ITCH

Functionⁱ

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 (PubMed:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509). Involved in the control of inflammatory signaling pathways (PubMed:19131965). Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965). Promotes the association of the complex after TNF stimulation (PubMed:19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251). Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, PubMed:20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448). Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation (PubMed:16387660). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885). 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 (PubMed:14602072, PubMed:23146885). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940). Ubiquitinates SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).By similarity17 Publications

Catalytic activityⁱ

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆-ubiquitinyl-[acceptor protein]-L-lysine.15 Publications

Activity regulationⁱ

Activated by NDFIP1- and NDFIP2-binding (PubMed:25631046). Activated by PI4K2A-binding (PubMed:23146885). Inhibited by DTX3L-binding (PubMed:24790097). Inhibited by N4BP1 binding (By similarity).By similarity3 Publications

Pathwayⁱ: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.15 Publications
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Active siteⁱ	871	Glycyl thioester intermediatePROSITE-ProRule annotation		1

GO - Molecular functionⁱ

arrestin family protein binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 23886940
CXCR chemokine receptor binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 19116316
ligase activity Source: Ensembl
ribonucleoprotein complex binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 19881509
ubiquitin-like protein ligase binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 24790097
ubiquitin-like protein transferase activity Source: Reactome
ubiquitin protein ligase activity
Source: MGI
Inferred from direct assayⁱ
- 15678106
ubiquitin-protein transferase activity
Source: UniProtKB
Inferred from direct assayⁱ
- 17592138

View the complete GO annotation on QuickGO ...

GO - Biological processⁱ

apoptotic process Source: UniProtKB-KW
defense response to virus Source: UniProtKB-KW
inflammatory response
Source: UniProtKB
Non-traceable author statementⁱ
- 9462742
innate immune response Source: UniProtKB-KW
negative regulation of alpha-beta T cell proliferation Source: Ensembl
negative regulation of apoptotic process
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 20068034
negative regulation of defense response to virus
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 19881509
negative regulation of JNK cascade Source: BHF-UCL
negative regulation of NF-kappaB transcription factor activity Source: BHF-UCL
negative regulation of type I interferon production Source: Reactome
Notch signaling pathway Source: Reactome
nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
positive regulation of protein catabolic process Source: Ensembl
positive regulation of receptor catabolic process
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 24790097
positive regulation of T cell anergy Source: Ensembl
proteasome-mediated ubiquitin-dependent protein catabolic process Source: GO_Central
protein autoubiquitination
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 24790097
protein K29-linked ubiquitination
Source: UniProtKB
Inferred from direct assayⁱ
- 17028573
- 18628966
protein K48-linked ubiquitination
Source: UniProtKB
Inferred from direct assayⁱ
- 19881509
protein K63-linked ubiquitination
Source: UniProtKB
Inferred from direct assayⁱ
- 18718448
- 19592251
protein ubiquitination
Source: UniProtKB
Inferred from direct assayⁱ
- 17592138
- 25631046
regulation of cell growth
Source: UniProtKB
Non-traceable author statementⁱ
- 9462742
regulation of hematopoietic stem cell differentiation Source: Reactome
regulation of protein deubiquitination Source: BHF-UCL
ubiquitin-dependent protein catabolic process
Source: MGI
Inferred from direct assayⁱ
- 15678106
viral entry into host cell
Source: UniProtKB
Traceable author statementⁱ
- 12450395

View the complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	Transferase
Biological process	Antiviral defense, Apoptosis, Host-virus interaction, Immunity, Innate immunity, Ubl conjugation pathway

Enzyme and pathway databases

BRENDAⁱ	6.3.2.19 2681
Reactomeⁱ	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-8939236 RUNX1 regulates transcription of genes involved in differentiation of HSCs R-HSA-936440 Negative regulators of DDX58/IFIH1 signaling R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SignaLinkⁱ	Q96J02
SIGNORⁱ	Q96J02
UniPathwayⁱ	UPA00143

Names & Taxonomyⁱ

Protein namesⁱ	Recommended name: E3 ubiquitin-protein ligase Itchy homolog (EC:2.3.2.267 Publications) Short name: Itch Alternative name(s): Atrophin-1-interacting protein 4 Short name: AIP4 HECT-type E3 ubiquitin transferase Itchy homolog NFE2-associated polypeptide 1 Short name: NAPP1
Gene namesⁱ	Name:ITCH
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome 20

Organism-specific databases

EuPathDBⁱ	HostDB:ENSG00000078747.12
Human Gene Nomenclature Database More...HGNCⁱ	HGNC:13890 ITCH
MIMⁱ	606409 gene
neXtProtⁱ	NX_Q96J02

Keywords - Cellular componentⁱ

Cell membrane, Cytoplasm, Endosome, Membrane, Nucleus

Pathology & Biotechⁱ

Involvement in diseaseⁱ

Autoimmune disease, multisystem, with facial dysmorphism (ADMFD)1 Publication

The disease is caused by mutations affecting the gene represented in this entry.

Disease descriptionA disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	343	Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. 1 Publication	1
Mutagenesisⁱ	420	Y → F: Greatly reduced phosphorylation on T-cell stimulation and in the presence of FYN. Increased ITCH-mediated Ub conjugation and degradation of JUNB. 1 Publication	1
Mutagenesisⁱ	455	Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. 1 Publication	1
Mutagenesisⁱ	871	C → A: Loss of ubiquitin protein ligase activity. Results in altered endosomal sorting and reduced degradation of CXCR4. Unable to inhibit MAVS-induced activation of INFB. 5 Publications	1

Organism-specific databases

DisGeNET More...DisGeNETⁱ	83737
MalaCards human disease database More...MalaCardsⁱ	ITCH
MIMⁱ	613385 phenotype
Open Targets More...OpenTargetsⁱ	ENSG00000078747
Orphanetⁱ	228426 Syndromic multisystem autoimmune disease due to Itch deficiency
PharmGKBⁱ	PA29934

Polymorphism and mutation databases

BioMutaⁱ	ITCH
DMDMⁱ	37537897

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Initiator methionineⁱ		RemovedCombined sources
ChainⁱPRO_0000120317	2 – 903	E3 ubiquitin-protein ligase Itchy homologAdd BLAST		902

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Modified residueⁱ	2	N-acetylserineCombined sources	1
Modified residueⁱ	240	Phosphoserine; by MAPK8By similarity	1
Modified residueⁱ	263	Phosphothreonine; by MAPK8By similarity	1
Modified residueⁱ	273	Phosphoserine; by MAPK8By similarity	1
Modified residueⁱ	385	Phosphothreonine; by SGK31 Publication	1
Modified residueⁱ	420	Phosphotyrosine; by FYN1 Publication	1
Modified residueⁱ	450	Phosphoserine; by SGK31 Publication	1

Post-translational modificationⁱ

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 (By similarity). Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation.By similarity4 Publications

Monoubiquitinated (PubMed:19116316). Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation (PubMed:18718449, PubMed:23146885, PubMed:24790097).4 Publications

Keywords - PTMⁱ

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDⁱ	Q96J02
MaxQB - The MaxQuant DataBase More...MaxQBⁱ	Q96J02
PaxDbⁱ	Q96J02
PeptideAtlas More...PeptideAtlasⁱ	Q96J02
PRIDEⁱ	Q96J02
ProteomicsDBⁱ	76882 76883 [Q96J02-2]

PTM databases

iPTMnetⁱ	Q96J02
PhosphoSitePlusⁱ	Q96J02

Expressionⁱ

Tissue specificityⁱ

Widely expressed.

Gene expression databases

Bgeeⁱ	ENSG00000078747 Expressed in 217 organ(s), highest expression level in sperm
CleanExⁱ	HS_ITCH
ExpressionAtlasⁱ	Q96J02 baseline and differential
Genevisibleⁱ	Q96J02 HS

Organism-specific databases

Human Protein Atlas More...HPAⁱ	HPA021126 HPA049032

HPAⁱ

HPA021126
HPA049032

Interactionⁱ

Subunit structureⁱ

Monomer. Interacts (via WW domains) with OCNL (By similarity). Interacts (via WW domains) with NOTCH1 (By similarity). Interacts (via WW domains) with JUN (By similarity). Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB (PubMed:16387660). Interacts with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB (PubMed:16387660). Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interacts with ARHGEF7 (PubMed:17652093). Interacts with RNF11 (PubMed:14559117, PubMed:19131965). 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 (PubMed:11318614, PubMed:18718448). Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation (PubMed:19116316). Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct) (PubMed:24790097). Interacts with HGS (PubMed:14602072). Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2 (PubMed:19881509). Interacts (via WW domains) with TXNIP (via C-terminus) (PubMed:20068034). Interacts with p15 BID (PubMed:20392206). Interacts with ERBB4 (PubMed:20858735). Interacts with DTX1 (PubMed:17028573). Interacts with SPART (PubMed:19580544). Interacts with SNX9 and SNX18 (PubMed:20491914). Interacts (via its WW domains) with ATN1 (PubMed:9647693). Interacts (via WW domains) with SGK3 (PubMed:16888620). Interacts with CBLC (PubMed:12226085). Interacts with OTUD7B (PubMed:22179831). Interacts (via WW domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity and promotes ITCH catalytic activity (PubMed:23146885). Interacts with ARRDC4 (PubMed:23236378). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008). Interacts with MAPK8/JNK1 (By similarity). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); the interaction is direct and participates to the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor (PubMed:21191027, PubMed:23886940). Interacts (via WW domains) with ARRDC2 (PubMed:21191027). Interacts (via WW domains) with ARRDC3 (PubMed:21191027, PubMed:23886940).By similarity25 Publications

(Microbial infection) Interacts with Epstein-Barr virus LMP2A.1 Publication

(Microbial infection) Interacts with Human cytomegalovirus (HCMV) protein UL42; this interaction induces ubiquitination and degradation of ITCH.1 Publication

(Microbial infection) Interacts with Herpes simplex virus 2 protein UL56.1 Publication

Binary interactionsⁱ

With	Entry	#Exp.	IntAct	Notes
Bid	P70444	2	EBI-1564678,EBI-783400	From Mus musculus.
CYLD	Q9NQC7	3	EBI-1564678,EBI-2117940
ERBB4	Q15303	3	EBI-6672198,EBI-80371
ERBB4	Q15303-3	2	EBI-6672198,EBI-15692884
GLI1	P08151	4	EBI-1564678,EBI-308084
LMP2	P13285	3	EBI-1564678,EBI-7181113	From Epstein-Barr virus (strain B95-8).
N4BP1	O75113	3	EBI-1564678,EBI-5278391
Numb	Q9QZS3-2	2	EBI-1564678,EBI-3896014	From a different organism.
PI4K2A	Q9BTU6	5	EBI-1564678,EBI-3239392
RNF11	Q9Y3C5	2	EBI-1564678,EBI-396669
SGK3	Q96BR1	5	EBI-1564678,EBI-2801236
SNX9	Q9Y5X1	7	EBI-1564678,EBI-77848
TP53BP2	Q13625	2	EBI-1564678,EBI-77642
TP63	Q9H3D4	2	EBI-1564678,EBI-2337775
TP73	O15350	3	EBI-1564678,EBI-389606
TP73	O15350-1	5	EBI-1564678,EBI-389619
TP73	O15350-8	2	EBI-1564678,EBI-5651259

GO - Molecular functionⁱ

arrestin family protein binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 23886940
CXCR chemokine receptor binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 19116316
ubiquitin-like protein ligase binding
Source: UniProtKB
Inferred from physical interactionⁱ
- 24790097

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridⁱ	123747, 187 interactors
CORUMⁱ	Q96J02
Database of interacting proteins More...DIPⁱ	DIP-29849N
ELMⁱ	Q96J02
IntActⁱ	Q96J02, 40 interactors
Molecular INTeraction database More...MINTⁱ	Q96J02
STRINGⁱ	9606.ENSP00000363998

Structureⁱ

Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area

Feature key	Position(s)	DescriptionActions	Length
Beta strandⁱ	18 – 29	Combined sources	12
Beta strandⁱ	41 – 47	Combined sources	7
Beta strandⁱ	50 – 53	Combined sources	4
Beta strandⁱ	64 – 73	Combined sources	10
Beta strandⁱ	78 – 85	Combined sources	8
Beta strandⁱ	88 – 90	Combined sources	3
Beta strandⁱ	93 – 101	Combined sources	9
Helixⁱ	102 – 108	Combined sources	7
Turnⁱ	109 – 111	Combined sources	3
Beta strandⁱ	112 – 126	Combined sources	15
Beta strandⁱ	130 – 143	Combined sources	14
Beta strandⁱ	332 – 336	Combined sources	5
Beta strandⁱ	342 – 346	Combined sources	5
Turnⁱ	347 – 349	Combined sources	3
Beta strandⁱ	352 – 355	Combined sources	4
Beta strandⁱ	365 – 368	Combined sources	4
Beta strandⁱ	374 – 377	Combined sources	4
Beta strandⁱ	379 – 381	Combined sources	3
Beta strandⁱ	444 – 448	Combined sources	5
Beta strandⁱ	454 – 458	Combined sources	5
Turnⁱ	459 – 462	Combined sources	4
Beta strandⁱ	463 – 467	Combined sources	5
Helixⁱ	469 – 471	Combined sources	3
Beta strandⁱ	484 – 488	Combined sources	5
Beta strandⁱ	494 – 498	Combined sources	5
Turnⁱ	499 – 502	Combined sources	4
Beta strandⁱ	503 – 507	Combined sources	5
Turnⁱ	509 – 511	Combined sources	3
Helixⁱ	528 – 539	Combined sources	12
Turnⁱ	540 – 542	Combined sources	3
Beta strandⁱ	545 – 551	Combined sources	7
Beta strandⁱ	554 – 556	Combined sources	3
Helixⁱ	557 – 567	Combined sources	11
Helixⁱ	572 – 574	Combined sources	3
Beta strandⁱ	575 – 580	Combined sources	6
Helixⁱ	589 – 603	Combined sources	15
Turnⁱ	607 – 609	Combined sources	3
Beta strandⁱ	611 – 614	Combined sources	4
Beta strandⁱ	621 – 624	Combined sources	4
Helixⁱ	626 – 630	Combined sources	5
Helixⁱ	634 – 650	Combined sources	17
Helixⁱ	661 – 667	Combined sources	7
Helixⁱ	675 – 677	Combined sources	3
Turnⁱ	678 – 680	Combined sources	3
Helixⁱ	682 – 692	Combined sources	11
Helixⁱ	696 – 699	Combined sources	4
Beta strandⁱ	704 – 709	Combined sources	6
Beta strandⁱ	716 – 721	Combined sources	6
Helixⁱ	724 – 726	Combined sources	3
Turnⁱ	731 – 733	Combined sources	3
Helixⁱ	735 – 747	Combined sources	13
Helixⁱ	751 – 764	Combined sources	14
Helixⁱ	767 – 770	Combined sources	4
Helixⁱ	775 – 783	Combined sources	9
Helixⁱ	790 – 795	Combined sources	6
Beta strandⁱ	798 – 801	Combined sources	4
Helixⁱ	807 – 818	Combined sources	12
Helixⁱ	821 – 832	Combined sources	12
Helixⁱ	842 – 844	Combined sources	3
Beta strandⁱ	848 – 851	Combined sources	4
Beta strandⁱ	855 – 858	Combined sources	4
Beta strandⁱ	867 – 869	Combined sources	3
Helixⁱ	870 – 872	Combined sources	3
Beta strandⁱ	874 – 877	Combined sources	4
Helixⁱ	883 – 895	Combined sources	13

Show more details

3D structure databases

ProteinModelPortalⁱ	Q96J02
SMRⁱ	Q96J02
ModBaseⁱ	Search...
MobiDBⁱ	Search...

Miscellaneous databases

EvolutionaryTraceⁱ	Q96J02

EvolutionaryTraceⁱ

Q96J02

Family & Domainsⁱ

Domains and Repeats

Feature key	Position(s)	DescriptionActions	Length
Domainⁱ	5 – 99	C2PROSITE-ProRule annotationAdd BLAST	95
Domainⁱ	326 – 359	WW 1PROSITE-ProRule annotationAdd BLAST	34
Domainⁱ	358 – 391	WW 2PROSITE-ProRule annotationAdd BLAST	34
Domainⁱ	438 – 471	WW 3PROSITE-ProRule annotationAdd BLAST	34
Domainⁱ	478 – 511	WW 4PROSITE-ProRule annotationAdd BLAST	34
Domainⁱ	569 – 903	HECTPROSITE-ProRule annotationAdd BLAST	335

Region

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Regionⁱ	395 – 471	Required for interaction with FYN1 PublicationAdd BLAST		77
Regionⁱ	574 – 583	MAP kinase docking siteBy similarity		10

Compositional bias

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Compositional biasⁱ	252 – 267	Arg/Pro-rich (PRR domain)Add BLAST		16

Domainⁱ

The WW domains mediate interaction with PPxY motif-containing proteins.1 Publication

Keywords - Domainⁱ

Repeat

Phylogenomic databases

eggNOGⁱ	KOG0940 Eukaryota COG5021 LUCA
Ensembl GeneTree More...GeneTreeⁱ	ENSGT00760000118966
HOVERGENⁱ	HBG004134
InParanoidⁱ	Q96J02
KEGG Orthology (KO) More...KOⁱ	K05632
OMAⁱ	SLIWVKE
Database of Orthologous Groups More...OrthoDBⁱ	EOG091G0SS8
PhylomeDBⁱ	Q96J02
TreeFamⁱ	TF323658

Family and domain databases

Conserved Domains Database More...CDDⁱ	cd00078 HECTc, 1 hit cd00201 WW, 4 hits
Gene3Dⁱ	2.60.40.150, 1 hit
InterProⁱ	View protein in InterPro IPR000008 C2_dom IPR035892 C2_domain_sf IPR024928 E3_ub_ligase_SMURF1 IPR000569 HECT_dom IPR035983 Hect_E3_ubiquitin_ligase IPR001202 WW_dom IPR036020 WW_dom_sf
Pfam protein domain database More...Pfamⁱ	View protein in Pfam PF00168 C2, 1 hit PF00632 HECT, 1 hit PF00397 WW, 4 hits
PIRSFⁱ	PIRSF001569 E3_ub_ligase_SMURF1, 1 hit
SMARTⁱ	View protein in SMART SM00239 C2, 1 hit SM00119 HECTc, 1 hit SM00456 WW, 4 hits
SUPFAMⁱ	SSF51045 SSF51045, 4 hits SSF56204 SSF56204, 1 hit
PROSITEⁱ	View protein in PROSITE PS50004 C2, 1 hit PS50237 HECT, 1 hit PS01159 WW_DOMAIN_1, 4 hits PS50020 WW_DOMAIN_2, 4 hits

Sequences (3+)ⁱ

Sequence statusⁱ: Complete.

Sequence processingⁱ: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsⁱ produced by alternative splicing. Align Add to basket

This entry has 3 described isoforms and 2 potential isoforms that are computationally mapped.ⁱShow all

Isoform 1 (identifier: Q96J02-1) [UniParc]FASTA Add to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ 
        60         70         80         90        100
SKKTEKCNNT NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL 
       110        120        130        140        150
DIYETLKSNN MKLEEVVVTL QLGGDKEPTE TIGDLSICLD GLQLESEVVT 
       160        170        180        190        200
NGETTCSENG VSLCLPRLEC NSAISAHCNL CLPGLSDSPI SASRVAGFTG 
       210        220        230        240        250
ASQNDDGSRS KDETRVSTNG SDDPEDAGAG ENRRVSGNNS PSLSNGGFKP 
       260        270        280        290        300
SRPPRPSRPP PPTPRRPASV NGSPSATSES DGSSTGSLPP TNTNTNTSEG 
       310        320        330        340        350
ATSGLIIPLT ISGGSGPRPL NPVTQAPLPP GWEQRVDQHG RVYYVDHVEK 
       360        370        380        390        400
RTTWDRPEPL PPGWERRVDN MGRIYYVDHF TRTTTWQRPT LESVRNYEQW 
       410        420        430        440        450
QLQRSQLQGA MQQFNQRFIY GNQDLFATSQ SKEFDPLGPL PPGWEKRTDS 
       460        470        480        490        500
NGRVYFVNHN TRITQWEDPR SQGQLNEKPL PEGWEMRFTV DGIPYFVDHN 
       510        520        530        540        550
RRTTTYIDPR TGKSALDNGP QIAYVRDFKA KVQYFRFWCQ QLAMPQHIKI 
       560        570        580        590        600
TVTRKTLFED SFQQIMSFSP QDLRRRLWVI FPGEEGLDYG GVAREWFFLL 
       610        620        630        640        650
SHEVLNPMYC LFEYAGKDNY CLQINPASYI NPDHLKYFRF IGRFIAMALF 
       660        670        680        690        700
HGKFIDTGFS LPFYKRILNK PVGLKDLESI DPEFYNSLIW VKENNIEECD 
       710        720        730        740        750
LEMYFSVDKE ILGEIKSHDL KPNGGNILVT EENKEEYIRM VAEWRLSRGV 
       760        770        780        790        800
EEQTQAFFEG FNEILPQQYL QYFDAKELEV LLCGMQEIDL NDWQRHAIYR 
       810        820        830        840        850
HYARTSKQIM WFWQFVKEID NEKRMRLLQF VTGTCRLPVG GFADLMGSNG 
       860        870        880        890        900
PQKFCIEKVG KENWLPRSHT CFNRLDLPPY KSYEQLKEKL LFAIEETEGF 

GQE

Note: No experimental confirmation available.

Length:903

Mass (Da):102,803

Last modified:October 3, 2003 - v2

Checksum:ⁱ6777A2043C7B67BC

GO

Isoform 2 (identifier: Q96J02-2) [UniParc]FASTA Add to basket

The sequence of this isoform differs from the canonical sequence as follows:
159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S

« Hide

        10         20         30         40         50
MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ 
        60         70         80         90        100
SKKTEKCNNT NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL 
       110        120        130        140        150
DIYETLKSNN MKLEEVVVTL QLGGDKEPTE TIGDLSICLD GLQLESEVVT 
       160        170        180        190        200
NGETTCSESA SQNDDGSRSK DETRVSTNGS DDPEDAGAGE NRRVSGNNSP 
       210        220        230        240        250
SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSATSESD GSSTGSLPPT 
       260        270        280        290        300
NTNTNTSEGA TSGLIIPLTI SGGSGPRPLN PVTQAPLPPG WEQRVDQHGR 
       310        320        330        340        350
VYYVDHVEKR TTWDRPEPLP PGWERRVDNM GRIYYVDHFT RTTTWQRPTL 
       360        370        380        390        400
ESVRNYEQWQ LQRSQLQGAM QQFNQRFIYG NQDLFATSQS KEFDPLGPLP 
       410        420        430        440        450
PGWEKRTDSN GRVYFVNHNT RITQWEDPRS QGQLNEKPLP EGWEMRFTVD 
       460        470        480        490        500
GIPYFVDHNR RTTTYIDPRT GKSALDNGPQ IAYVRDFKAK VQYFRFWCQQ 
       510        520        530        540        550
LAMPQHIKIT VTRKTLFEDS FQQIMSFSPQ DLRRRLWVIF PGEEGLDYGG 
       560        570        580        590        600
VAREWFFLLS HEVLNPMYCL FEYAGKDNYC LQINPASYIN PDHLKYFRFI 
       610        620        630        640        650
GRFIAMALFH GKFIDTGFSL PFYKRILNKP VGLKDLESID PEFYNSLIWV 
       660        670        680        690        700
KENNIEECDL EMYFSVDKEI LGEIKSHDLK PNGGNILVTE ENKEEYIRMV 
       710        720        730        740        750
AEWRLSRGVE EQTQAFFEGF NEILPQQYLQ YFDAKELEVL LCGMQEIDLN 
       760        770        780        790        800
DWQRHAIYRH YARTSKQIMW FWQFVKEIDN EKRMRLLQFV TGTCRLPVGG 
       810        820        830        840        850
FADLMGSNGP QKFCIEKVGK ENWLPRSHTC FNRLDLPPYK SYEQLKEKLL 
       860 
FAIEETEGFG QE

Show »

Length:862

Mass (Da):98,676

Checksum:ⁱA3D960E7F4DBF9D3

GO

Isoform 3 (identifier: Q96J02-3) [UniParc]FASTA Add to basket

The sequence of this isoform differs from the canonical sequence as follows:
1-110: Missing.
159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S

« Hide

        10         20         30         40         50
MKLEEVVVTL QLGGDKEPTE TIGDLSICLD GLQLESEVVT NGETTCSESA 
        60         70         80         90        100
SQNDDGSRSK DETRVSTNGS DDPEDAGAGE NRRVSGNNSP SLSNGGFKPS 
       110        120        130        140        150
RPPRPSRPPP PTPRRPASVN GSPSATSESD GSSTGSLPPT NTNTNTSEGA 
       160        170        180        190        200
TSGLIIPLTI SGGSGPRPLN PVTQAPLPPG WEQRVDQHGR VYYVDHVEKR 
       210        220        230        240        250
TTWDRPEPLP PGWERRVDNM GRIYYVDHFT RTTTWQRPTL ESVRNYEQWQ 
       260        270        280        290        300
LQRSQLQGAM QQFNQRFIYG NQDLFATSQS KEFDPLGPLP PGWEKRTDSN 
       310        320        330        340        350
GRVYFVNHNT RITQWEDPRS QGQLNEKPLP EGWEMRFTVD GIPYFVDHNR 
       360        370        380        390        400
RTTTYIDPRT GKSALDNGPQ IAYVRDFKAK VQYFRFWCQQ LAMPQHIKIT 
       410        420        430        440        450
VTRKTLFEDS FQQIMSFSPQ DLRRRLWVIF PGEEGLDYGG VAREWFFLLS 
       460        470        480        490        500
HEVLNPMYCL FEYAGKDNYC LQINPASYIN PDHLKYFRFI GRFIAMALFH 
       510        520        530        540        550
GKFIDTGFSL PFYKRILNKP VGLKDLESID PEFYNSLIWV KENNIEECDL 
       560        570        580        590        600
EMYFSVDKEI LGEIKSHDLK PNGGNILVTE ENKEEYIRMV AEWRLSRGVE 
       610        620        630        640        650
EQTQAFFEGF NEILPQQYLQ YFDAKELEVL LCGMQEIDLN DWQRHAIYRH 
       660        670        680        690        700
YARTSKQIMW FWQFVKEIDN EKRMRLLQFV TGTCRLPVGG FADLMGSNGP 
       710        720        730        740        750
QKFCIEKVGK ENWLPRSHTC FNRLDLPPYK SYEQLKEKLL FAIEETEGFG 

QE

Note: No experimental confirmation available.

Show »

Length:752

Mass (Da):86,498

Checksum:ⁱB08AB68B285391F8

GO

Computationally mapped potential isoform sequencesⁱ

There are 2 potential isoforms mapped to this entry.BLAST Align Show all Add to basket

	Entry	Entry name		Protein names	Gene names	Length	Annotation
	A0A1W2PNZ8	A0A1W2PNZ8_HUMAN		E3 ubiquitin-protein ligase Itchy h... E3 ubiquitin-protein ligase Itchy homolog	ITCH	37	Annotation score:
	A0A1W2PR79	A0A1W2PR79_HUMAN		E3 ubiquitin-protein ligase Itchy h... E3 ubiquitin-protein ligase Itchy homolog	ITCH	158	Annotation score:

Experimental Info

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Sequence conflictⁱ	297	T → I in BAG64996 (PubMed:14702039).Curated		1

Alternative sequence

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Alternative sequenceⁱVSP_044732	1 – 110	Missing in isoform 3. 1 PublicationAdd BLAST		110
Alternative sequenceⁱVSP_008451	159 – 200	NGVSL…AGFTG → S in isoform 2 and isoform 3. 5 PublicationsAdd BLAST		42

Sequence databases

Select the link destinations: EMBLⁱ GenBankⁱ DDBJⁱ Links Updated	AF095745 mRNA Translation: AAK39399.1 AB056663 mRNA Translation: BAB39389.1 AK304090 mRNA Translation: BAG64996.1 AK315212 mRNA Translation: BAG37647.1 AL109923 Genomic DNA No translation available. AL356299 Genomic DNA No translation available. CH471077 Genomic DNA Translation: EAW76272.1 CH471077 Genomic DNA Translation: EAW76274.1 CH471077 Genomic DNA Translation: EAW76276.1 BC006848 mRNA Translation: AAH06848.1 BC011571 mRNA Translation: AAH11571.1 AF038564 mRNA Translation: AAC04845.1
The Consensus CDS (CCDS) project More...CCDSⁱ	CCDS13234.1 [Q96J02-2] CCDS58768.1 [Q96J02-1] CCDS58769.1 [Q96J02-3]
NCBI Reference Sequences More...RefSeqⁱ	NP_001244066.1, NM_001257137.2 [Q96J02-1] NP_001244067.1, NM_001257138.2 [Q96J02-3] NP_001311126.1, NM_001324197.1 [Q96J02-1] NP_001311127.1, NM_001324198.1 [Q96J02-2] NP_113671.3, NM_031483.6 [Q96J02-2] XP_016883578.1, XM_017028089.1 [Q96J02-1] XP_016883580.1, XM_017028091.1 [Q96J02-3]
UniGeneⁱ	Hs.632272

Genome annotation databases

Ensemblⁱ	ENST00000262650; ENSP00000262650; ENSG00000078747 [Q96J02-1] ENST00000374864; ENSP00000363998; ENSG00000078747 [Q96J02-2] ENST00000535650; ENSP00000445608; ENSG00000078747 [Q96J02-3]
GeneIDⁱ	83737
KEGGⁱ	hsa:83737
UCSC genome browser More...UCSCⁱ	uc002xak.3 human [Q96J02-1]

Keywords - Coding sequence diversityⁱ

Alternative splicing

Similar proteinsⁱ

100% Identity
90% Identity
50% Identity

Protein	Similar proteins		Species	Score	Length	Source
Q96J02-2	E3 ubiquitin-protein ligase		PANTR		862	UniRef100_K7BGN1
E3 ubiquitin-protein ligase		PANPA		862
Q96J02-3	E3 ubiquitin-protein ligase		PANTR		902	UniRef100_A0A2J8JYF3
E3 ubiquitin-protein ligase		PANTR		752

Protein	Similar proteins		Species	Score	Length	Source
Q96J02	E3 ubiquitin-protein ligase		NOMLE		905	UniRef90_Q96J02
E3 ubiquitin-protein ligase Itchy homolog (Fragment)		HUMAN		158
ITCH isoform 2 (Fragment)		PANTR		158
E3 ubiquitin-protein ligase		MACMU		903
E3 ubiquitin-protein ligase		MACFA		903
+14
Q96J02-2	E3 ubiquitin-protein ligase Itchy	)	MOUSE		864	UniRef90_Q8C863
E3 ubiquitin-protein ligase		PANTR		902
Isoform 3 of E3 ubiquitin-protein ligase Itchy homolog		HUMAN		752
E3 ubiquitin-protein ligase Itchy homolog isoform X1		PHYCD		901
E3 ubiquitin-protein ligase		MYODS		895
+193
Q96J02-3	E3 ubiquitin-protein ligase Itchy	)	MOUSE		864	UniRef90_Q8C863
E3 ubiquitin-protein ligase		PANTR		902
E3 ubiquitin-protein ligase Itchy homolog isoform X1		PHYCD		901
E3 ubiquitin-protein ligase		MYODS		895
E3 ubiquitin-protein ligase		RAT		882
+193

Protein	Similar proteins		Species	Score	Length	Source
Q96J02	E3 ubiquitin-protein ligase Itchy	)	MOUSE		864	UniRef50_Q96J02
E3 ubiquitin-protein ligase		NOMLE		905
E3 ubiquitin-protein ligase Itchy homolog (Fragment)		HUMAN		158
ITCH isoform 2 (Fragment)		PANTR		158
E3 ubiquitin-protein ligase		GORGO		903
+345

Entry informationⁱ

Entry nameⁱ	ITCH_HUMAN
Accessionⁱ	Q96J02Primary (citable) accession number: Q96J02 Secondary accession number(s): A6NEW4 Q9H4U5
Entry historyⁱ	Integrated into UniProtKB/Swiss-Prot:	October 3, 2003
	Last sequence update:	October 3, 2003
	Last modified:	September 12, 2018
	This is version 173 of the entry and version 2 of the sequence. See complete history.
Entry statusⁱ	Reviewed (UniProtKB/Swiss-Prot)
Annotation program	Chordata Protein Annotation Program
Disclaimer	Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousⁱ

Keywords - Technical termⁱ

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

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Supporting data

UniProtKB - Q96J02 (ITCH_HUMAN)

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E3 ubiquitin-protein ligase Itchy homolog

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<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section describes the metabolic pathway(s) associated with a protein.<p><a href='/help/pathway' target='_top'>More...</a></p>Pathwayi: protein ubiquitination

Sites

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

Enzyme and pathway databases

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

Organism-specific databases

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Plasma membrane

Endosome

Nucleus

Other locations

Cytosol

Endosome

Extracellular region or secreted

Nucleus

Plasma Membrane

Other locations

Keywords - Cellular componenti

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

Mutagenesis

Organism-specific databases

Polymorphism and mutation databases

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Amino acid modifications

Keywords - PTMi

Proteomic databases

PTM databases

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

Gene expression databases

Organism-specific databases

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

GO - Molecular functioni

Protein-protein interaction databases

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

3D structure databases

Miscellaneous databases

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

Domains and Repeats

Region

Compositional bias

Keywords - Domaini

Phylogenomic databases

Family and domain databases

Computationally mapped potential isoform sequencesi

Experimental Info

Alternative sequence

Sequence databases

Genome annotation databases

Keywords - Coding sequence diversityi

<p>This section provides general information on the entry.<p><a href='/help/entry_information_section' target='_top'>More...</a></p>Entry informationi

<p>This section contains any relevant information that doesn’t fit in any other defined sections<p><a href='/help/miscellaneous_section' target='_top'>More...</a></p>Miscellaneousi

Keywords - Technical termi

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Functionⁱ

Pathwayⁱ: protein ubiquitination

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Keywords - Cellular componentⁱ

Pathology & Biotechⁱ

PTM / Processingⁱ

Keywords - PTMⁱ

Expressionⁱ

Interactionⁱ

GO - Molecular functionⁱ

Structureⁱ

Family & Domainsⁱ

Keywords - Domainⁱ

Computationally mapped potential isoform sequencesⁱ

Keywords - Coding sequence diversityⁱ

Entry informationⁱ

Miscellaneousⁱ

Keywords - Technical termⁱ