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): 556 total — 17 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_031483

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: 28 — 21 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000262650, ENST00000374864, 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

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.

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

293 total, 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

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

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

269 targeting ITCH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-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

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)

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): Q96J02, A0A1W2PNZ8, A0A590UIY0, A0A590UJ55, A0A590UJQ1, A0A590UJW8, A0A590UK44, A0A8V8TKI4, A0A8V8TKK4

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 (96 total): strand 33, helix 23, 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.

PDB	Method	Resolution (Å)
5CQ2	X-RAY DIFFRACTION	1.4
5DZD	X-RAY DIFFRACTION	1.57
5DWS	X-RAY DIFFRACTION	1.65
5SXP	X-RAY DIFFRACTION	1.65
2NQ3	X-RAY DIFFRACTION	1.8
2P4R	X-RAY DIFFRACTION	2
4ROF	X-RAY DIFFRACTION	2.03
3TUG	X-RAY DIFFRACTION	2.27
5C7M	X-RAY DIFFRACTION	3.03
2DMV	SOLUTION NMR
2KYK	SOLUTION NMR
2YSF	SOLUTION NMR

Predicted structure (AlphaFold)

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

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): 871 (glycyl thioester intermediate)

Post-translational modifications (7): 2, 240, 263, 273, 385, 420, 450

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
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

Function

Pathways and Gene Ontology

Reactome pathways

36 pathways

ID	Pathway
R-HSA-1253288	Downregulation of ERBB4 signaling
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1236394	Signaling by ERBB4
R-HSA-1280218	Adaptive Immune System
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-1980143	Signaling by NOTCH1
R-HSA-212436	Generic Transcription Pathway
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5218859	Regulated Necrosis
R-HSA-5357801	Programmed Cell Death
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
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 (45): regulation of cell growth (GO:0001558), positive regulation of T cell anergy (GO:0002669), T cell anergy (GO:0002870), 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), CD4-positive, alpha-beta T cell proliferation (GO:0035739), 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), positive regulation of protein catabolic process (GO:0045732), 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), negative regulation of CD4-positive, alpha-beta T cell proliferation (GO:2000562), positive regulation of receptor catabolic process (GO:2000646), protein polyubiquitination (GO:0000209), immune system process (GO:0002376), negative regulation of immune system process (GO:0002683), positive regulation of immune system process (GO:0002684), cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), response to oxidative stress (GO:0006979), positive regulation of catabolic process (GO:0009896), regulation of gene expression (GO:0010468)

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 (16): 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), endosome (GO:0005768), early endosome (GO:0005769), endosome membrane (GO:0010008), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-15 pathways:

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

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
protein ubiquitination	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
positive regulation of T cell tolerance induction	1
regulation of T cell anergy	1
T cell anergy	1
positive regulation of lymphocyte anergy	1
lymphocyte anergy	1
T cell tolerance induction	1
modification-dependent protein catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	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
CD4-positive, alpha-beta T cell activation	1
alpha-beta T cell proliferation	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

Protein interactions and networks

STRING

2500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITCH	RNF11	Q9Y3C5	978
ITCH	TAX1BP1	Q86VP1	909
ITCH	CYLD	Q9NQC7	870
ITCH	PCBP2	Q15366	864
ITCH	NUMBL	Q9Y6R0	815
ITCH	NUMB	P49757	815
ITCH	JUN	P05412	742
ITCH	YOD1	Q5VVQ6	715
ITCH	NDFIP1	Q9BT67	669
ITCH	LATS1	O95835	646
ITCH	ATN1	P54259	631
ITCH	ARRB2	P32121	618
ITCH	FOXO3	O43524	606
ITCH	CDC34	P49427	594
ITCH	STAMBP	O95630	594

IntAct

262 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
ARRDC3	ITCH	psi-mi:“MI:0915”(physical association)	0.820
GRAP2	STAMBP	psi-mi:“MI:0914”(association)	0.810
ITCH	ARRDC1	psi-mi:“MI:0915”(physical association)	0.800
ARRDC3	WWP2	psi-mi:“MI:0914”(association)	0.770
ITCH	TP73	psi-mi:“MI:0914”(association)	0.750
TP73	ITCH	psi-mi:“MI:0407”(direct interaction)	0.750
ITCH	TP73	psi-mi:“MI:0407”(direct interaction)	0.750
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.740
ITCH	ENTREP1	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ITCH	TMEM51	psi-mi:“MI:0407”(direct interaction)	0.690
ADRB2	ARRDC3	psi-mi:“MI:0914”(association)	0.680
SARAF	ITCH	psi-mi:“MI:0914”(association)	0.670
SARAF	ITCH	psi-mi:“MI:0915”(physical association)	0.670
SPART	ITCH	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640

BioGRID (826): ITCH (Affinity Capture-Western), ITCH (Affinity Capture-Western), ITCH (Biochemical Activity), UBE2L3 (Reconstituted Complex), ITCH (Affinity Capture-Western), ITCH (Biochemical Activity), UBE2D2 (Reconstituted Complex), Pi4k2a (Affinity Capture-Western), Pi4k2a (Biochemical Activity), ITCH (Biochemical Activity), Pi4k2a (Reconstituted Complex), ITCH (Protein-peptide), ITCH (Biochemical Activity), ITCH (Affinity Capture-Western), RASSF5 (Reconstituted Complex)

ESM2 similar proteins: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4GEU5, B8N7E5, G0S9J5, G5ECY0, H2L056, O00308, O14326, O42643, P10823, P39055, P39940, P46935, Q0CCL1, Q2TAS2, Q2UBP1, Q45FX5, Q4WTF3, Q5BDP1, Q5RBF2, Q5RD78, Q5U5R9, Q62940, Q757T0, Q8BZZ3, Q8C863, Q8CFI0, Q92462, Q96J02, Q96PU5, Q9CUN6, Q9DBH0, Q9H0M0, Q9HAU4, Q9HCE7

Diamond homologs: A0A096LPI5, A6NIU2, A6NJG6, F2Z398, P0DTE4, P51957, Q09FC8, Q5H9K5, Q5T7P6, Q68CZ1, Q6B4Z3, Q6UX73, Q86U02, Q8IV13, Q8N7M2, Q8N9N2, Q8NDZ0, Q8NEM8, Q8TDM0, Q92918, Q96J02, Q96MD7, Q9BUA6, Q9NXG0, A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5

SIGNOR signaling

49 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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 151 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
Regulation of PTEN stability and activity	5	9.9×	9e-03
RHOQ GTPase cycle	5	9.8×	9e-03
Ub-specific processing proteases	9	5.1×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein tetramerization	5	24.2×	9e-04
ubiquitin-dependent protein catabolic process	12	6.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	8
Uncertain significance	197
Likely benign	271
Benign	17

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1028416	NM_031483.7(ITCH):c.2256G>A (p.Trp752Ter)	Pathogenic
1456938	NM_031483.7(ITCH):c.2119C>T (p.Arg707Ter)	Pathogenic
2116656	NM_031483.7(ITCH):c.2334del (p.Ile778fs)	Pathogenic
2426982	NC_000020.10:g.(?33057833)(33077751_?)del	Pathogenic
2765211	NM_031483.7(ITCH):c.378_394del (p.Lys126fs)	Pathogenic
2840554	NM_031483.7(ITCH):c.194G>A (p.Trp65Ter)	Pathogenic
2842542	NM_031483.7(ITCH):c.1664G>A (p.Trp555Ter)	Pathogenic
3248292	NC_000020.10:g.(?32981618)(33095599_?)del	Pathogenic
3248293	NC_000020.10:g.(?32981618)(32981707_?)del	Pathogenic
3670935	NM_031483.7(ITCH):c.361C>T (p.Gln121Ter)	Pathogenic
4391	NM_031483.7(ITCH):c.394dup (p.Ile132fs)	Pathogenic
4718472	NM_031483.7(ITCH):c.1300_1303del (p.Leu434fs)	Pathogenic
4718475	NM_031483.7(ITCH):c.1737C>G (p.Tyr579Ter)	Pathogenic
832691	NC_000020.11:g.(?34457370)(34457494_?)del	Pathogenic
929409	NM_031483.7(ITCH):c.1954G>T (p.Glu652Ter)	Pathogenic
977646	NM_031483.7(ITCH):c.603del (p.Leu202fs)	Pathogenic
977647	NM_031483.7(ITCH):c.2005_2008del (p.Glu669fs)	Pathogenic
1298868	NM_031483.7(ITCH):c.2004del (p.Glu669fs)	Likely pathogenic
2070828	NM_031483.7(ITCH):c.1099_1140+38dup	Likely pathogenic
2117941	NM_031483.7(ITCH):c.1569+1G>T	Likely pathogenic
2426984	NC_000020.10:g.(?33044890)(33049935_?)del	Likely pathogenic
3064498	NM_031483.7(ITCH):c.3G>A (p.Met1Ile)	Likely pathogenic
4717903	NM_031483.7(ITCH):c.2214+1G>T	Likely pathogenic
4718712	NM_031483.7(ITCH):c.337+1G>A	Likely pathogenic
930463	NM_031483.7(ITCH):c.1952+3_1952+6del	Likely pathogenic

SpliceAI

4972 predictions. Top by Δscore:

Variant	Effect	Δscore
20:34369443:G:GT	donor_gain	1.0000
20:34392915:G:GG	donor_gain	1.0000
20:34408646:C:G	acceptor_gain	1.0000
20:34408646:CATA:C	acceptor_loss	1.0000
20:34408647:A:AG	acceptor_gain	1.0000
20:34408648:T:G	acceptor_gain	1.0000
20:34408649:A:AC	acceptor_loss	1.0000
20:34408649:A:AG	acceptor_gain	1.0000
20:34408650:G:GG	acceptor_gain	1.0000
20:34408650:GT:G	acceptor_gain	1.0000
20:34408650:GTC:G	acceptor_gain	1.0000
20:34408650:GTCA:G	acceptor_gain	1.0000
20:34408650:GTCAT:G	acceptor_gain	1.0000
20:34408766:TCCC:T	donor_gain	1.0000
20:34408773:TGG:T	donor_gain	1.0000
20:34408775:G:GT	donor_gain	1.0000
20:34408775:G:T	donor_gain	1.0000
20:34408791:GT:G	donor_gain	1.0000
20:34408792:TG:T	donor_loss	1.0000
20:34408793:G:GG	donor_gain	1.0000
20:34408793:GTAA:G	donor_loss	1.0000
20:34408802:G:GT	donor_gain	1.0000
20:34408802:G:T	donor_gain	1.0000
20:34412513:A:AG	acceptor_gain	1.0000
20:34412514:G:GG	acceptor_gain	1.0000
20:34412514:GTATC:G	acceptor_gain	1.0000
20:34412640:GTAT:G	donor_gain	1.0000
20:34412644:GTAT:G	donor_gain	1.0000
20:34413739:CA:C	acceptor_loss	1.0000
20:34413740:A:AG	acceptor_gain	1.0000

AlphaMissense

5679 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:34393870:T:C	L20P	1.000
20:34408773:T:A	W65R	1.000
20:34408773:T:C	W65R	1.000
20:34408775:G:C	W65C	1.000
20:34408775:G:T	W65C	1.000
20:34412520:T:A	V73D	1.000
20:34442209:T:A	W332R	1.000
20:34442209:T:C	W332R	1.000
20:34442211:G:C	W332C	1.000
20:34442211:G:T	W332C	1.000
20:34442220:A:C	R335S	1.000
20:34442220:A:T	R335S	1.000
20:34442242:T:G	Y343D	1.000
20:34442249:T:A	V345E	1.000
20:34442275:T:A	W354R	1.000
20:34442275:T:C	W354R	1.000
20:34442277:G:C	W354C	1.000
20:34442277:G:T	W354C	1.000
20:34445288:T:A	W364R	1.000
20:34445288:T:C	W364R	1.000
20:34445289:G:C	W364S	1.000
20:34445290:G:C	W364C	1.000
20:34445290:G:T	W364C	1.000
20:34445298:G:C	R367P	1.000
20:34445316:G:C	R373P	1.000
20:34445321:T:G	Y375D	1.000
20:34445324:T:G	Y376D	1.000
20:34445328:T:A	V377D	1.000
20:34445331:A:T	D378V	1.000
20:34445354:T:A	W386R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001160 (20:34497092 G>A,C), RS1000001340 (20:34429765 T>G), RS1000032085 (20:34438888 A>G), RS1000033101 (20:34475879 T>TA), RS1000047566 (20:34483207 T>C,G), RS1000148321 (20:34395025 A>T), RS1000157042 (20:34477205 G>A), RS1000169813 (20:34460816 T>A), RS1000175083 (20:34391651 G>A,T), RS1000179832 (20:34467526 A>T), RS1000183992 (20:34382891 G>A), RS1000249900 (20:34445700 A>C,G), RS1000277676 (20:34470819 A>G), RS1000280957 (20:34421007 T>C), RS1000319723 (20:34388968 T>G)

Disease associations

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

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (1)

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

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

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

66 total (30 of 66 shown, 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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST004785_56	Vitiligo	1.000000e-19
GCST006288_408	Heel bone mineral density	5.000000e-10
GCST006288_685	Heel bone mineral density	2.000000e-14
GCST006288_84	Heel bone mineral density	2.000000e-06
GCST007856_83	Colorectal cancer or advanced adenoma	3.000000e-07
GCST007876_125	Estimated glomerular filtration rate	7.000000e-18
GCST008058_171	Estimated glomerular filtration rate	1.000000e-35
GCST008103_149	Bipolar disorder	3.000000e-06
GCST010135_33	Oily fish consumption	7.000000e-09
GCST010140_23	Pork consumption	7.000000e-09
GCST010142_10	Fish- and plant-related diet	8.000000e-12
GCST90000025_641	Appendicular lean mass	7.000000e-13
GCST90020028_1626	Hip circumference adjusted for BMI	7.000000e-09

EFO canonical traits (4, from GWAS)

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 (VIP=true, CPIC=false)

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	affects expression, decreases 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	increases expression, increases secretion, increases ubiquitination, decreases expression, decreases reaction	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

6 cell lines: 4 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_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)

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