E3 ubiquitin-protein ligase Itchy homolog; Itch; atrophin-1-interacting protein 4; AIP4; NFE2-associated polypeptide 1; NAPP1 (ITCH)

Function: - E3 ubiquitin-protein ligase - catalyzes Lys-29-, Lys-48- & Lys-63-linked ubiquitin conjugation - involved in the control of inflammatory signaling pathways - component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 & RNF11, that ensures the transient nature of inflammatory signaling pathways - promotes association of the complex after TNF stimulation - once the complex is formed, TNFAIP3 deubiquitinates Lys-63 polyubiquitin chains on RIPK1 & catalyzes formation of Lys-48-polyubiquitin chains - this leads to RIPK1 proteosomal degradation & consequently termination of the TNF- or LPS-mediated activation of NFKB1 - ubiquitinates RIPK2 by Lys-63-linked conjugation & influences NOD2-dependent signal transduction pathways - regulates transcriptional activity of several transcription factors, & probably plays a role in regulation of the immune response - ubiquitinates NFE2 by Lys-63 linkages & is implicated in control of the development of hematopoietic lineages - regulator of T helper (TH2) cytokine development through its ability to induce JUNB ubiquitination & degradation (putative) - ubiquitinates SNX9 - ubiquitinates CXCR4 & HGS/HRS & regulates sorting of CXCR4 to the degradative pathway - involved in negative regulation of MAVS-dependent cellular antiviral responses - ubiquitinates MAVS through Lys-48-linked conjugation resulting in MAVS proteosomal degradation - involved in regulation of apoptosis & reactive oxygen species levels through ubiquitination & proteosomal degradation of TXNIP - mediates antiapoptotic activity of EGF through ubiquitination & proteosomal degradation of p15 BID - targets DTX1 for lysosomal degradation & controls NOTCH1 degradation, in the absence of ligand, through Lys-29- linked polyubiquitination - activated by NDFIP1- & NDFIP2-binding - protein modification; protein ubiquitination - on T-cell activation, phosphorylation by the JNK cascade on Ser & Thr surrounding the PRR domain accelerates ubiquitination & degradation of JUN & JUNB - 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 & the HECT domain &, thus exposing the HECT domain (putative) - phosphorylation by FYN reduces interaction with JUNB & negatively controls JUN ubiquitination & degradation - ubiquitinated; autopolyubiquitination with Lys-63 linkages which does not lead to protein degradation - monomer (putative) interacts (via its WW domains) with DRPLA - interacts with epstein-Barr virus LMP2A - interacts (via its WW domains) with OCNL, NOTCH1 & JUN - interacts (via WW domain 2) with N4BP1; leading to inhibits its E3 ubiquitin-protein ligase activity (putative) - interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination & degradation of JUNB - interacts with NDFIP1 & NDFIP2; this interaction activates the E3 ubiquitin-protein ligase & may induce its recruitment to exosomes (putative) - interacts with ARHGEF7 - interacts with RNF11 - interacts (via the WW 1 domain) with NFE2 (via 1st PXY motif); the interaction promotes Lys-63-linked ubiquitination of NFE2, retains it in the cytoplasm & 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 & PCBP2 - interacts (via WW domains) with TXNIP (via C-terminus) - interacts with p15 BID - interacts with SNX9 & SNX18 - interacts with SPG20 - interacts with DTX1 Structure: - contains 1 C2 domain - contains 1 HECT domain - contains 4 WW domains Compartment: - cell membrane - cytoplasm (putative) - nucleus (putative) - associates with endocytic vesicles - may be recruited to exosomes by NDFIP1 Alternative splicing: named isoforms=2 Expression: widely expressed Pathology: - defects in ITCH are the cause of syndromic multisystem autoimmune disease

General

phosphoprotein E3 ubiquitin ligase; ubiquitin-ligating enzyme E3; N end-recognizing protein

Properties

SIZE: entity length = 903 aa MW = 103 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: C2 domain {5-99} MOTIF: binding site FOR-BINDING-OF: phospholipid Ca+2-binding site Ser phosphorylation site {S240} proline-rich region SITE: 252-267 MOTIF: proline residue (SEVERAL) Thr phosphorylation site {T263} Ser phosphorylation site {S273} WW domain (W/rsp5/WWP domain) {326-359} WW domain (W/rsp5/WWP domain) {358-391} FYN interaction {395-471} MOTIF: Tyr phosphorylation site {Y420} WW domain (W/rsp5/WWP domain) {438-471} WW domain (W/rsp5/WWP domain) {478-511} HECT domain {569-903} MOTIF: MAP kinase docking site {574-583} cysteine residue {C871}

Database Correlations

OMIM correlations UniProt Q96J02 PFAM correlations Entrez Gene 83737 Kegg hsa:83737

References

UniProt :accession Q96J02