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:15358865, PubMed:11828324). 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). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (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). S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. 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). Protein modification; protein ubiquitination. Monomer. Interacts (via WW domains) with OCNL (PubMed:11782481). Interacts (via WW domains) with NOTCH1 (PubMed:10940313, PubMed:18628966). Interacts (via WW domains) JUN (PubMed:11828324). Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB (PubMed:11828324). Interacts with FYN; the interaction phosphorylates ITCH on Tyr-381 decreasing binding of JUNB (By similarity). Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity (PubMed:17592138). Interacts with NDFIP1 and NDFIP2; the interaction with NDFIP proteins activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (PubMed:11748237, PubMed:17137798, PubMed:25632008). Interacts with ARHGEF7 (By similarity). Interacts with RNF11 (By similarity). 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 (By similarity). Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation (By similarity). Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM (By similarity). Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct) (By similarity). Interacts with HGS (By similarity). Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2 (By similarity). Interacts (via WW domains) with TXNIP (via C-terminus) (By similarity). Interacts with p15 BID (PubMed:20392206). Interacts with ERBB4 (By similarity).Interacts with DTX1 (By similarity). Interacts with SPART (By similarity). Interacts with SNX9 and SNX18 (By similarity). Interacts (via its WW domains) with ATN1 (By similarity). Interacts (via WW domains) with SGK3 (By similarity). Interacts with CBLC (By similarity). Interacts with OTUD7B (By similarity). 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 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008). Interacts with MAPK8/JNK1 (PubMed:16446428). 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 (By similarity). Interacts (via WW domains) with ARRDC2 (By similarity). Interacts (via WW domains) with ARRDC3 (By similarity). Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353). (Microbial infection) Interacts with Epstein-Barr virus LMP2A. 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. Detected in uterus (at protein level) (PubMed:23146885). Widely expressed (PubMed:9462742). The WW domains mediate interaction with PPxY motif-containing proteins. 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). Monoubiquitinated. Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation. 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. Major form. It is uncertain whether Met-1 or Met-11 is the initiator. Truncated N-terminus.