ID:ITCH_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase Itchy homolog; Short=Itch; EC=6.3.2.-; AltName: Full=Atrophin-1-interacting protein 4; Short=AIP4; AltName: Full=NFE2-associated polypeptide 1; Short=NAPP1; 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. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. 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. 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. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation (By similarity). Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding (By similarity). PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Monomer (By similarity). Interacts (via its WW domains) with OCNL, NOTCH1 AND JUN. Interacts (via WW domain 2) with N4BP1; leading to inhibiting its E3 ubiquitin-protein ligase activity. Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB. 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. 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 with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB. Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation. 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, DTX1, SPG20, SNX9 and SNX18. Interacts (via its WW domains) with ATN1. Interacts with Epstein-Barr virus LMP2A. Interacts (via WW domains) with SGK3. INTERACTION: P08151:GLI1; NbExp=4; IntAct=EBI-1564678, EBI-308084; Q9QZS3-2:Numb (xeno); NbExp=2; IntAct=EBI-1564678, EBI-3896014; Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-1564678, EBI-396669; SUBCELLULAR LOCATION: Cell membrane. Cytoplasm (By similarity). Nucleus. Note=Associates with endocytic vesicles. May be recruited to exosomes by NDFIP1. TISSUE SPECIFICITY: Widely expressed. 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. PTM: Ubiquitinated; autopolyubiquitination with 'Lys-63' linkages which does not lead to protein degradation. DISEASE: Defects in ITCH are the cause of syndromic multisystem autoimmune disease (SMAD) [MIM:613385]. SMAD is characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut. SIMILARITY: Contains 1 C2 domain. SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. SIMILARITY: Contains 4 WW domains.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q96J02
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0004842 ubiquitin-protein transferase activity GO:0005515 protein binding GO:0016740 transferase activity GO:0016874 ligase activity GO:0019787 ubiquitin-like protein transferase activity GO:0043021 ribonucleoprotein complex binding GO:0044389 ubiquitin-like protein ligase binding GO:0045236 CXCR chemokine receptor binding GO:0061630 ubiquitin protein ligase activity GO:1990763 arrestin family protein binding
Biological Process: GO:0000209 protein polyubiquitination GO:0001558 regulation of cell growth GO:0002376 immune system process GO:0002669 positive regulation of T cell anergy GO:0006511 ubiquitin-dependent protein catabolic process GO:0006915 apoptotic process GO:0006954 inflammatory response GO:0007219 Notch signaling pathway GO:0016032 viral process GO:0016567 protein ubiquitination GO:0032088 negative regulation of NF-kappaB transcription factor activity GO:0032480 negative regulation of type I interferon production GO:0035519 protein K29-linked ubiquitination GO:0043066 negative regulation of apoptotic process GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0045087 innate immune response GO:0045732 positive regulation of protein catabolic process GO:0046329 negative regulation of JNK cascade GO:0046642 negative regulation of alpha-beta T cell proliferation GO:0046718 viral entry into host cell GO:0050687 negative regulation of defense response to virus GO:0051607 defense response to virus GO:0051865 protein autoubiquitination GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway GO:0070534 protein K63-linked ubiquitination GO:0070936 protein K48-linked ubiquitination GO:0090085 regulation of protein deubiquitination GO:1902036 regulation of hematopoietic stem cell differentiation GO:2000646 positive regulation of receptor catabolic process
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
