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ITCH 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. 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. Monomer Interacts (via its WW domains) with OCNL, NOTCH1 AND JUN. 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. 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 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. Widely expressed. 2 isoforms of the human protein are produced by alternative splicing. Note: This description may include information from UniProtKB.
Protein type: EC 6.3.2.-; EC; Ligase; Ubiquitin conjugating system; Ubiquitin ligase
Chromosomal Location of Human Ortholog: 20q11.22
Cellular Component: cytoplasm; cytosol; membrane; nucleoplasm; plasma membrane
Molecular Function: CXCR chemokine receptor binding; protein binding; ribonucleoprotein binding; small conjugating protein ligase activity; ubiquitin-protein ligase activity
Biological Process: entry of virus into host cell; inhibition of NF-kappaB transcription factor; negative regulation of apoptosis; negative regulation of defense response to virus; negative regulation of interferon type I production; negative regulation of JNK cascade; Notch signaling pathway; proteasomal ubiquitin-dependent protein catabolic process; protein ubiquitination; protein ubiquitination during ubiquitin-dependent protein catabolic process; ubiquitin-dependent protein catabolic process
Disease: Autoimmune Disease, Multisystem, With Facial Dysmorphism
Reference #:  Q96J02 (UniProtKB)
Alt. Names/Synonyms: AIF4; AIP4; atrophin-1 interacting protein 4; Atrophin-1-interacting protein 4; dJ468O1.1; dJ468O1.1 (atrophin 1 interacting protein 4 (AIP4)); E3 ubiquitin-protein ligase Itchy homolog; ITCH; itchy E3 ubiquitin protein ligase homolog (mouse); itchy homolog E3 ubiquitin protein ligase; NAPP1; NFE2-associated polypeptide 1; ubiquitin protein ligase ITCH
Gene Symbols: ITCH
Molecular weight: 102,803 Da
Basal Isoelectric point: 5.94  Predict pI for various phosphorylation states
CST Pathways:  Apoptosis Regulation  |  NF-kB Signaling
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