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. Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. Involved in the control of inflammatory signaling pathways. 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. Mediates JUN ubiquitination and degradation. Mediates JUNB ubiquitination and degradation. Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation. Involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity. Ubiquitinates PI4K2A and negatively regulates its catalytic activity. 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. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. Ubiquitinates SNX9. Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation. 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. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Widely expressed. 3 alternatively spliced human isoforms have been reported. Note: This description may include information from UniProtKB.
Protein type: EC 6.3.2.-; EC; Ligase; Ubiquitin conjugating system; Ubiquitin ligase
Chromosomal Location of mouse Ortholog: 2 H1|2 76.94 cM
Cellular Component:  cell cortex; cytoplasm; cytoplasmic vesicle; cytosol; early endosome; endosome; intracellular membrane-bounded organelle; membrane; nucleoplasm; nucleus; plasma membrane; protein-containing complex; ubiquitin ligase complex
Molecular Function:  arrestin family protein binding; CXCR chemokine receptor binding; ligase activity; protein binding; ribonucleoprotein complex binding; transferase activity; ubiquitin protein ligase activity; ubiquitin-like protein ligase binding; ubiquitin-protein transferase activity
Biological Process:  apoptotic process; CD4-positive, alpha-beta T cell proliferation; defense response to virus; immune system process; innate immune response; negative regulation of apoptotic process; negative regulation of CD4-positive, alpha-beta T cell proliferation; negative regulation of defense response to virus; negative regulation of JNK cascade; negative regulation of NF-kappaB transcription factor activity; positive regulation of protein catabolic process; positive regulation of receptor catabolic process; positive regulation of T cell anergy; proteasome-mediated ubiquitin-dependent protein catabolic process; protein autoubiquitination; protein catabolic process; protein K29-linked ubiquitination; protein K48-linked ubiquitination; protein K63-linked ubiquitination; protein monoubiquitination; protein polyubiquitination; protein ubiquitination; regulation of protein deubiquitination; T cell anergy; ubiquitin-dependent protein catabolic process
Reference #:  Q8C863 (UniProtKB)
Alt. Names/Synonyms: 6720481N21Rik; 8030492O04Rik; A130065M08; AIP4; C230047C07Rik; E3 ubiquitin protein ligase; E3 ubiquitin-protein ligase Itchy; HECT-type E3 ubiquitin transferase Itchy homolog; Itch; itchy, E3 ubiquitin protein ligase; KIAA4011; mKIAA4011; OTTMUSP00000017091; OTTMUSP00000017092
Gene Symbols: Itch
Molecular weight: 98,994 Da
Basal Isoelectric point: 5.93  Predict pI for various phosphorylation states
CST Pathways:  Apoptosis Regulation  |  NF-kB Signaling
Protein-Specific Antibodies, siRNAs or Recombinant Proteins from Cell Signaling Technology® Total Proteins
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Protein Structure Not Found.

Cross-references to other databases:  AlphaFold  |  STRING  |  Reactome  |  BioGPS  |  Pfam  |  RCSB PDB  |  ENZYME  |  Phospho3D  |  Phospho.ELM  |  NetworKIN  |  UniProtKB  |  Entrez-Gene  |  Ensembl Gene