ITCH

Summary

ITCH (itchy E3 ubiquitin protein ligase, HGNC:13890) is a protein-coding gene on chromosome 20q11.22, encoding E3 ubiquitin-protein ligase Itchy homolog (Q96J02). Acts as an Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 83737 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic multisystem autoimmune disease due to ITCH deficiency (Definitive, ClinGen)
• GWAS associations: 13
• Clinical variants (ClinVar): 564 total — 17 pathogenic, 8 likely-pathogenic (top 6% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 15 tissues, sQTL in 7 (q < 0.05)
• Phenotypes (HPO): 66
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.34 (highly constrained)
• MANE Select transcript: NM_031483
• Interaction hub: 2,188 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13890
Approved symbol	ITCH
Name	itchy E3 ubiquitin protein ligase
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	AIP4
Ensembl gene	ENSG00000078747
Ensembl biotype	protein_coding
OMIM	606409
Entrez	83737

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 33 protein_coding, 4 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000374864

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

ENST00000374864, ENST00000262650, ENST00000461661, ENST00000479215, ENST00000535650, ENST00000654846, ENST00000658310, ENST00000660337, ENST00000662871, ENST00000665346, ENST00000665428, ENST00000665484, ENST00000670516, ENST00000696974, ENST00000696975, ENST00000696976, ENST00000696977, ENST00000696984, ENST00000696985, ENST00000884253, ENST00000884254, ENST00000884255, ENST00000884256, ENST00000884257, ENST00000884258, ENST00000884259, ENST00000938729, ENST00000943493, ENST00000975978, ENST00001012914, ENST00001012915, ENST00001012916, ENST00001012917, ENST00001109869, ENST00001109870, ENST00001109871, ENST00001109872, ENST00001116983, ENST00001116984, ENST00001128249, ENST00001128250, ENST00001132351

RefSeq mRNA: 5 — MANE Select: NM_031483 NM_001257137, NM_001257138, NM_001324197, NM_001324198, NM_031483

CCDS: CCDS13234, CCDS58768, CCDS58769

Canonical transcript exons

ENST00000374864 — 25 exons

Exon	Start	End
ENSE00001365031	34369394	34369470
ENSE00001860457	34363273	34363349
ENSE00003622518	34408651	34408792
ENSE00003636605	34412515	34412639
ENSE00003669122	34393791	34393881
ENSE00003801726	34489266	34489386
ENSE00003804081	34480599	34480732
ENSE00003804206	34442208	34442303
ENSE00003804490	34489822	34489926
ENSE00003805082	34492501	34492597
ENSE00003805344	34424480	34424525
ENSE00003805491	34477772	34477860
ENSE00003806435	34445287	34445461
ENSE00003806553	34479630	34479789
ENSE00003806634	34449411	34449480
ENSE00003808235	34457390	34457474
ENSE00003808749	34481066	34481206
ENSE00003808972	34413742	34413879
ENSE00003809161	34440155	34440344
ENSE00003809654	34470048	34470120
ENSE00003809836	34438474	34438631
ENSE00003810844	34504331	34504403
ENSE00003811128	34471444	34471515
ENSE00003811218	34462093	34462221
ENSE00003969122	34507695	34511773

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 99.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.0934 / max 1354.0259, expressed in 1824 samples.

Highest expression (Bgee): sperm, male germ cell, calcaneal tendon, sural nerve, adrenal tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ITCH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	1.0e-42	-0.73	20:34399860:A:G
Skin Sun Exposed Lower leg	eqtl	5.2e-16	+0.15	20:34397349:A:G
Thyroid	eqtl	3.1e-07	-0.13	20:34336065:G:A
Testis	eqtl	3.0e-06	-0.17	20:34326463:C:T
Thyroid	sqtl	7.1e-06	-1.42	20:34858806:G:A
Skin Not Sun Exposed Suprapubic	eqtl	1.1e-05	+0.11	20:34337819:C:G
Muscle Skeletal	sqtl	2.1e-05	-1.31	20:34519436:C:G
Esophagus Mucosa	sqtl	3.5e-05	-1.45	20:35106217:C:T
Esophagus Muscularis	eqtl	9.1e-04	-0.07	20:34569413:T:C
Brain Cortex	eqtl	1.6e-03	+0.14	20:34573323:C:T
Esophagus Mucosa	eqtl	2.4e-03	+0.25	20:35021829:A:T
Cells Cultured fibroblasts	sqtl	4.5e-03	-0.32	20:34474620:G:C
Prostate	sqtl	4.5e-03	-2.29	20:34325380:G:A
Skin Sun Exposed Lower leg	sqtl	1.3e-02	+0.99	20:33862744:G:A
Colon Transverse	eqtl	1.6e-02	-0.23	20:33723487:A:G
Whole Blood	eqtl	2.7e-02	+0.23	20:34987874:T:A
Artery Tibial	eqtl	3.0e-02	-0.16	20:35120794:C:T
Artery Aorta	eqtl	3.6e-02	-0.15	20:34977952:G:A
Adipose Subcutaneous	eqtl	3.7e-02	-0.06	20:34528678:T:C
Brain Hypothalamus	eqtl	4.0e-02	-0.27	20:33885320:G:A

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
184212	46.8577	1823
184210	1.5038	927
184211	0.5864	298
184218	0.1456	43

Top tissues by expression

showing 100 of 293 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.34	gold quality
male germ cell	CL:0000015	98.37	gold quality
calcaneal tendon	UBERON:0003701	96.93	gold quality
sural nerve	UBERON:0015488	95.44	gold quality
adrenal tissue	UBERON:0018303	94.33	gold quality
colonic epithelium	UBERON:0000397	94.12	gold quality
islet of Langerhans	UBERON:0000006	92.25	gold quality
tendon	UBERON:0000043	91.88	gold quality
monocyte	CL:0000576	91.82	gold quality
mononuclear cell	CL:0000842	91.69	gold quality
esophagus squamous epithelium	UBERON:0006920	91.60	gold quality
leukocyte	CL:0000738	91.57	gold quality
epithelium of esophagus	UBERON:0001976	91.11	gold quality
medial globus pallidus	UBERON:0002477	90.70	gold quality
rectum	UBERON:0001052	90.51	gold quality
lower esophagus mucosa	UBERON:0035834	90.47	gold quality
stromal cell of endometrium	CL:0002255	90.10	gold quality
corpus callosum	UBERON:0002336	89.96	gold quality
esophagus mucosa	UBERON:0002469	89.83	gold quality
left testis	UBERON:0004533	89.50	gold quality
right testis	UBERON:0004534	89.49	gold quality
ventricular zone	UBERON:0003053	89.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.40	gold quality
testis	UBERON:0000473	89.24	gold quality
bone marrow cell	CL:0002092	88.83	gold quality
smooth muscle tissue	UBERON:0001135	88.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.34	gold quality
globus pallidus	UBERON:0001875	87.95	gold quality
gall bladder	UBERON:0002110	87.85	gold quality
right lobe of liver	UBERON:0001114	87.80	gold quality
esophagus	UBERON:0001043	87.66	gold quality
tonsil	UBERON:0002372	87.48	gold quality
ganglionic eminence	UBERON:0004023	87.35	gold quality
blood	UBERON:0000178	87.15	gold quality
gastrocnemius	UBERON:0001388	86.96	gold quality
popliteal artery	UBERON:0002250	86.84	gold quality
tibial artery	UBERON:0007610	86.83	gold quality
liver	UBERON:0002107	86.82	gold quality
muscle of leg	UBERON:0001383	86.77	gold quality
spinal cord	UBERON:0002240	86.73	gold quality
pancreas	UBERON:0001264	86.65	gold quality
cortical plate	UBERON:0005343	86.65	gold quality
tongue squamous epithelium	UBERON:0006919	86.61	gold quality
amniotic fluid	UBERON:0000173	86.54	gold quality
ectocervix	UBERON:0012249	86.54	gold quality
tibial nerve	UBERON:0001323	86.41	gold quality
artery	UBERON:0001637	86.40	gold quality
lymph node	UBERON:0000029	86.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.14	gold quality
right lung	UBERON:0002167	86.08	gold quality
buccal mucosa cell	CL:0002336	86.02	gold quality
aorta	UBERON:0000947	85.97	gold quality
granulocyte	CL:0000094	85.78	gold quality
mucosa of stomach	UBERON:0001199	85.48	gold quality
prefrontal cortex	UBERON:0000451	85.32	gold quality
vagina	UBERON:0000996	85.16	gold quality
descending thoracic aorta	UBERON:0002345	85.16	gold quality
squamous epithelium	UBERON:0006914	85.10	gold quality
minor salivary gland	UBERON:0001830	85.04	gold quality
endocervix	UBERON:0000458	85.03	gold quality
thoracic aorta	UBERON:0001515	85.01	gold quality
ascending aorta	UBERON:0001496	84.96	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.93	gold quality
body of pancreas	UBERON:0001150	84.91	gold quality
skin of leg	UBERON:0001511	84.89	gold quality
lower esophagus	UBERON:0013473	84.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.72	gold quality
right coronary artery	UBERON:0001625	84.71	gold quality
left ovary	UBERON:0002119	84.64	gold quality
left coronary artery	UBERON:0001626	84.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.58	gold quality
oral cavity	UBERON:0000167	84.57	gold quality
body of uterus	UBERON:0009853	84.55	gold quality
adrenal gland	UBERON:0002369	84.40	gold quality
mucosa of transverse colon	UBERON:0004991	84.38	gold quality
vermiform appendix	UBERON:0001154	84.37	gold quality
right ovary	UBERON:0002118	84.35	gold quality
upper lobe of left lung	UBERON:0008952	84.33	gold quality
transverse colon	UBERON:0001157	84.25	gold quality
mouth mucosa	UBERON:0003729	84.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.18	gold quality
omental fat pad	UBERON:0010414	84.14	gold quality
peritoneum	UBERON:0002358	84.11	gold quality
left adrenal gland	UBERON:0001234	84.09	gold quality
left adrenal gland cortex	UBERON:0035825	84.03	gold quality
coronary artery	UBERON:0001621	83.99	gold quality
right atrium auricular region	UBERON:0006631	83.89	gold quality
skin of abdomen	UBERON:0001416	83.81	gold quality
colon	UBERON:0001155	83.80	gold quality
ovary	UBERON:0000992	83.69	gold quality
intestine	UBERON:0000160	83.64	gold quality
stomach	UBERON:0000945	83.64	gold quality
right adrenal gland	UBERON:0001233	83.53	gold quality
cartilage tissue	UBERON:0002418	83.53	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.51	gold quality
saliva-secreting gland	UBERON:0001044	83.49	gold quality
large intestine	UBERON:0000059	83.48	gold quality
upper lobe of lung	UBERON:0008948	83.46	gold quality
right adrenal gland cortex	UBERON:0035827	83.40	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	62.01
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	79.0
Choroid plexus	tissue	58.0
Spinal cord	tissue	56.1
Midbrain	tissue	54.5
Medulla oblongata	tissue	52.0
Nucleus accumbens	tissue	50.5
Thalamus	tissue	50.3
Substantia nigra	tissue	50.0
Superior colliculi	tissue	48.7
Pons	tissue	48.3
Hippocampus	tissue	45.9	high
Putamen	tissue	43.2
Hippocampal formation	tissue	41.9
Periaqueductal gray	tissue	41.9
Locus coeruleus	tissue	41.6
Postcentral gyrus	tissue	40.7
Cerebral cortex	tissue	40.6	high
Somatosensory cortex	tissue	40.6
Occipital cortex	tissue	39.5
Ventral forebrain	tissue	38.6
Hypothalamus	tissue	38.3
Liver	tissue	37.9	medium
Motor cortex	tissue	37.2
Septum	tissue	36.3
Retrosplenial cortex	tissue	34.7
Temporal cortex	tissue	33.6
Entorhinal cortex	tissue	33.5
Cerebellum	tissue	33.4	medium
Prefrontal cortex	tissue	32.8
Retrosplenial and cingulate cortex	tissue	32.7
Insular cortex	tissue	30.8
Amygdala	tissue	30.5
Caudate putamen	tissue	30.3
Olfactory bulb	tissue	27.8
Basal ganglia	tissue	27.7	medium
Frontal cortex	tissue	23.5
Esophagus	tissue	21.5	low
Bone marrow	tissue	18.0	medium
Urinary bladder	tissue	16.3	medium
Testis	tissue	15.6	medium
Thyroid gland	tissue	15.1	medium
Retina	tissue	15.0
Tonsil	tissue	15.0	high
Vagina	tissue	14.2	low
Cervix	tissue	13.8	low
Placenta	tissue	13.8	high
Rectum	tissue	13.7	medium
Kidney	tissue	13.2	medium
Lymph node	tissue	13.1	high
Parathyroid gland	tissue	13.1	medium
Thymus	tissue	13.1
Small intestine	tissue	13.0	high
Colon	tissue	12.7	medium
Duodenum	tissue	12.4	high
Smooth muscle	tissue	12.3	medium
Stomach 1	tissue	12.1	high
Spleen	tissue	11.9	high
Endometrium 1	tissue	11.6	medium
Heart muscle	tissue	11.5	medium
Breast	tissue	11.4	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Parieto-temporal junction (white matter) (102.2), Corpus callosum, genu (white matter) (94.1), Temporal white matter (91.3), Corpus callosum, splenium (white matter) (88.2), White matter (79.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, NFKBID, RELA, TP63, TP73

miRNA regulators (miRDB)

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

showing 30 of 269 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
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-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.343, missense Z 4.36 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000374864 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
20:34,393,812–34,393,857	19 / 17.5	1.08	no
20:34,393,858–34,408,676	2 / 17.6	0.11	yes (p 2.1e-04)
20:34,408,677–34,440,245	220 / 265.7	0.83	no
20:34,440,246–34,507,791	390 / 731.6	0.53	no
ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• gene expression regulation; coregulates hematopoietic transcription factor NF-E2 (PMID:11318614)
• The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch (PMID:11782481)
• novel E3 ubiquitin-protein ligase; role in regulation of immune response - review (PMID:11826757)
• Data demonstrate that two E3 ligases of different classes, CBLC and AIP4, can interact and cooperate to down-regulate EGFR signaling. (PMID:12226085)
• First demonstration of ubiquitin-protein ligase AIP4 from human lung cDNA library recruited by penton base proteins of adenovirus serotypes Ad2 and Ad3 in vitro and in vivo. (PMID:12450395)
• Data show that the Nedd4-like E3 ubiquitin ligase AIP4 mediates ubiquitination of CXCR4 at the plasma membrane, and of the ubiquitin binding protein Hrs on endosomes. (PMID:14602072)
• Reults demonstrate the function of atrophin-1-interacting protein 4 as an ubiquitin E3 ligase for human enhancer of filamentation 1. (PMID:15051726)
• The visualization of ubiquitinated Jun in living cells has uncovered a lysosomal pathway for Jun degradation that involves ubiquitination by Itch/AIP4. (PMID:15469925)
• Upon DNA damage Itch itself is downregulated, allowing p73 protein levels to rise and thus interfere with p73 function (PMID:15678106)
• Both neural precursor cell expressed, developmentally down-regulated 4 and Itch participate in the degradation of Melan-A (PMID:15703212)
• AIP4 restricts transforming growth factor-beta signaling through a ubiquitination-independent mechanism (PMID:15946939)
• CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4 (PMID:16888620)
• AIP4-generated polyubiquitin chains are mainly conjugated through lysine 29 of ubiquitin in vivo, indicating a link between this type of chain and lysosomal degradation. (PMID:17028573)
• transient overexpression of FAM/USP9X resulted in the deubiquitylation of Itch. Moreover, we show that Itch auto-ubiquitylation leads to its degradation in the proteasome (PMID:17038327)
• AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. TRPC4, another member of the TRP channel family, is also strongly ubiquitinated in the presence of AIP4 (PMID:17110928)
• Hedgehog transcription factor Gli1 is targeted by Numb for Itch-dependent ubiquitination, which suppresses Hedgehog signals, thus arresting growth and promoting cell differentiation. (PMID:17115028)
• the AIP4.arrestin-2 complex functions on endosomes to regulate sorting of CXCR4 into the degradative pathway (PMID:17947233)
• AIP4/Itch regulates Notch receptor degradation in the absence of ligand (PMID:18628966)
• The modified Yap1 does not co-activate Runx in supporting Itch transcription. The subsequent reduction in the Itch level gives rise to p73 accumulation. (PMID:18701449)
• This is the first in vivo evidence for the interaction between p45/NF-E2 and the E3 ubiquitin ligase Itch, and the subsequent ubiquitination of p45/NF-E2 by Itch. (PMID:18718448)
• demonstrate that the decay rate of a catalytic inactive Itch mutant, which is devoided of self-ubiquitylating activity, is barely indistinguishable from the one of the wild-type protein (PMID:18718449)
• hypothesize a correlated slow-frequency motion that involves two different hinge regions of the HECT domain of itch (PMID:18805400)
• Itch gene sequence is highly conserved in healthy subjects; no relevant SNPs located in putative functional regions of Itch were found in atopic dermatitis and rheumatoid arthritis patients (PMID:19001863)
• ITCH is a putative target for a novel 20q11.22 amplification detected in anaplastic thyroid carcinoma cells by array-based comparative genomic hybridization. (PMID:19016753)
• These data suggests that caspase-dependent Itch cleavage might be an important regulator of Itch at the endogenous level under both physiological and stressed conditions. (PMID:19073138)
• Ubiquitination of cFLIP(L) inhibits the interaction between cFLIP(L) and Itch in T. cruzi-infected cells. (PMID:19090833)
• Ectopic expression of miR106b in CLL cells demonstrated that Itch was a direct target of miR106b such that miR106b-induced decreases in Itch resulted in an accumulation of p73. (PMID:19096009)
• AIP4 can interact directly with CXCR4 via a novel noncanonical WW domain-mediated interaction involving serine residues 324 and 325 within the carboxy-terminal tail of CXCR4. (PMID:19116316)
• Itch protein is a key regulatory locus for Epidermal Growth Factor receptor degradation. (PMID:19341794)
• Data show that the small PY-containing membrane proteins, NDFIP1 and NDFIP2 (NEDD4 family-interacting proteins), activate the catalytic activity of ITCH and of several other HECT ligases by binding to them. (PMID:19343052)
• SPG20 is ubiquitinated and interacts with AIP4 and AIP5. (PMID:19580544)
• ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. (PMID:19592251)
• PCBP2-AIP4 axis defines a new signaling cascade for MAVS degradation and ‘fine tuning’ of antiviral innate immunity. (PMID:19881509)
• itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation (PMID:20068034)
• Inducible regulatory T cells (iTregs) from recent onset type 1 diabetes (RO T1D) subjects had increased expression of Foxp3, E3 ubiquitin ligase (ITCH) and TGF-beta-inducible early gene 1 (TIEG1) compared with control and long-standing T1D subjects. (PMID:20143240)
• describe, in ten patients, identification of a mutation resulting in truncation of ITCH. These patients not only have multisystem autoimmune disease but also display morphologic and developmental abnormalities. (PMID:20170897)
• Results indicate that cystatin B regulates Itch-mediated degradation of FLIP(L) and thereby TRAIL-induced apoptosis in melanoma cells. (PMID:20300110)
• Cbl-b and itch are key regulators of peripheral T-cell tolerance [review] (PMID:20395198)
• Itch ubiquitylates SNX9 and regulates intracellular SNX9 levels. Interaction with the proline-rich domain of Itch is essential for SNX9 ubiquitylation and degradation. (PMID:20491914)
• UL56 interacted with Itch, independent of additional viral proteins, and mediated more striking degradation of Itch, compared to Nedd4. (PMID:20682038)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	itcha	ENSDARG00000074903
danio_rerio	itchb	ENSDARG00000099199
mus_musculus	Itch	ENSMUSG00000027598
rattus_norvegicus	Itch	ENSRNOG00000059043

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1202301) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 66 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased leukocyte cell number	2
enlarged spleen	2
increased eosinophil cell number	2
decreased bone mineral density	1
increased circulating calcium level	1
decreased hematocrit	1
increased neutrophil cell number	1
abnormal esophagus morphology	1
enlarged lymph nodes	1
tremors	1
dermatitis	1
skin lesions	1
weight loss	1
decreased exploration in new environment	1
abnormal startle reflex	1
increased circulating phosphate level	1
increased inflammatory response	1
lung inflammation	1
premature death	1
abnormal tooth morphology	1
abnormal lymph organ size	1
abnormal lymphopoiesis	1
abnormal immunoglobulin level	1
increased IgA level	1
increased IgE level	1

+41 more (showing top 25).

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
Aspergillus fumigatus A1163	B0XQ72	100.0%	Diamond
Aspergillus fumigatus Af293	Q4WTF3	100.0%	Diamond
Aspergillus flavus NRRL3357	B8N7E5	99.8%	Diamond
Aspergillus oryzae RIB40	Q2UBP1	99.8%	Diamond
Macaca fascicularis	Q4R383	99.4%	Diamond
Pongo abelii	Q5R9W5	99.0%	Diamond
Bos taurus	F1N6G5	98.5%	Diamond
Aspergillus fischeri NRRL 181	A1D3C5	97.2%	Diamond
Canis lupus familiaris	A0A8I3PQN6	96.3%	Diamond
Aspergillus terreus NIH2624	Q0CCL1	95.7%	Diamond
Aspergillus clavatus NRRL 1	A1CQG2	95.0%	Diamond
Xenopus tropicalis	Q28BK1	94.9%	Diamond
Xenopus laevis	Q2TAS2	94.9%	Diamond
Aspergillus niger CBS 513.88	A2QQ28	94.6%	Diamond
Aspergillus nidulans FGSC A4	Q5BDP1	92.6%	Diamond
Arabidopsis thaliana	Q8H0T4	91.8%	Diamond
Gallus gallus	E1C656	91.7%	Diamond
Thermochaetoides thermophila DSM 1495	G0S9J5	74.0%	Diamond
Caenorhabditis elegans	Q9N2Z7	68.4%	Diamond
Schizosaccharomyces pombe 972h-	Q92462	68.2%	Diamond
Drosophila melanogaster	Q9Y0H4	67.7%	Diamond
Saccharomyces cerevisiae S288C	P39940	67.1%	Diamond
Dictyostelium discoideum	Q54T86	66.7%	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
MIR644A	ncRNA	693229
DYNLRB1	protein-coding	83658
MAP1LC3A	protein-coding	84557
PIGU	protein-coding	128869
AHCY	protein-coding	191
ASIP	protein-coding	434
EIF2S2	protein-coding	8894

Protein

Protein identifiers

E3 ubiquitin-protein ligase Itchy homolog — Q96J02 (reviewed: Q96J02)

Alternative names: Atrophin-1-interacting protein 4, HECT-type E3 ubiquitin transferase Itchy homolog, NFE2-associated polypeptide 1

All UniProt accessions (9): A0A1W2PNZ8, A0A590UIY0, A0A590UJ55, A0A590UJQ1, A0A590UJW8, A0A590UK44, A0A8V8TKI4, A0A8V8TKK4, Q96J02

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Catalyzes ‘Lys-29’-, ‘Lys-48’- and ‘Lys-63’-linked ubiquitin conjugation. Involved in the control of inflammatory signaling pathways. Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates ‘Lys-63’ polyubiquitin chains on RIPK1 and catalyzes the formation of ‘Lys-48’-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by ‘Lys-63’-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by ‘Lys-63’ linkages and is implicated in the control of the development of hematopoietic lineages. Mediates JUN ubiquitination and degradation. Mediates JUNB ubiquitination and degradation. Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation. Involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through ‘Lys-48’-linked conjugation resulting in MAVS proteasomal degradation. Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity. Ubiquitinates PI4K2A and negatively regulates its catalytic activity. Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through ‘Lys-29’-linked polyubiquitination. Ubiquitinates SNX9. Ubiquitinates MAP3K7 through ‘Lys-48’-linked conjugation. Together with UBR5, involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP: catalyzes ‘Lys-48’-/‘Lys-63’-branched ubiquitination of TXNIP. ITCH synthesizes ‘Lys-63’-linked chains, while UBR5 is branching multiple ‘Lys-48’-linked chains of substrate initially modified. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Inhibits the replication of influenza A virus (IAV) via ubiquitination of IAV matrix protein 1 (M1) through ‘Lys-48’-linked conjugation resulting in M1 proteasomal degradation. Ubiquitinates NEDD9/HEF1, resulting in proteasomal degradation of NEDD9/HEF1.

Subunit / interactions. Monomer. Part of a ternary complex composed of SMAD3, ITCH/AIP4 and NEDD9/HEF1; within the complex NEDD9/HEF1 interacts (via N-terminus) with ITCH/AIP4 (via WW domains); the complex mediates ubiquitination and proteasomal degradation of NEDD9/HEF1. Interacts (via WW domains) with OCNL. Interacts (via WW domains) with NOTCH1. Interacts (via WW domains) with JUN. Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB. Interacts with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB. Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes. Interacts with ARHGEF7. Interacts with RNF11. Interacts (via the WW 1 domain) with NFE2 (via the PXY motif 1); the interaction promotes ‘Lys-63’-linked ubiquitination of NFE2, retains it in the cytoplasm and prevents its transactivation activity. Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation. Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM. Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct). Interacts with HGS. Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2. Interacts (via WW domains) with TXNIP (via C-terminus). Interacts with p15 BID. Interacts with ERBB4. Interacts with DTX1. Interacts with SPART. Interacts with SNX9 and SNX18. Interacts (via its WW domains) with ATN1. Interacts (via WW domains) with SGK3. Interacts with CBLC. Interacts with OTUD7B. Interacts (via WW domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity and promotes ITCH catalytic activity. Interacts with ARRDC4. Part of a complex containing ITCH, NDFIP1 and MAP3K7. Interacts with UBE2L3; the interaction is mediated by NDFIP1. Interacts with MAPK8/JNK1. Interacts (via WW domains) with ARRDC1 (via PPxY motifs); the interaction is direct and participates in the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor. Interacts (via WW domains) with ARRDC2. Interacts (via WW domains) with ARRDC3. Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation. Interacts with ENTREP1; enhances the ubiquitination of CXCR4 by ITCH and its subsequent endocytosis. Interacts with USP12 and WDR48/UAF1; the interaction is more efficient when both USP12 and WDR48/UAF1 are involved and may facilitate the recruitment of the USP12 deubiquitinase complex to Notch. (Microbial infection) Interacts with Epstein-Barr virus LMP2A. (Microbial infection) Interacts with Human cytomegalovirus (HCMV) protein UL42; this interaction induces ubiquitination and degradation of ITCH. (Microbial infection) Interacts with herpesvirus 1 (HHV-1) UL56 protein; this interaction induces ubiquitination and probably degradation of ITCH. (Microbial infection) Interacts with herpesvirus 2 (HHV-2) UL56 protein. (Microbial infection) Interacts with varicella-zoster virus (VZV) Orf0 protein. (Microbial infection) Interacts with herpesvirus 6A (HHV-6A) U24 protein. (Microbial infection) Interacts with ebola virus protein VP40; this interaction is required for efficient viral egress from the infected cell. (Microbial infection) Interacts with influenza A virus matrix protein 1. (Microbial infection) Interacts with human herpesvirus 8 (KSHV) protein RTA/ORF50; this interaction targets viral vFLIP for proteasomal degradation.

Subcellular location. Cell membrane. Cytoplasm. Nucleus. Early endosome membrane. Endosome membrane.

Tissue specificity. Widely expressed.

Post-translational modifications. On T-cell activation, phosphorylation by the JNK cascade on serine and threonine residues surrounding the PRR domain accelerates the ubiquitination and degradation of JUN and JUNB. The increased ITCH catalytic activity due to phosphorylation by JNK1 may occur due to a conformational change disrupting the interaction between the PRR/WW motifs domain and the HECT domain and, thus exposing the HECT domain. Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation. Monoubiquitinated. Autopolyubiquitinated with ‘Lys-63’ linkages which does not lead to protein degradation.

Disease relevance. Autoimmune disease, multisystem, with facial dysmorphism (ADMFD) [MIM:613385] A disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by NDFIP1- and NDFIP2-binding. Activated by PI4K2A-binding. Inhibited by DTX3L-binding. Inhibited by N4BP1 binding.

Domain organisation. The WW domains mediate interaction with PPxY motif-containing proteins. The WW domain 4 mediates interaction with ENTREP1.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96J02-1	1	yes
Q96J02-2	2
Q96J02-3	3

RefSeq proteins (5): NP_001244066, NP_001244067, NP_001311126, NP_001311127, NP_113671* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000569	HECT_dom	Domain
IPR001202	WW_dom	Domain
IPR024928	E3_ub_ligase_SMURF1	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00168, PF00397, PF00632

Enzyme classification (BRENDA)

• EC 2.3.2.26 — HECT-type E3 ubiquitin transferase (BRENDA: 14 organisms, 64 substrates, 19 inhibitors, 5 Km, 5 kcat entries)
• EC 2.3.2.B8 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBC5B]-L-LYSINE	0.0046–0.037	5

UniProt features (103 total): strand 33, helix 30, turn 9, modified residue 7, domain 6, compositionally biased region 5, mutagenesis site 4, region of interest 3, splice variant 2, initiator methionine 1, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures by resolution:

PDB	Title	Method	Resolution (Å)
5CQ2	Crystal Structure of tandem WW domains of ITCH in complex with TXNIP peptide	X-RAY DIFFRACTION	1.4
5DZD	Crystal Structure of WW4 domain of ITCH in complex with TXNIP peptide	X-RAY DIFFRACTION	1.57
5DWS	Crystal Structure of ITCH WW3 domain in complex with TXNIP peptide	X-RAY DIFFRACTION	1.65
5SXP	STRUCTURAL BASIS FOR THE INTERACTION BETWEEN ITCH PRR AND BETA-PIX	X-RAY DIFFRACTION	1.65
2NQ3	Crystal structure of the C2 Domain of Human Itchy Homolog E3 Ubiquitin Protein Ligase	X-RAY DIFFRACTION	1.8
2P4R	Structural basis for a novel interaction between AIP4 and beta-PIX	X-RAY DIFFRACTION	2
4ROF	Crystal Structure of WW3 domain of ITCH in complex with TXNIP peptide	X-RAY DIFFRACTION	2.03
3TUG	Crystal structure of the HECT domain of ITCH E3 ubiquitin ligase	X-RAY DIFFRACTION	2.27
5C7M	CRYSTAL STRUCTURE OF E3 LIGASE ITCH WITH A UB VARIANT	X-RAY DIFFRACTION	3.03
2DMV	Solution structure of the second ww domain of Itchy homolog E3 ubiquitin protein ligase …	SOLUTION NMR
2KYK	The sandwich region between two LMP2A PY motif regulates the interaction between …	SOLUTION NMR
2YSF	Solution structure of the fourth WW domain from the human E3 ubiquitin-protein ligase …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96J02-F1	76.39	0.38

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; vesicles

Antibody reliability (HPA): IH supported · IF enhanced

Functional residue map

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

Catalytic / active sites (1)

Position	Role
871	glycyl thioester intermediate

Post-translational modifications (7)

Type	Positions
N-acetylserine	2
Phosphoserine	240, 273, 450
Phosphothreonine	263, 385
Phosphotyrosine	420

Mutagenesis-validated functional residues (4)

Position	Phenotype
343	no effect on phosphorylation on t-cell stimulation nor in the presence of fyn.
420	greatly reduced phosphorylation on t-cell stimulation and in the presence of fyn. increased itch-mediated ub conjugation and degradation of …
455	no effect on phosphorylation on t-cell stimulation nor in the presence of fyn.
871	loss of ubiquitin protein ligase activity. results in altered endosomal sorting and reduced degradation of cxcr4. unable to inhibit …

Function

Pathways and Gene Ontology

Reactome pathways

9 curated (TAS) of 36; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

36 pathways:

ID	Pathway	Evidence
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses ⚕	curated
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-5610780	Degradation of GLI1 by the proteasome	curated
R-HSA-1253288	Downregulation of ERBB4 signaling	curated
R-HSA-5632684	Hedgehog ‘on’ state	curated
R-HSA-168638	NOD1/2 Signaling Pathway	curated
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling	curated
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs	curated
R-HSA-5675482	Regulation of necroptotic cell death	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9678108	SARS-CoV-1 Infection ⚕	—
R-HSA-9692914	SARS-CoV-1-host interactions ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus	electronic
R-HSA-1280218	Adaptive Immune System	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-5610787	Hedgehog ‘off’ state	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	—
R-HSA-5357801	Programmed Cell Death	—
R-HSA-5213460	RIPK1-mediated regulated necrosis	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-5218859	Regulated Necrosis	—
R-HSA-162582	Signal Transduction	—
R-HSA-1236394	Signaling by ERBB4	—
R-HSA-5358351	Signaling by Hedgehog	—
R-HSA-157118	Signaling by NOTCH	—
R-HSA-1980143	Signaling by NOTCH1	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-8878171	Transcriptional regulation by RUNX1	—

MSigDB gene sets: 594 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_TOLERANCE_INDUCTION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION

GO Biological Process (34): regulation of cell growth (GO:0001558), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), apoptotic process (GO:0006915), inflammatory response (GO:0006954), protein ubiquitination (GO:0016567), receptor internalization (GO:0031623), negative regulation of type I interferon production (GO:0032480), protein K29-linked ubiquitination (GO:0035519), nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0035872), negative regulation of cytoplasmic pattern recognition receptor signaling pathway (GO:0039532), negative regulation of apoptotic process (GO:0043066), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), innate immune response (GO:0045087), negative regulation of JNK cascade (GO:0046329), symbiont entry into host cell (GO:0046718), negative regulation of defense response to virus (GO:0050687), defense response to virus (GO:0051607), protein autoubiquitination (GO:0051865), regulation of necroptotic process (GO:0060544), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), regulation of protein deubiquitination (GO:0090085), protein branched polyubiquitination (GO:0141198), regulation of hematopoietic stem cell differentiation (GO:1902036), positive regulation of receptor catabolic process (GO:2000646), immune system process (GO:0002376), negative regulation of immune system process (GO:0002683), positive regulation of immune system process (GO:0002684), positive regulation of catabolic process (GO:0009896), positive regulation of macromolecule metabolic process (GO:0010604), negative regulation of multicellular organismal process (GO:0051241), negative regulation of intracellular signal transduction (GO:1902532)

GO Molecular Function (11): ubiquitin-protein transferase activity (GO:0004842), ligase activity (GO:0016874), ubiquitin-like protein transferase activity (GO:0019787), ubiquitin-ubiquitin ligase activity (GO:0034450), ribonucleoprotein complex binding (GO:0043021), ubiquitin-like protein ligase binding (GO:0044389), CXCR chemokine receptor binding (GO:0045236), ubiquitin protein ligase activity (GO:0061630), arrestin family protein binding (GO:1990763), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (15): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), cell cortex (GO:0005938), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), nucleus (GO:0005634), early endosome (GO:0005769), endosome membrane (GO:0010008), cell periphery (GO:0071944)

Reactome top-level categories

15 top-level categories:

Category	Pathways
Immune System	2
Innate Immune System	2
Signaling by ERBB4	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Signaling by NOTCH1	1
Hedgehog ‘off’ state	1
Signaling by Hedgehog	1
RIPK1-mediated regulated necrosis	1
Transcriptional regulation by RUNX1	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
SARS-CoV-1-host interactions	1
Class I MHC mediated antigen processing & presentation	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1
Signaling by NOTCH	1

GO top-level categories

showing 60 of 66 GO namespaces:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
protein ubiquitination	3
defense response	2
cytoplasmic pattern recognition receptor signaling pathway	2
negative regulation of intracellular signal transduction	2
catalytic activity	2
intracellular membrane-bounded organelle	2
cell periphery	2
endosome	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
modification-dependent protein catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein modification by small protein conjugation	1
receptor-mediated endocytosis	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
protein polyubiquitination	1
negative regulation of immune system process	1
regulation of cytoplasmic pattern recognition receptor signaling pathway	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
immune response	1
defense response to symbiont	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
viral life cycle	1
symbiont entry into host	1
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of defense response to virus	1
defense response to virus	1
response to virus	1
ubiquitin-like protein transferase activity	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
ubiquitin protein ligase activity	1
protein-containing complex binding	1
enzyme binding	1
chemokine receptor binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
protein binding	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
membrane	1
intracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 60 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of apoptotic process	BP	mutant phenotype
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	BP	direct assay
negative regulation of defense response to virus	BP	mutant phenotype
positive regulation of receptor catabolic process	BP	mutant phenotype
proteasome-mediated ubiquitin-dependent protein catabolic process	BP	direct assay
protein K29-linked ubiquitination	BP	direct assay
protein K48-linked ubiquitination	BP	direct assay
protein K63-linked ubiquitination	BP	direct assay
protein autoubiquitination	BP	mutant phenotype
protein branched polyubiquitination	BP	direct assay
protein monoubiquitination	BP	direct assay
protein ubiquitination	BP	direct assay
receptor internalization	BP	mutant phenotype
ubiquitin-dependent protein catabolic process	BP	direct assay
cytoplasmic vesicle	CC	direct assay
extracellular exosome	CC	high-throughput assay
membrane	CC	high-throughput assay
nucleoplasm	CC	direct assay
plasma membrane	CC	direct assay
protein-containing complex	CC	direct assay
CXCR chemokine receptor binding	MF	physical interaction
arrestin family protein binding	MF	physical interaction
ribonucleoprotein complex binding	MF	physical interaction
ubiquitin protein ligase activity	MF	direct assay
ubiquitin-like protein ligase binding	MF	physical interaction
ubiquitin-protein transferase activity	MF	experiment
ubiquitin-ubiquitin ligase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,188 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITCH	RNF11	Q9Y3C5	798
ITCH	PTEN	P60484	612
ITCH	CFLAR	O15519	590
ITCH	STAMBP	O95630	572
ITCH	JUN	P05412	568
ITCH	FBXW7	Q969H0	556
ITCH	RRN3	Q9NYV6	552
ITCH	FMNL2	Q96PY5	542
ITCH	LGR5	O75473	523
ITCH	AHCY	P23526	515
ITCH	BAG4	O95429	492
ITCH	RBX1	P62877	490
ITCH	KDM2B	Q8NHM5	490
ITCH	ASIP	P42127	488
ITCH	HIPK3	Q9H422	484

IntAct

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

showing 30 of 51 partners by confidence:

Partner	Interaction type	MIscore	Records
ARRDC3	physical association	0.820	1
ARRDC1	physical association	0.800	1
TP73	association	0.750	12
ENTREP1	physical association	0.740	1
TMEM51	direct interaction	0.690	2
SARAF	association	0.670	2
SGK3	physical association	0.640	5
SPART	association	0.640	2
SNX9	physical association	0.620	6
CBLC	physical association	0.600	5
GLI1	physical association	0.600	4
LMP2	direct interaction	0.590	2
N4BP1	physical association	0.590	2
MLANA	direct interaction	0.590	1
NEDD9	physical association	0.580	3
PI4K2A	physical association	0.570	5
RNF11	direct interaction	0.540	2
SH3GL2	colocalization	0.530	3
TP63	physical association	0.500	2
DTX1	physical association	0.460	2
M	direct interaction	0.440	18
VP40	direct interaction	0.440	12
TTYH3	direct interaction	0.440	2
HNRNPUL1	direct interaction	0.440	1
KIAA1210	direct interaction	0.440	1
LRRK1	direct interaction	0.440	1
MAP2	direct interaction	0.440	1
MAP3K2	direct interaction	0.440	1
MYCT1	direct interaction	0.440	1
PIP4P2	direct interaction	0.440	1

BioGRID (831 interactions; top human partners by supporting records in a sample of 600 records): UBE2L3 (Reconstituted Complex; 16 records), TXNIP (Co-crystal Structure; 10 records), WBP2 (Affinity Capture-MS; 7 records), ERBB4 (Affinity Capture-Western; 6 records), SH3GL2 (FRET; 6 records), TP53BP2 (Affinity Capture-Western; 6 records), TP73 (Affinity Capture-Western; 6 records), UBE2D1 (Reconstituted Complex; 6 records), BRAF (Affinity Capture-Western; 5 records), CFLAR (Affinity Capture-Western; 5 records), CXCR4 (Affinity Capture-Western; 5 records), FAM189A2 (Affinity Capture-MS; 5 records), PACSIN1 (FRET; 5 records), SPG20 (Affinity Capture-MS; 5 records), UBE2D2 (Reconstituted Complex; 5 records)

SIGNOR signaling

showing 42 of 49 signaling interactions:

A	Effect	B	Mechanism
ITCH	up-regulates	SMAD2	ubiquitination
ITCH	down-regulates	SMAD7	ubiquitination
ITCH	down-regulates	TNIP2	ubiquitination
MAPK8	up-regulates	ITCH	phosphorylation
ITCH	down-regulates	DTX1	ubiquitination
ITCH	down-regulates	GLI1	ubiquitination
ITCH	“up-regulates activity”	TNFAIP3	binding
NUMB	up-regulates	ITCH	binding
RNF11	“up-regulates activity”	ITCH	binding
MAPK8	“up-regulates activity”	ITCH	phosphorylation
CSK	“down-regulates activity”	ITCH	phosphorylation
ITCH	down-regulates	NOTCH	ubiquitination
PCBP2	“up-regulates activity”	ITCH	binding
ITCH	“down-regulates quantity by destabilization”	MAVS	ubiquitination
SPART	“up-regulates activity”	ITCH	binding
ITCH	“up-regulates activity”	SPART	binding
Ub:E2	“up-regulates activity”	ITCH	ubiquitination
ITCH	“down-regulates quantity by destabilization”	BCL10	ubiquitination
ITCH	“down-regulates quantity by destabilization”	BID	ubiquitination
ITCH	“down-regulates quantity by destabilization”	ERBB4	polyubiquitination
ITCH	“down-regulates activity”	TRPC4	ubiquitination
ITCH	“down-regulates activity”	TRPV4	ubiquitination
ITCH	“down-regulates quantity by destabilization”	LAPTM5	polyubiquitination
AKT1	“up-regulates quantity”	ITCH	phosphorylation
ITCH	“up-regulates activity”	H1-2	polyubiquitination
ITCH	“down-regulates activity”	NFE2	ubiquitination
ATM	“up-regulates activity”	ITCH	phosphorylation
ITCH	“down-regulates quantity”	LATS1	destabilization
ITCH	“down-regulates quantity”	GLIS3	ubiquitination
ITCH	“down-regulates quantity by destabilization”	FOXO1	ubiquitination
ITCH	“down-regulates quantity by destabilization”	TP73	ubiquitination
ITCH	“down-regulates quantity by destabilization”	OCLN	ubiquitination
ITCH	“down-regulates quantity by destabilization”	CD274	ubiquitination
ITCH	“down-regulates quantity by destabilization”	LATS1	ubiquitination
ITCH	“up-regulates activity”	TGIF1	ubiquitination
ITCH	“up-regulates activity”	RIPK2	binding
ITCH	down-regulates	NOTCH1	ubiquitination
ITCH	“down-regulates quantity”	CFLAR	ubiquitination
FYN	“down-regulates activity”	ITCH	phosphorylation
ITCH	“down-regulates quantity by destabilization”	JUNB	polyubiquitination
ITCH	“down-regulates quantity by destabilization”	ERBB4	ubiquitination
ITCH	“down-regulates quantity by destabilization”	EGFR	polyubiquitination

Protein complexes (CORUM) (9)

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

9 complexes by size:

Complex	Subunits	Members
CPSF6-EWSR1-ITCH-NUDT21-POLR2A-UBAP2L complex	6	CPSF6, EWSR1, ITCH, NUDT21, POLR2A, UBAP2L
CPSF6-ITCH-NUDT21-POLR2A-UBAP2L complex	5	CPSF6, ITCH, NUDT21, POLR2A, UBAP2L
CPSF6-ITCH-NUDT21-POLR2A complex	4	NUDT21, POLR2A, CPSF6, ITCH
ITCH-MAVS-PCBP2 complex	3	ITCH, MAVS, PCBP2
ITCH-MAP3K7-NDFIP1 complex	3	MAP3K7, NDFIP1, ITCH
ITCH-NDFIP1-UBE2L3 complex	3	ITCH, NDFIP1, UBE2L3
AIP4-DTX3L complex	2	ITCH, DTX3L
CYLD-ITCH complex	2	CYLD, ITCH
ITCH-USP9X complex	2	ITCH, USP9X

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
Clathrin-mediated endocytosis	6	17.6×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
DNA damage response	6	7.3×	1e-02

Disease & clinical

Genetic variants

Variant evidence for ITCH: 564 ClinVar records (25 pathogenic / likely pathogenic); 13 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	8
Uncertain significance	196
Likely benign	278
Benign	14

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 25 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
4391	NM_031483.7(ITCH):c.394dup (p.Ile132fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1028416	NM_031483.7(ITCH):c.2256G>A (p.Trp752Ter)	Pathogenic	criteria provided, single submitter	1
1456938	NM_031483.7(ITCH):c.2119C>T (p.Arg707Ter)	Pathogenic	criteria provided, single submitter	1
2116656	NM_031483.7(ITCH):c.2334del (p.Ile778fs)	Pathogenic	criteria provided, single submitter	1
2765211	NM_031483.7(ITCH):c.378_394del (p.Lys126fs)	Pathogenic	criteria provided, single submitter	1
2840554	NM_031483.7(ITCH):c.194G>A (p.Trp65Ter)	Pathogenic	criteria provided, single submitter	1
2842542	NM_031483.7(ITCH):c.1664G>A (p.Trp555Ter)	Pathogenic	criteria provided, single submitter	1
3670935	NM_031483.7(ITCH):c.361C>T (p.Gln121Ter)	Pathogenic	criteria provided, single submitter	1
4718472	NM_031483.7(ITCH):c.1300_1303del (p.Leu434fs)	Pathogenic	criteria provided, single submitter	1
4718475	NM_031483.7(ITCH):c.1737C>G (p.Tyr579Ter)	Pathogenic	criteria provided, single submitter	1
930463	NM_031483.7(ITCH):c.1952+3_1952+6del	Likely pathogenic	criteria provided, single submitter	1
1298868	NM_031483.7(ITCH):c.2004del (p.Glu669fs)	Likely pathogenic	criteria provided, single submitter	1
2070828	NM_031483.7(ITCH):c.1099_1140+38dup	Likely pathogenic	criteria provided, single submitter	1
2117941	NM_031483.7(ITCH):c.1569+1G>T	Likely pathogenic	criteria provided, single submitter	1
3064498	NM_031483.7(ITCH):c.3G>A (p.Met1Ile)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ITCH’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; 28 predictions of 2,806):

Position(s)	Effect	Δscore	Sites
20:34408646–34408648	acceptor_gain	1.0000	2
20:34408649–34408650	acceptor_loss	1.0000	5
20:34408775	donor_gain	1.0000
20:34408793–34408794	donor_loss	1.0000	5
20:34408802	donor_gain	1.0000
20:34413740	acceptor_loss	1.0000	2
20:34413880–34413881	donor_loss	1.0000	5
20:34442206	acceptor_gain	1.0000
20:34442304–34442305	donor_loss	1.0000	5
20:34445279	acceptor_gain	1.0000

AlphaMissense

2,967 missense substitutions predicted likely pathogenic (of 5,679 scored), across 614 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
M608	9	0.940	0.997
M566	9	0.916	0.992
M785	9	0.854	0.975
H869	8	0.999	1.000
D588	8	0.998	1.000
F612	8	0.998	1.000
H347	8	0.997	0.999
H634	8	0.997	0.999
D876	8	0.997	0.999
F638	8	0.996	1.000
H379	8	0.995	0.999
F872	8	0.995	1.000
D369	8	0.994	0.999
F659	8	0.994	1.000
D346	8	0.993	0.999
F558	8	0.992	0.998
F830	8	0.992	1.000
D378	8	0.991	1.000
F842	8	0.988	0.999
D676	8	0.987	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	5.27e-07
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9e-06
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	1.26e-05
Lung Squamous Cell Carcinoma (TCGA)	unfavorable	0.000169
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000848

Disease associations

OMIM: gene MIM:606409 | disease phenotypes: MIM:613385

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
syndromic multisystem autoimmune disease due to ITCH deficiency	Definitive	Autosomal recessive	6

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
syndromic multisystem autoimmune disease due to ITCH deficiency	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
COVID-19 research	green
DDG2P	green
Paediatric disorders	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Autoinflammatory disorders	amber

Mondo (1): syndromic multisystem autoimmune disease due to ITCH deficiency (MONDO:0013245)

Orphanet (1): Syndromic multisystem autoimmune disease due to Itch deficiency (Orphanet:228426)

HPO phenotypes

showing 60 of 66 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000453	Choanal atresia
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000767	Pectus excavatum
HP:0000821	Hypothyroidism
HP:0000872	Hashimoto thyroiditis
HP:0000954	Single transverse palmar crease
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001377	Limited elbow extension
HP:0001394	Cirrhosis
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001531	Failure to thrive in infancy
HP:0001744	Splenomegaly
HP:0001822	Hallux valgus
HP:0001876	Pancytopenia
HP:0001904	Autoimmune neutropenia
HP:0001971	Hypersplenism
HP:0001999	Abnormal facial shape
HP:0002007	Frontal bossing
HP:0002020	Gastroesophageal reflux
HP:0002028	Chronic diarrhea
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002242	Abnormal intestine morphology
HP:0002719	Recurrent infections
HP:0002720	Decreased circulating IgA concentration
HP:0002750	Delayed skeletal maturation
HP:0002938	Lumbar hyperlordosis
HP:0002960	Autoimmunity
HP:0003100	Slender long bone
HP:0003262	Anti-smooth muscle antibody positivity
HP:0003453	Antineutrophil antibody positivity
HP:0004322	Short stature
HP:0004482	Relative macrocephaly
HP:0004570	Increased vertebral height
HP:0005659	Thoracic kyphoscoliosis
HP:0006528	Chronic lung disease
HP:0006554	Acute hepatic failure
HP:0008872	Feeding difficulties in infancy
HP:0008947	Floppy infant
HP:0009765	Low hanging columella
HP:0011471	Gastrostomy tube feeding in infancy
HP:0011800	Midface retrusion
HP:0012115	Hepatitis
HP:0012385	Camptodactyly
HP:0025329	Anti-glutamic acid decarboxylase antibody positivity
HP:0025379	Anti-thyroid peroxidase antibody positivity

GWAS associations

13 associations:

Study	Trait	p-value
GCST008058_39	Estimated glomerular filtration rate	1e-35
GCST004785_56	Vitiligo	1e-19
GCST007876_74	Estimated glomerular filtration rate	7e-18
GCST006288_585	Heel bone mineral density	2e-14
GCST90000025_91	Appendicular lean mass	7e-13
GCST010142_10	Fish- and plant-related diet	8e-12
GCST006288_449	Heel bone mineral density	5e-10
GCST010135_6	Oily fish consumption	7e-9
GCST010140_32	Pork consumption	7e-9
GCST90020028_1926	Hip circumference adjusted for BMI	7e-9
GCST007856_79	Colorectal cancer or advanced adenoma	3e-7
GCST006288_425	Heel bone mineral density	2e-6
GCST008103_135	Bipolar disorder	3e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008111	diet measurement
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295925 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 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 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.19	Kd	6517	nM	CHEMBL5653589
5.19	ED50	6517	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 3 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	2148605: Binding affinity to human ITCH incubated for 45 mins by Kinobead based pull down assay	kd	6.5168	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	decreases expression, affects expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
torcetrapib	increases expression	1
abrine	increases expression	1
enzalutamide	affects expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	decreases expression, decreases reaction, increases expression, increases secretion, increases ubiquitination	1
Phenobarbital	affects expression	1
Thiram	increases expression	1
Zinc	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4133914	Binding	Inhibition of Itch (unknown origin) assessed as reduction in Itch-mediated ubiquitination in presence of E1 enzyme, E2 enzyme and ATP incubated for 20 mins by SDS-PAGE method	1,4-Naphthoquinones as inhibitors of Itch, a HECT domain-E3 ligase, and tumor growth suppressors in multiple myeloma. — *Eur J Med Chem*

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 1 finite cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1US	Abcam HeLa ITCH KO	Cancer cell line	Female
CVCL_B7MV	HeLa ITCH KO	Cancer cell line	Female
CVCL_E0FE	Ubigene HeLa ITCH KO	Cancer cell line	Female
CVCL_F5E0	EDITGENE ITCH Knockout HAP1 Cell Line	Cancer cell line	Male
CVCL_ST16	HAP1 ITCH (-)	Cancer cell line	Male
CVCL_ZI03	GM27898	Finite cell line	Female
CVCL_ZI04	GM27900	Transformed cell line	Female

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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