Q96J02 · ITCH_HUMAN
- ProteinE3 ubiquitin-protein ligase Itchy homolog
- GeneITCH
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids903 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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).
Catalytic activity
Activity regulation
Activated by PI4K2A-binding (PubMed:23146885).
Inhibited by DTX3L-binding (PubMed:24790097).
Inhibited by N4BP1 binding (By similarity).
Pathway
Features
Showing features for active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Active site | 871 | Glycyl thioester intermediate | ||||
Sequence: C |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
The subsequence SGLIIPLTISGGSGPRPLNPVTQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTR, which contains the WW domain, shows transcriptional activator activity in a high-throughput recruitment assay.
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase Itchy homolog
- EC number
- Short namesItch
- Alternative names
Gene names
- Community suggested namesITCH
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ96J02
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Autoimmune disease, multisystem, with facial dysmorphism (ADMFD)
- Note
- DescriptionA disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.
- See alsoMIM:613385
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 343 | No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. | ||||
Sequence: Y → F | ||||||
Mutagenesis | 420 | Greatly reduced phosphorylation on T-cell stimulation and in the presence of FYN. Increased ITCH-mediated Ub conjugation and degradation of JUNB. | ||||
Sequence: Y → F | ||||||
Mutagenesis | 455 | No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. | ||||
Sequence: Y → F | ||||||
Mutagenesis | 871 | Loss of ubiquitin protein ligase activity. Results in altered endosomal sorting and reduced degradation of CXCR4. Unable to inhibit MAVS-induced activation of INFB. | ||||
Sequence: C → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 722 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, modified residue, modified residue (large scale data), chain.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Modified residue | 2 | UniProt | N-acetylserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 2 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Chain | PRO_0000120317 | 2-903 | UniProt | E3 ubiquitin-protein ligase Itchy homolog | |||
Sequence: SDSGSQLGSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPLTVIVTPVSKLHFRVWSHQTLKSDVLLGTAALDIYETLKSNNMKLEEVVVTLQLGGDKEPTETIGDLSICLDGLQLESEVVTNGETTCSENGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTGASQNDDGSRSKDETRVSTNGSDDPEDAGAGENRRVSGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSATSESDGSSTGSLPPTNTNTNTSEGATSGLIIPLTISGGSGPRPLNPVTQAPLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTLESVRNYEQWQLQRSQLQGAMQQFNQRFIYGNQDLFATSQSKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRSQGQLNEKPLPEGWEMRFTVDGIPYFVDHNRRTTTYIDPRTGKSALDNGPQIAYVRDFKAKVQYFRFWCQQLAMPQHIKITVTRKTLFEDSFQQIMSFSPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECDLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYARTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE | |||||||
Modified residue (large scale data) | 6 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 217 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 221 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 236 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 240 | UniProt | Phosphoserine; by MAPK8 | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 240 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 263 | UniProt | Phosphothreonine; by MAPK8 | ||||
Sequence: T | |||||||
Modified residue | 273 | UniProt | Phosphoserine; by MAPK8 | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 375 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 385 | UniProt | Phosphothreonine; by SGK3 | ||||
Sequence: T | |||||||
Modified residue | 420 | UniProt | Phosphotyrosine; by FYN | ||||
Sequence: Y | |||||||
Modified residue (large scale data) | 420 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 450 | UniProt | Phosphoserine; by SGK3 | ||||
Sequence: S |
Post-translational modification
Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation
Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation (PubMed:18718449, PubMed:23146885, PubMed:24790097).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Gene expression databases
Organism-specific databases
Interaction
Subunit
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 in 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).
Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353).
Interacts with ENTREP1; enhances the ubiquitination of CXCR4 by ITCH and its subsequent endocytosis (PubMed:34927784).
Binary interactions
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 1-115 | C2 | ||||
Sequence: MSDSGSQLGSMGSLTMKSQLQITVISAKLKENKKNWFGPSPYVEVTVDGQSKKTEKCNNTNSPKWKQPLTVIVTPVSKLHFRVWSHQTLKSDVLLGTAALDIYETLKSNNMKLEE | ||||||
Region | 197-301 | Disordered | ||||
Sequence: GFTGASQNDDGSRSKDETRVSTNGSDDPEDAGAGENRRVSGNNSPSLSNGGFKPSRPPRPSRPPPPTPRRPASVNGSPSATSESDGSSTGSLPPTNTNTNTSEGA | ||||||
Compositional bias | 206-230 | Basic and acidic residues | ||||
Sequence: DGSRSKDETRVSTNGSDDPEDAGAG | ||||||
Compositional bias | 233-247 | Polar residues | ||||
Sequence: RRVSGNNSPSLSNGG | ||||||
Compositional bias | 252-268 | Pro residues | ||||
Sequence: RPPRPSRPPPPTPRRPA | ||||||
Compositional bias | 269-301 | Polar residues | ||||
Sequence: SVNGSPSATSESDGSSTGSLPPTNTNTNTSEGA | ||||||
Domain | 326-359 | WW 1 | ||||
Sequence: APLPPGWEQRVDQHGRVYYVDHVEKRTTWDRPEP | ||||||
Domain | 358-391 | WW 2 | ||||
Sequence: EPLPPGWERRVDNMGRIYYVDHFTRTTTWQRPTL | ||||||
Region | 395-471 | Required for interaction with FYN | ||||
Sequence: RNYEQWQLQRSQLQGAMQQFNQRFIYGNQDLFATSQSKEFDPLGPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRS | ||||||
Domain | 438-471 | WW 3 | ||||
Sequence: GPLPPGWEKRTDSNGRVYFVNHNTRITQWEDPRS | ||||||
Domain | 478-511 | WW 4 | ||||
Sequence: KPLPEGWEMRFTVDGIPYFVDHNRRTTTYIDPRT | ||||||
Domain | 569-903 | HECT | ||||
Sequence: SPQDLRRRLWVIFPGEEGLDYGGVAREWFFLLSHEVLNPMYCLFEYAGKDNYCLQINPASYINPDHLKYFRFIGRFIAMALFHGKFIDTGFSLPFYKRILNKPVGLKDLESIDPEFYNSLIWVKENNIEECDLEMYFSVDKEILGEIKSHDLKPNGGNILVTEENKEEYIRMVAEWRLSRGVEEQTQAFFEGFNEILPQQYLQYFDAKELEVLLCGMQEIDLNDWQRHAIYRHYARTSKQIMWFWQFVKEIDNEKRMRLLQFVTGTCRLPVGGFADLMGSNGPQKFCIEKVGKENWLPRSHTCFNRLDLPPYKSYEQLKEKLLFAIEETEGFGQE | ||||||
Region | 574-583 | MAP kinase docking site | ||||
Sequence: RRRLWVIFPG |
Domain
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
Q96J02-1
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.
- Name1
- Length903
- Mass (Da)102,803
- Last updated2003-10-03 v2
- Checksum6777A2043C7B67BC
Q96J02-2
- Name2
- Differences from canonical
- 159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S
Q96J02-3
- Name3
Computationally mapped potential isoform sequences
There are 8 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A1W2PNZ8 | A0A1W2PNZ8_HUMAN | ITCH | 555 | ||
A0A590UK44 | A0A590UK44_HUMAN | ITCH | 779 | ||
A0A590UJQ1 | A0A590UJQ1_HUMAN | ITCH | 900 | ||
A0A590UJW8 | A0A590UJW8_HUMAN | ITCH | 830 | ||
A0A590UIY0 | A0A590UIY0_HUMAN | ITCH | 91 | ||
A0A590UJ55 | A0A590UJ55_HUMAN | ITCH | 73 | ||
A0A8V8TKI4 | A0A8V8TKI4_HUMAN | ITCH | 41 | ||
A0A8V8TKK4 | A0A8V8TKK4_HUMAN | ITCH | 866 |
Features
Showing features for alternative sequence, compositional bias, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_044732 | 1-110 | in isoform 3 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_008451 | 159-200 | in isoform 2 and isoform 3 | |||
Sequence: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S | ||||||
Compositional bias | 206-230 | Basic and acidic residues | ||||
Sequence: DGSRSKDETRVSTNGSDDPEDAGAG | ||||||
Compositional bias | 233-247 | Polar residues | ||||
Sequence: RRVSGNNSPSLSNGG | ||||||
Compositional bias | 252-268 | Pro residues | ||||
Sequence: RPPRPSRPPPPTPRRPA | ||||||
Compositional bias | 269-301 | Polar residues | ||||
Sequence: SVNGSPSATSESDGSSTGSLPPTNTNTNTSEGA | ||||||
Sequence conflict | 297 | in Ref. 3; BAG64996 | ||||
Sequence: T → I |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF095745 EMBL· GenBank· DDBJ | AAK39399.1 EMBL· GenBank· DDBJ | mRNA | ||
AB056663 EMBL· GenBank· DDBJ | BAB39389.1 EMBL· GenBank· DDBJ | mRNA | ||
AK304090 EMBL· GenBank· DDBJ | BAG64996.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315212 EMBL· GenBank· DDBJ | BAG37647.1 EMBL· GenBank· DDBJ | mRNA | ||
AL109923 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AL356299 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471077 EMBL· GenBank· DDBJ | EAW76272.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471077 EMBL· GenBank· DDBJ | EAW76274.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471077 EMBL· GenBank· DDBJ | EAW76276.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC006848 EMBL· GenBank· DDBJ | AAH06848.1 EMBL· GenBank· DDBJ | mRNA | ||
BC011571 EMBL· GenBank· DDBJ | AAH11571.1 EMBL· GenBank· DDBJ | mRNA | ||
AF038564 EMBL· GenBank· DDBJ | AAC04845.1 EMBL· GenBank· DDBJ | mRNA |