ITCH
entrez
83737
canonical
uniprot
Q96J02
canonical
ensembl
ENSG00000078747
resolver
ensembl
ENSG00000289720
resolver
ensp
ENSP00000262650
resolver
ensp
ENSP00000363998
resolver
ensp
ENSP00000445608
resolver
ensp
ENSP00000499786
resolver
ensp
ENSP00000554312
resolver
ensp
ENSP00000682732
resolver
genesymbol
ITCH
resolver
hgnc
HGNC:13890
resolver
uniprot
A6NEW4
resolver
uniprot
B4E234
resolver
uniprot
E1P5P3
resolver
uniprot
F5H217
resolver
uniprot
O43584
resolver
uniprot
Q5QP37
resolver
uniprot
Q5TEL0
resolver
uniprot
Q96F66
resolver
uniprot
Q9BY75
resolver
uniprot
Q9H451
resolver
uniprot
Q9H4U5
resolver
uniprot_entry
ITCH_HUMAN
resolver
uniprot_sec
A6NEW4
resolver
uniprot_sec
B4E234
resolver
uniprot_sec
E1P5P3
resolver
uniprot_sec
F5H217
resolver
uniprot_sec
O43584
resolver
uniprot_sec
Q5QP37
resolver
uniprot_sec
Q5TEL0
resolver
uniprot_sec
Q96F66
resolver
uniprot_sec
Q9BY75
resolver
uniprot_sec
Q9H451
resolver
uniprot_sec
Q9H4U5
resolver
activity_regulation
ACTIVITY REGULATION: 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). {ECO:0000250|UniProtKB:Q8C863, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046}.
uniprot
proteins
amino_acid_sequence
MSDSGSQLGSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPLTVIVTPVSKLHFRVWSHQTLKSDVLLGTAALDIYETLKSNNMKLEEVVVTLQLGGDKEPTETIGDLSICLDGLQLESEVVTNGETTCSENGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTGASQNDDGSRSKDETRVSTNGSDDPEDAGAGENRRVSGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSATSESDGSSTGSLPPTNTNTNTSEGATSGLIIPLTISGGSGPRPLNPVTQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQFNQRFIYGNQDLFATSQSKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPLPEGWEMRFTVDGIPYFVDHNRRTTTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQQLAMPQHIKITVTRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECDLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYARTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE
uniprot
proteins
disease_involvement
DISEASE: 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. {ECO:0000269|PubMed:20170897}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
2.3.2.26
uniprot
proteins
function
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 (PubMed:11046148, PubMed:14602072, PubMed:15051726, PubMed:16387660, PubMed:17028573, PubMed:18718448, PubMed:18718449, PubMed:19116316, PubMed:19592251, PubMed:19881509, PubMed:20068034, PubMed:20392206, PubMed:20491914, 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, PubMed:34927784). 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). 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 (PubMed:20068034, PubMed:29378950). ITCH synthesizes 'Lys-63'-linked chains, while UBR5 is branching multiple 'Lys-48'-linked chains of substrate initially modified (PubMed:29378950). 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). 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 (PubMed:30328013). Ubiquitinates NEDD9/HEF1, resulting in proteasomal degradation of NEDD9/HEF1 (PubMed:15051726). {ECO:0000250|UniProtKB:Q8C863, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:15051726, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046, ECO:0000269|PubMed:29378950, ECO:0000269|PubMed:30328013}.
uniprot
proteins
mass_dalton
102803
uniprot
proteins
mutagenesis
MUTAGEN 343; /note="Y->F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN."; /evidence="ECO:0000269|PubMed:16387660"; MUTAGEN 420; /note="Y->F: Greatly reduced phosphorylation on T-cell stimulation and in the presence of FYN. Increased ITCH-mediated Ub conjugation and degradation of JUNB."; /evidence="ECO:0000269|PubMed:16387660"; MUTAGEN 455; /note="Y->F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN."; /evidence="ECO:0000269|PubMed:16387660"; MUTAGEN 871; /note="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."; /evidence="ECO:0000269|PubMed:11046148, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046, ECO:0000269|PubMed:29378950}.
uniprot
proteins
post_translational_modification
PTM: 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. {ECO:0000250, ECO:0000269|PubMed:12226085, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16888620, ECO:0000269|PubMed:18718449}.; PTM: Monoubiquitinated (PubMed:19116316). Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation (PubMed:18718449, PubMed:23146885, PubMed:24790097). {ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097}.
uniprot
proteins
pubmed
11046148
uniprot
proteins
pubmed
11318614
uniprot
proteins
pubmed
11780052
uniprot
proteins
pubmed
12226085
uniprot
proteins
pubmed
14559117
uniprot
proteins
pubmed
14602072
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15051726
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16387660
uniprot
proteins
pubmed
16888620
uniprot
proteins
pubmed
17028573
uniprot
proteins
pubmed
17652093
uniprot
proteins
pubmed
18628966
uniprot
proteins
pubmed
18718448
uniprot
proteins
pubmed
18718449
uniprot
proteins
pubmed
18819914
uniprot
proteins
pubmed
19116316
uniprot
proteins
pubmed
19131965
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19580544
uniprot
proteins
pubmed
19592251
uniprot
proteins
pubmed
19881509
uniprot
proteins
pubmed
20068034
uniprot
proteins
pubmed
20170897
uniprot
proteins
pubmed
20392206
uniprot
proteins
pubmed
20491914
uniprot
proteins
pubmed
20682038
uniprot
proteins
pubmed
20858735
uniprot
proteins
pubmed
21191027
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22179831
uniprot
proteins
pubmed
22778262
uniprot
proteins
pubmed
23146885
uniprot
proteins
pubmed
23236378
uniprot
proteins
pubmed
23886940
uniprot
proteins
pubmed
24790097
uniprot
proteins
pubmed
25631046
uniprot
proteins
pubmed
25632008
uniprot
proteins
pubmed
26555021
uniprot
proteins
pubmed
26854353
uniprot
proteins
pubmed
27489272
uniprot
proteins
pubmed
27912080
uniprot
proteins
pubmed
29378950
uniprot
proteins
pubmed
29535361
uniprot
proteins
pubmed
30328013
uniprot
proteins
pubmed
34927784
uniprot
proteins
pubmed
9647693
uniprot
proteins
sequence_length
903
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14602072}; Peripheral membrane protein {ECO:0000305|PubMed:14602072}; Cytoplasmic side {ECO:0000305|PubMed:14602072}. Cytoplasm {ECO:0000269|PubMed:14602072}. Nucleus {ECO:0000269|PubMed:20858735}. Early endosome membrane {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097}; Peripheral membrane protein {ECO:0000305|PubMed:14602072, ECO:0000305|PubMed:23146885, ECO:0000305|PubMed:24790097}; Cytoplasmic side {ECO:0000305|PubMed:14602072, ECO:0000305|PubMed:23146885, ECO:0000305|PubMed:24790097}. Endosome membrane {ECO:0000269|PubMed:23146885}; Peripheral membrane protein {ECO:0000305|PubMed:23146885}; Cytoplasmic side {ECO:0000305|PubMed:23146885}. Note=May be recruited to exosomes by NDFIP1 (PubMed:18819914). Localizes to plasma membrane upon CXCL12 stimulation where it co-localizes with CXCL4 (PubMed:14602072). Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4 (PubMed:24790097). {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:18819914, ECO:0000269|PubMed:24790097}.
uniprot
proteins