra	tissue	25.3
Locus coeruleus	tissue	25.0
Hippocampus	tissue	25.0	high
Nucleus accumbens	tissue	24.9
Ovary	tissue	24.2	high
Hippocampal formation	tissue	23.7
Choroid plexus	tissue	23.5
Periaqueductal gray	tissue	23.2
Salivary gland	tissue	23.0	high
Putamen	tissue	23.0
Rectum	tissue	22.8	high
Septum	tissue	22.6
Cerebellum	tissue	22.5	high
Fallopian tube	tissue	22.5	high
Cerebral cortex	tissue	22.4	high
Somatosensory cortex	tissue	22.4
Thyroid gland	tissue	22.3	high
Lung	tissue	21.4	high
Pancreas	tissue	21.3	high
Ventral forebrain	tissue	21.3
Adrenal gland	tissue	20.5	high
Endometrium 1	tissue	20.3	high
Basal ganglia	tissue	20.3	high
Parathyroid gland	tissue	20.0	high
Tongue	tissue	19.8
Smooth muscle	tissue	19.7	high
Motor cortex	tissue	19.7
Prostate	tissue	19.6	high
Occipital cortex	tissue	19.4
Entorhinal cortex	tissue	19.1
Retrosplenial and cingulate cortex	tissue	18.6

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (35.2), Lateral funiculus (white matter) (32.9), Cervical spinal cord, ventral horn (30.8), Dorsal tegmental nucleus (30.7), Dorsal funiculus (white matter) (30.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

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

18 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-4733-5P	97.75	67.44	866

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.235, missense Z -0.175 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000505490 splits into 3 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
17:81,888,134–81,888,556	108 / 110.5	0.98	no
17:81,888,557–81,890,799	70 / 129.9	0.54	no
17:81,890,800–81,891,580	150 / 135.3	1.11	no
DepMap (CRISPR cell-line fitness): dependent in 98.1% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): HPAF-II (-2.22), SK-LMS-1 (-2.108), OCI-LY-19 (-1.931), LS1034 (-1.862), JVM-3 (-1.852), AsPC-1 (-1.771), SW 1990 (-1.712), MFE-280 (-1.664), OCUM-1 (-1.66), KE-37 (-1.633), RI-1 (-1.627), Calu-6 (-1.626), TF-1 (-1.624), CAL-62 (-1.623), PSN1 (-1.585).

Literature-anchored findings (GeneRIF, showing 33)

• recruitment of the human TREX complex to spliced mRNA is not directly coupled to transcription, but is instead coupled to transcription indirectly through splicing (PMID:15998806)
• suggest a central role for ALY in T-cell enhancer function and oncogene activation (PMID:17229714)
• Increased TAP binding correlates with increased SF2/ASF binding, but not increased REF/Aly or Y14 binding. (PMID:18243119)
• Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. (PMID:18562279)
• Adaptor Aly functions in the Tap-p15-mediated nuclear export of HSP70 mRNA. (PMID:19165146)
• The authors demonstrate that ORF57 recruits several members of hTREX, namely Aly, UAP56 and hTHO-complex proteins, onto the viral mRNAs to assemble an export-competent ribonucleoprotein particle. (PMID:19264631)
• TAP/NXF1, but not Aly/REF, is required for RNA export during HSV-1 infection. (PMID:19369354)
• These results indicate that ICP27 RGG box methylation regulates interaction ALY and SRPK1 proteins. (PMID:19553338)
• Results describe the subcellular localization of ICP27 and its colocalization with cellular RNA export factors Aly/REF and TAP/NXF1. (PMID:20015986)
• When the TREX components UAP56 or Aly are knocked down, spliced mRNA, as well as total polyA+ RNA, accumulates in nuclear speckle domains. (PMID:20981025)
• A differential connection between tumorogenesis and the expression levels of human THO and ALY. (PMID:21329510)
• REF/Aly-ORF57 interaction is not essential for KSHV lytic replication but may contribute to target RNA stability independent of effects on RNA export, suggesting a novel role for REF/Aly in viral RNA metabolism. (PMID:22761374)
• Authors propose that Aly, THO and UAP56 form a highly integrated unit to associate with the spliced mRNA and function in mRNA export. (PMID:23222130)
• High ALY expression is associated with lymph node metastasis in oral squamous cell carcinoma. (PMID:23242234)
• ALY is a novel E2F2-interacting protein and a relevant modulator of E2F-responsive gene expression. (PMID:23297349)
• The interaction of the cellular export adaptor protein Aly/REF with ICP27 contributes to the efficiency of herpes simplex virus 1 mRNA export. (PMID:23637401)
• a spatial map is produced in living cells of the sites for the interaction of two TREX subunits, Alyref and Chtop, with Nxf1. (PMID:23826332)
• the data provides the first site-specific description of how viral mRNA is locked by a herpes viral adaptor protein in complex with cellular ALYREF, giving herpesvirus access to the cellular mRNA export machinery (PMID:24550725)
• A short conserved motif in ALYREF directs cap- and exon junction complex-dependent assembly of export complexes on spliced mRNAs. (PMID:26773052)
• small hairpin RNA-mediated down-regulation of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions. Furthermore, a peptide, TAT-HDAg-L(198-210), containing the 10-amino acid TAT peptide and HDAg-L(198-210), inhibited the interaction between HDAg-L and TAP and blocked HDV virion assembly and secretion. (PMID:27807029)
• Dysregulation of ALYREF-mediated mRNA export upon NSUN2 depletion could be restored by reconstitution of wild-type but not methyltransferase-defective NSUN2. (PMID:28418038)
• The competition between hMTR4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export. (PMID:28801509)
• ALYREF mainly binds to the 5’ and the 3’ regions of the mRNA. ALYREF is likely recruited to mRNAs by PABPN1 and the 3’ processing machinery. (PMID:28934468)
• In both ORF57 and ICP27 the interaction sites for ALYREF and UIF partially overlap, suggestive of mutually exclusive binding. The data provide a map of the binding sites responsible for promoting herpes virus mRNA export, enabling future studies to accurately probe these interactions and reveal the functional consequences for UIF and ALYREF redundancy (PMID:30301920)
• We demonstrate that eIF4A3 stimulates Alyref deposition not only on spliced RNAs close to exon junction complex sites but also on single-exon transcripts (PMID:31104896)
• An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability. (PMID:33767157)
• The role of the HIF-1alpha/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. (PMID:33991457)
• ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform. (PMID:35776213)
• m[5]C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization. (PMID:36806253)
• ALYREF (Aly/REF export factor): A potential biomarker for predicting cancer occurrence and therapeutic efficacy. (PMID:38135116)
• Pan-cancer analysis of RNA 5-methylcytosine reader (ALYREF). (PMID:38361753)
• HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development. (PMID:38626369)
• ALYREF promotes the metastasis of nasopharyngeal carcinoma by increasing the stability of NOTCH1 mRNA. (PMID:39117671)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
mus_musculus	Alyref	ENSMUSG00000025134
mus_musculus	Alyref2	ENSMUSG00000060244
mus_musculus	Alyreffm1	ENSMUSG00000086727
mus_musculus	Alyreffm10	ENSMUSG00000090854
mus_musculus	Alyreffm5	ENSMUSG00000091101
mus_musculus	Alyreffm11	ENSMUSG00000091779
mus_musculus	Alyreffm17	ENSMUSG00000094144
mus_musculus	Alyreffm2	ENSMUSG00000094215
mus_musculus	Alyreffm4	ENSMUSG00000094314
mus_musculus	Alyreffm15	ENSMUSG00000095022
mus_musculus	Alyreffm12	ENSMUSG00000095673
mus_musculus	Alyreffm9	ENSMUSG00000096640
mus_musculus	Alyreffm8	ENSMUSG00000096744
mus_musculus	Alyreffm14	ENSMUSG00000097427
mus_musculus	Alyreffm16	ENSMUSG00000097550
mus_musculus	Alyreffm13	ENSMUSG00000097878
mus_musculus	Alyreffm7	ENSMUSG00000112856
mus_musculus	Alyreffm6	ENSMUSG00000112931
mus_musculus	Alyreffm3	ENSMUSG00000117091
rattus_norvegicus	Alyref	ENSRNOG00000036687
caenorhabditis_elegans		WBGENE00000121
caenorhabditis_elegans		WBGENE00000122

Paralogs (2): POLDIP3 (ENSG00000100227), CHTOP (ENSG00000160679)

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
Bos taurus	Q3T0I4	99.2%	Diamond
Xenopus tropicalis	Q28FB9	91.2%	Diamond
Xenopus laevis	Q58EA2	91.2%	Diamond
Taeniopygia guttata	B5FXN8	84.9%	Diamond
Danio rerio	Q7ZT82	73.8%	Diamond
Arabidopsis thaliana	Q6NQ72	67.4%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q6CQR6	63.8%	Diamond
Bombyx mori	Q1HE00	59.5%	Diamond
Dictyostelium discoideum	Q1ZXC2	54.7%	Diamond
Schizosaccharomyces pombe 972h-	Q9P3U1	48.4%	Diamond
Neurospora crassa OR74A	Q7SG09	46.9%	Diamond
Mycosarcoma maydis	A0A0D1DZT6	40.7%	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
PPP1R27	protein-coding	116729
NPB	protein-coding	256933
ARHGDIA	protein-coding	396
P4HB	protein-coding	5034
ANAPC11	protein-coding	51529
PCYT2	protein-coding	5833
MCRIP1	protein-coding	348262
MAFG-AS1	ncRNA	128385369
MAFG	protein-coding	4097
SIRT7	protein-coding	51547
MILIP	ncRNA	92659

Protein

Protein identifiers

THO complex subunit 4 — Q86V81 (reviewed: Q86V81)

Alternative names: Ally of AML-1 and LEF-1, Aly/REF export factor, Transcriptional coactivator Aly/REF, bZIP-enhancing factor BEF

All UniProt accessions (1): E9PB61

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an mRNA export adapter; component of the transcription/export (TREX) complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5’ end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NXF1 pathway. Involved in the nuclear export of intronless mRNA; proposed to be recruited to intronless mRNA by ATP-bound DDX39B. Plays a key role in mRNP recognition and mRNA packaging by bridging the mRNP-bound EJC and the TREX core complex. TREX recruitment occurs via an interaction between ALYREF/THOC4 and the cap-binding protein NCBP1. Required for TREX complex assembly and for linking DDX39B to the cap-binding complex (CBC). Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NXF1 pathway). In conjunction with THOC5 functions in NXF1-NXT1 mediated nuclear export of HSP70 mRNA; both proteins enhance the RNA binding activity of NXF1 and are required for NXF1 localization to the nuclear rim. Involved in mRNA export of C5-methylcytosine (m5C)-containing mRNAs: specifically recognizes and binds m5C mRNAs and mediates their nucleo-cytoplasmic shuttling. Acts as a chaperone and promotes the dimerization of transcription factors containing basic leucine zipper (bZIP) domains and thereby promotes transcriptional activation. Involved in transcription elongation and genome stability. (Microbial infection) The TREX complex is essential for the export of Kaposi’s sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production; ALYREF/THOC4 mediates the recruitment of the TREX complex to the intronless viral mRNA.

Subunit / interactions. Homomultimer; predominantly hexamer when bound to EJC-RNA complex. Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex (THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7); in the complex interacts (via UAP56-binding motif) with DDX39B with low affinity but this interaction is likely stabilized by multimerization. TREX seems to have a dynamic structure involving ATP-dependent remodeling; in the complex interacts with THOC1, THOC2 and THOC5. Component of the ALYREF/THOC4-EJC-RNA complex; in the complex interacts (via the WXHD motif) with EIF4A3 and interacts (via the RRM domain) with MAGOH; these interactions are likely specific to RNA-bound EJC. Bridges the THO-DDX39B and EJC-RNA complexes to form the TREX-EJC-RNA complex; this interaction is essential for mRNP recognition and mRNA packaging. Identified in the spliceosome C complex. Found in a mRNP complex with UPF3A and UPF3B. Interacts with RBM8A, RBM15B, NCBP1, LEF1, RUNX1, RNPS1, SRRM1, IWS1 and EXOSC1. Interacts with RBM15B. Interacts with NXF1; the interaction is direct. Interacts with IVNS1ABP (via BACK domain); the interaction is indirect and likely plays a role in mRNA nuclear export. (Microbial infection) Interacts with human Kaposi’s sarcoma-associated herpesvirus (HHV-8) ORF57 protein; this interaction allows efficient export of HHV-8 early and late intronless transcripts. (Microbial infection) Interacts with HHV-1 ICP27 protein; this interaction recruits ALYREF to viral replication compartments and probably directs viral mRNA to the TAP/NXF1 pathway.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Tissue specificity. Expressed in a wide variety of cancer types.

Post-translational modifications. Arg-204 is dimethylated, probably to asymmetric dimethylarginine. Arginine methylation reduces RNA binding. Citrullinated by PADI4.

Miscellaneous. Antibodies against ALYREF/THOC4 are found in sera of patients with systemic lupus erythematosus (SLE).

Similarity. Belongs to the ALYREF family.

RefSeq proteins (1): NP_005773* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR025715	YRA2_C	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR051229	ALYREF_mRNA_export	Family

Pfam: PF00076, PF13865

UniProt features (52 total): modified residue 18, region of interest 9, compositionally biased region 5, mutagenesis site 5, sequence conflict 5, strand 4, helix 2, initiator methionine 1, chain 1, short sequence motif 1, domain 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
7ZNJ	Structure of an ALYREF-exon junction complex hexamer	ELECTRON MICROSCOPY	2.4
3ULH	Crystal structure of a RNA binding domain of THO complex subunit 4 protein (THOC4) from …	X-RAY DIFFRACTION	2.54
7ZNK	Structure of an endogenous human TREX complex bound to mRNA	ELECTRON MICROSCOPY	3.9
8R7L	Cryo-EM structure of the human TREX complex	ELECTRON MICROSCOPY	4.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86V81-F1	65.65	0.25

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear speckles; nucleoplasm

Antibody reliability (HPA): IH supported · 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 (18)

Type	Positions
N-acetylalanine	2
Phosphoserine	8, 94, 239
Asymmetric dimethylarginine	38, 197, 204
Omega-n-methylarginine	38, 58, 63, 71, 197, 204, 220
N6-acetyllysine	86
Citrulline	141
Dimethylated arginine	204
N6-methyllysine	235

Mutagenesis-validated functional residues (5)

Position	Phenotype
87	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-92.
92	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-87.
115	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with 139-y–r-144 del and 165-e–a-170.
139–144	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-115 and 165-e–a-170.
165–170	disrupts interaction with the ejc-rna complex and abolishes multimerization; when associated with s-115 and 139-y–r-144 del.

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 8; 1 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-159231	Transport of Mature mRNA Derived from an Intronless Transcript	curated
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript	curated
R-HSA-159230	Transport of the SLBP Dependant Mature mRNA	curated
R-HSA-159227	Transport of the SLBP independent Mature mRNA	curated
R-HSA-72187	mRNA 3’-end processing	curated
R-HSA-72163	mRNA Splicing - Major Pathway	curated
R-HSA-73856	RNA Polymerase II Transcription Termination	—

MSigDB gene sets: 175 (showing top): GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NUCLEAR_TRANSPORT, GOBP_REGULATION_OF_CATABOLIC_PROCESS, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, GOBP_OSSIFICATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, BASAKI_YBX1_TARGETS_UP, GOBP_NUCLEAR_EXPORT

GO Biological Process (8): osteoblast differentiation (GO:0001649), mRNA processing (GO:0006397), RNA export from nucleus (GO:0006405), mRNA export from nucleus (GO:0006406), RNA splicing (GO:0008380), mRNA metabolic process (GO:0016071), regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:2000622), mRNA transport (GO:0051028)

GO Molecular Function (4): RNA binding (GO:0003723), mRNA binding (GO:0003729), C5-methylcytidine-containing RNA reader activity (GO:0062153), nucleic acid binding (GO:0003676)

GO Cellular Component (9): transcription export complex (GO:0000346), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607), extracellular exosome (GO:0070062), catalytic step 2 spliceosome (GO:0071013)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Transport of Mature mRNAs Derived from Intronless Transcripts	3
Transport of Mature Transcript to Cytoplasm	1
mRNA Splicing	1
Processing of Capped Intron-Containing Pre-mRNA	1
RNA Polymerase II Transcription	1
Dengue Virus Infection	1

GO top-level categories

28 GO namespaces:

Category	Terms
cellular anatomical structure	4
RNA processing	2
RNA transport	2
RNA binding	2
ossification	1
cell differentiation	1
mRNA metabolic process	1
nuclear export	1
RNA export from nucleus	1
gene expression	1
mRNA transport	1
RNA metabolic process	1
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1
regulation of mRNA catabolic process	1
nucleic acid binding	1
protein-RNA adaptor activity	1
binding	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
extracellular vesicle	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
RNA export from nucleus	BP	direct assay
mRNA export from nucleus	BP	direct assay
mRNA metabolic process	BP	direct assay
osteoblast differentiation	BP	high-throughput assay
catalytic step 2 spliceosome	CC	direct assay
cytoplasm	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
nucleus	CC	direct assay
transcription export complex	CC	direct assay
C5-methylcytidine-containing RNA reader activity	MF	direct assay
RNA binding	MF	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 2,702 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALYREF	DDX39B	Q13838	961
ALYREF	THOC2	Q8NI27	957
ALYREF	NXF1	Q9UBU9	897
ALYREF	THOC1	Q96FV9	896
ALYREF	THOC3	Q96J01	896
ALYREF	RAE1	P78406	858
ALYREF	NSUN2	Q08J23	841
ALYREF	RBM8A	Q9Y5S9	780
ALYREF	TRDMT1	O14717	774
ALYREF	UPF3A	Q9H1J1	769
ALYREF	MAGOHB	Q96A72	765
ALYREF	NSUN5	Q96P11	761
ALYREF	MAGOH	P50606	761
ALYREF	UPF3B	Q9BZI7	758
ALYREF	UPF2	Q9HAU5	750

IntAct

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

showing 30 of 32 partners by confidence:

Partner	Interaction type	MIscore	Records
DDX39B	association	0.770	2
EIF4A3	physical association	0.750	5
THOC5	association	0.710	4
CHTOP	physical association	0.680	2
NCBP1	physical association	0.670	1
NXF1	physical association	0.660	2
AKT1	direct interaction	0.640	5
UPF1	association	0.530	1
CDK1	physical association	0.500	1
DDX5	physical association	0.400	1
FYTTD1	physical association	0.400	1
MEX67	physical association	0.400	1
SUB2	physical association	0.400	1
TAP1	physical association	0.400	1
CASC3	association	0.350	1
NCBP3	association	0.350	1
ORF44	association	0.350	1
PRMT5	association	0.350	1
THOC7	association	0.350	1
CHCHD2	physical association	0.000	1
FAU	physical association	0.000	1
LSM4	physical association	0.000	1
LSM6	physical association	0.000	1
LSM8	physical association	0.000	1
OLA1	physical association	0.000	1
PPIH	physical association	0.000	1
PRPF3	physical association	0.000	1
PRPF4	physical association	0.000	1
RNH1	physical association	0.000	1
RPL26L1	physical association	0.000	1

BioGRID (575 interactions; top human partners by supporting records): DDX39B (Reconstituted Complex; 19 records), THOC2 (Affinity Capture-MS; 11 records), THOC5 (Affinity Capture-MS; 9 records), NCBP1 (Affinity Capture-Western; 6 records), EIF4A3 (Co-fractionation; 5 records), THOC3 (Co-fractionation; 5 records), THOC7 (Affinity Capture-MS; 5 records), AKT1 (Biochemical Activity; 4 records), C17orf85 (Affinity Capture-MS; 4 records), ESR1 (Reconstituted Complex; 4 records), THOC1 (Affinity Capture-MS; 4 records), BRD4 (Affinity Capture-MS; 3 records), C1QBP (Affinity Capture-MS; 3 records), DDX39A (Reconstituted Complex; 3 records), EP300 (Affinity Capture-MS; 3 records)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
AKT	up-regulates	ALYREF	phosphorylation
AKT1	up-regulates	ALYREF	phosphorylation
ALYREF	“form complex”	“TREX complex”	binding

Protein complexes (CORUM) (11)

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

11 complexes by size:

Complex	Subunits	Members
Spliceosome, E complex	129	RBM17, DDX39A, GEMIN2, NCBP2, PRPF31, SART3, SF3A2, SNRPA, SRSF7, DDX39B, DHX15, GEMIN5, SCAF4, SMARCB1, SNRPD3, SYNCRIP, U2AF2, HNRNPC, SF3B2, SMARCC2, SFSWAP, USP39, GEMIN6, HNRNPK, RBM42, SF3B1, SF3B4, SNRPG, SRSF6, BCAS2, SMN1, CPSF7, SMARCE1, SRSF8, ARID1A, LSM4, SNRPC, CHD8, FUS, SNRNP70, SRSF11, NUDT21, PBRM1, SNRPB2, SNRPD1, YBX1, SF1, SNRPD2, SRSF2, SRSF5, PPIH, SRSF3, DDX20, SART1, SRSF1, SRSF4, PRPF19, RBM39, RBMXL2, SREK1, PRPF3, SMARCA2, U2AF1, SF3B6, SMARCA1, CPSF1, DDX23, DHX9, RUVBL1, SNRPF, SRRM2, ALYREF, HNRNPA0, HNRNPH1, PCBP2, RBM10, SF3B3, STRAP, HNRNPR, RBM25, ACTBL2, CHERP, SNRPA1, ACTL6A, DDX46, HNRNPL, RBM7, CPSF6, ARID2, DNAJC8, EFTUD2, KHSRP, RUVBL2, SMARCA4, PCBP1, SNRNP40, SNRPE, PRPF4, PRPF8, SF3A1, SF3A3, SNRNP200, ZCCHC8, DDX5, LUC7L3, SMARCC1, HNRNPA2B1, HNRNPD, HTATSF1, LUC7L2, PHF5A, PRPF6, SMARCD1, SNRPB, GEMIN8, U2SURP, NCBP1, GEMIN4, HNRNPU, MTREX, ARID1B, CHD4, HNRNPM, PRPF40A, HNRNPF, SRRT, DDX17, HNRNPA1, PUF60
C complex spliceosome	80	RBM8A, ZCCHC8, EFTUD2, HNRNPK, PNN, SRSF1, CDC40, DHX35, HNRNPA2B1, HNRNPC, SF3B3, SYNCRIP, U2AF1, PLRG1, RBM22, SNRNP40, SNRPB2, EIF4A3, FRG1, GPATCH1, HNRNPA3, PPIL1, SF3B1, DHX38, HNRNPR, LSM2, LSM3, SNRPE, DDX23, HNRNPU, MTREX, SLU7, AQR, CWC15, CWC22, DDX41, PABPC1, SF3B2, SNRPD1, SNRPD2, DHX8, CWC27, HNRNPA1, HNRNPH1, MAGOH, SF3A1, PPIE, PPIL3, PRP4K, PRPF6, RALY, SNRPA1, SYF2, TFIP11, CACTIN, CRNKL1, DDX5, SF3A3, SNRNP200, SNRPD3, SNRPF, SRRM1, ALYREF, PPWD1, PRPF19, RBMX, SF3A2, SRRM2, WDR83, XAB2, CDC5L, HNRNPF, SART1, SNRPG, ESS2, ISY1, SNRPB, SNW1, HNRNPM, PRPF8
TREX complex	8	THOC1, THOC2, THOC3, THOC5, THOC6, THOC7, ALYREF, DDX39B
Exon junction complex	8	UPF3B, ALYREF, DDX39B, EIF4A3, MAGOH, RBM8A, RNPS1, SRRM1
Exon junction complex	7	SRRM1, UPF2, UPF3B, ALYREF, NXF1, RBM8A, RNPS1
Splicing-associated factors complex (ALYREF, DEK, RBM8A, RNPS1, SRRM1)	5	ALYREF, DEK, RBM8A, RNPS1, SRRM1
★ NARC1 complex	5	ALYREF, CDC5L, PRPF19, RBMX, TOP1
ALYREF-NXF1-RBM8A-UPF3A complex	4	RBM8A, UPF3A, ALYREF, NXF1
ALYREF-NXF1-RBM8A-UPF3B complex	4	ALYREF, NXF1, RBM8A, UPF3B
ALYREF-DDX39B-SARNP complex	3	ALYREF, DDX39B, SARNP
ALYREF-MYCN complex	2	ALYREF, MYCN

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA 3’-end processing	8	60.6×	4e-11
Transport of Mature mRNA derived from an Intron-Containing Transcript	9	52.7×	1e-11
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	7	26.3×	3e-07
mRNA Splicing - Major Pathway	11	23.1×	4e-11
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	5	22.6×	7e-05
Processing of Capped Intron-Containing Pre-mRNA	7	22.1×	9e-07
mRNA Splicing	5	21.1×	9e-05
Metabolism of RNA	10	16.0×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
mRNA export from nucleus	11	112.1×	2e-18
mRNA splicing, via spliceosome	12	37.9×	1e-14
RNA splicing	8	24.3×	8e-08

Disease & clinical

Genetic variants

Variant evidence for ALYREF: 15 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	6
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3391935	GRCh37/hg19 17q25.3(chr17:79663142-81041938)x1	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ALYREF’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 395):

Position(s)	Effect	Δscore	Sites
17:81889180–81889181	donor_loss	1.0000	5
17:81889330–81889331	acceptor_loss	1.0000	5
17:81889337	acceptor_gain	1.0000
17:81890687–81890688	donor_loss	1.0000	4
17:81890821–81890822	acceptor_loss	1.0000	4
17:81890834	acceptor_gain	1.0000
17:81891322	donor_loss	1.0000	3
17:81888419–81888420	acceptor_loss	0.9900	6
17:81888518–81888519	donor_loss	0.9900	5
17:81888584–81888585	acceptor_loss	0.9900	5

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
Lung Adenocarcinoma (validation)	unfavorable	2.19e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000139

Disease associations

OMIM: gene MIM:604171 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296014 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.35	Kd	4451	nM	CHEMBL5653589
5.35	ED50	4451	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 11 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147848: Binding affinity to human ALYREF incubated for 45 mins by Kinobead based pull down assay	kd	4.4509	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases expression	4
bisphenol F	increases expression, affects cotreatment	3
bisphenol S	increases expression, affects cotreatment	3
bisphenol A	decreases expression, increases expression	2
Nickel	increases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
lead acetate	increases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenate	decreases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
versicolorin A	increases expression	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
phenanthrene	decreases expression	1
perfluorodecanoic acid	increases expression	1
yessotoxin	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	affects response to substance	1
Caffeine	increases phosphorylation	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118564	Binding	Binding affinity to ALYREF in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *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_B7VZ	Abcam Raji ALYREF KO	Cancer cell line	Male
CVCL_B9WH	Abcam THP-1 ALYREF KO	Cancer cell line	Male
CVCL_C6YI	Abcam PC-3 ALYREF KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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