Itch
entrez
16396
canonical
uniprot
Q8C863
canonical
ensembl
ENSMUSG00000027598
resolver
ensp
ENSMUSP00000029126
resolver
ensp
ENSMUSP00000105307
resolver
genesymbol
Itch
resolver
uniprot
O54971
resolver
uniprot_entry
ITCH_MOUSE
resolver
uniprot_sec
O54971
resolver
activity_regulation
ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding (PubMed:25632008). Activated by PI4K2A-binding (By similarity). Inhibited by DTX3L-binding (By similarity). Inhibited by N4BP1 binding (PubMed:17592138). {ECO:0000250|UniProtKB:Q96J02, ECO:0000269|PubMed:17592138, ECO:0000269|PubMed:25632008}.
uniprot
proteins
amino_acid_sequence
MSDSGPQLDSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPLTVIVTPTSKLCFRVWSHQTLKSDVLLGTAGLDIYETLKSNNMKLEEVVMTLQLVGDKEPTETMGDLSVCLDGLQVEAEVVTNGETSCSESTTQNDDGCRTRDDTRVSTNGSEDPEVAASGENKRANGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSTNSDSDGSSTGSLPPTNTNVNTSTSEGATSGLIIPLTISGGSGPRPLNTVSQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQFNQRFIYGNQDLFATSQNKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPLPEGWEMRFTVDGIPYFVDHNRRATTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQQLAMPQHIKITVTRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECGLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYTRTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE
uniprot
proteins
disease_involvement
DISEASE: Note=Defects in Itch are the cause of the itchy phenotype which is an inflammatory and immunological condition characterized by inflammation in the lung and stomach, hyperplasia in lymphoid and hematopoietic cells and constant itching in the skin. {ECO:0000269|PubMed:9462742}.
uniprot
proteins
ec_number
2.3.2.26
uniprot
proteins
function
FUNCTION: 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:15358865, PubMed:16446428, PubMed:17592138, PubMed:18628966, PubMed:20392206, PubMed:25632008). It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (By similarity). Involved in the control of inflammatory signaling pathways (By similarity). Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (By similarity). Promotes the association of the complex after TNF stimulation (By similarity). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (By similarity). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (By similarity). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (By similarity). Regulates the transcriptional activity of several transcription factors involved in immune response (PubMed:11828324, PubMed:15358865). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (By similarity). Mediates JUN ubiquitination and degradation (PubMed:15358865). Mediates JUNB ubiquitination and degradation (PubMed:11828324, PubMed:15358865). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (PubMed:11828324). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (By similarity). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (By similarity). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (By similarity). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (By similarity). 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 (By similarity). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:18628966). Ubiquitinates SNX9 (By similarity). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (PubMed:25632008). 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 (By similarity). ITCH synthesizes 'Lys-63'-linked chains, while UBR5 is branching multiple 'Lys-48'-linked chains of substrate initially modified (By similarity). 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 (By similarity). Ubiquitinates NEDD9/HEF1, resulting in proteasomal degradation of NEDD9/HEF1 (By similarity). {ECO:0000250|UniProtKB:Q96J02, ECO:0000269|PubMed:11828324, ECO:0000269|PubMed:15358865, ECO:0000269|PubMed:16446428, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:25632008}.
uniprot
proteins
mass_dalton
98994
uniprot
proteins
mutagenesis
MUTAGEN 199; /note="S->A: No loss of MAPK8-mediated phosphorylation and no effect on ligase activity. Almost complete inactivation of ligase activity; when associated with A-232. Greatly reduced MAPK8-mediated phosphorylation; when associated with A-222 or A-232. Completely abolishes MAPK8-mediated phosphorylation; when associated with A-222 and A-232."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 199; /note="S->D: More sensitive to in vitro proteolysis."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 222; /note="T->A: No loss of MAPK8-mediated phosphorylation. Greatly reduced MAPK8-mediated phosphorylation; when associated with A-199 or A-232. Completely abolishes MAPK8-mediated phosphorylation; when associated with A-199 and A-232."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 222; /note="T->D: Inhibits in vitro interaction between ITCHHECT domain and PRR/WW motifs. More sensitive to in vitro proteolysis."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 232; /note="S->A: No loss of MAPK8-mediated phosphorylation and no effect on ligase activity. Almost complete inactivation of ligase activity; when associated with A-199. Greatly reduced MAPK8-mediated phosphorylation; when associated with A-199 or A-222. Completely abolishes MAPK8-mediated phosphorylation; when associated with A-199 and A-222."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 232; /note="S->D: More sensitive to in vitro proteolysis."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 535..540; /note="RRRLWV->AAALWA: Abolishes interaction with MAPK8."; /evidence="ECO:0000269|PubMed:16446428"; MUTAGEN 535..537; /note="RRR->AAA: Almost complete loss of interaction with MAPK8."; MUTAGEN 535..536; /note="RR->AA: Greatly decreased interaction with MAPK8 and ligase activity."; MUTAGEN 832; /note="C->A: Loss of ubiquitin protein ligase activity."; /evidence="ECO:0000269|PubMed:10940313
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:15358865, ECO:0000269|PubMed:16446428, ECO:0000269|PubMed:17592138, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:25632008}.
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. Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation. Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353). {ECO:0000269|PubMed:15358865, ECO:0000269|PubMed:16446428, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:26854353}.; PTM: Monoubiquitinated. Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation. {ECO:0000250|UniProtKB:Q96J02}.
uniprot
proteins
pubmed
10940313
uniprot
proteins
pubmed
11748237
uniprot
proteins
pubmed
11782481
uniprot
proteins
pubmed
11828324
uniprot
proteins
pubmed
15358865
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15971201
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16446428
uniprot
proteins
pubmed
17137798
uniprot
proteins
pubmed
17437719
uniprot
proteins
pubmed
17592138
uniprot
proteins
pubmed
18628966
uniprot
proteins
pubmed
20392206
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
23146885
uniprot
proteins
pubmed
25632008
uniprot
proteins
pubmed
26854353
uniprot
proteins
pubmed
9462742
uniprot
proteins
sequence_length
864
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side {ECO:0000250|UniProtKB:Q96J02}. Cytoplasm {ECO:0000250|UniProtKB:Q96J02}. Nucleus {ECO:0000250|UniProtKB:Q96J02}. Early endosome membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side {ECO:0000250|UniProtKB:Q96J02}. Endosome membrane {ECO:0000250|UniProtKB:Q96J02}; Peripheral membrane protein {ECO:0000250|UniProtKB:Q96J02}; Cytoplasmic side {ECO:0000250|UniProtKB:Q96J02}. Note=May be recruited to exosomes by NDFIP1. Localizes to plasma membrane upon CXCL12 stimulation where it co-localizes with CXCL4. Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4. {ECO:0000250|UniProtKB:Q96J02}.
uniprot
proteins