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Symbol ITCH contributors: mct/pgu - updated : 12-09-2016
HGNC name itchy E3 ubiquitin protein ligase homolog (mouse)
HGNC id 13890
Corresponding disease
ITCHD ITCH deficiency
Location 20q11.22      Physical location : 32.951.061 - 33.099.197
Synonym name
  • NFE2 associated polypeptide 1
  • atrophin-1 interacting protein 4
  • itchy homolog E3 ubiquitin protein ligase
  • ubiquitin protein ligase ITCH
  • dJ468O1.1 (atrophin 1 interacting protein 4 (AIP4))
  • Synonym symbol(s) AIF4, AIP4, NAPP1, dJ468O1.1
    EC.number 6.3.2.-
    TYPE functioning gene
    STRUCTURE 148.14 kb     25 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    25 - 6412 - 862 - 2001 11318614
    26 - 6535 - 903 - -
    24 - 6270 - 752 - -
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     mouth   highly
    Respiratoryrespiratory tractlarynx  highly
    cell lineage
    cell lines
    at STAGE
  • one C2 domain
  • four WW domains
  • PPXY motif, not required for spartin ubiquitination
  • one HECT domain (homolog to E6 associated protein C-terminus)
  • mono polymer monomer
    interspecies homolog to murine Itch (95.9pc)
    homolog to rattus Itch (95.4pc)
  • NEDD4-like protein family
  • E6AP carboxy terminus (HECT) domain-containing family of ubiquitin E3 ligases
  • CATEGORY immunity/defense , regulatory
    SUBCELLULAR LOCALIZATION     plasma membrane
    text binding partner for the endocytic protein Endophilin and localized to endosomes
    basic FUNCTION
  • ubiquitin ligase that has been implicated in the regulation of a number of cellular processes
  • regulation of immune response by modifying NOTCH mediated signaling
  • regulate key trafficking decisions, including targeting of proteins to proteosomes or lysosomes
  • restricts transforming growth factor-beta signaling through a ubiquitination-independent mechanism
  • regulates endosomal sorting of activated CXCR4 by targeting the receptor to the endosomal sorting complex required for transport pathway
  • acts in concert with the ubiquitin activating enzyme (E1) and the ubiquitin conjugating enzyme (E2) to catalyze ubiquitylation of protein targets
  • together with TAX1BP1 and RNF11, is an essential component of an TNFAIP3 ubiquitin-editing protein complex that ensures transient activation of inflammatory signalling pathways
  • mediating polyubiquitination of TXNIP
  • can act as a transcriptional corepressor of NFE2
  • involved in a new signaling cascade for MAVS degradation and "fine tuning" of antiviral innate immunity
  • is responsible for RIP2 polyubiquitination in response to infection with listeria monocytogenes
  • helps regulate NOD2-dependent signal transduction pathways and such may be involved in the pathogenesis of NOD2-mediated inflammatory disease
  • ubiquitinates JUN and targets its for degradation in lysosomes
  • binding, ubiquitylating and promoting TP63 degradation
  • critical regulator of T helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation
  • attaches ubiquitin to substrate proteins
  • function of ITCH as a negative regulator of LAPTM5 protein might be exerted under specific conditions where the transcription of LAPTM5 is activated
  • plays a negative regulatory role in modulating canonical Wnt signaling by targeting the phosphorylated form of DVL1
  • is a regulator of POU5F1 stability and transcriptional activity, establishing a functional link between an E3 ligase and the regulation of pluripotency
  • CELLULAR PROCESS protein, degradation
  • constitutive lysosomal pathway regulating cell surface expression of BMPR2 and implicating the likely involvement of the mammalian E3 ligase, ITCH, in this process
  • a component
  • AIP4/arrestin-2 complex functions on endosomes to regulate sorting of CXCR4 into the degradative pathway
  • component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11
  • APBB1 facilitates stable association between NOTCH11 and E3 ligase ITCH through the formation of a trimeric complex
    small molecule
  • E3 ubiquitin ligase that specifically targets SMAD7 for ubiquitin-dependent degradation without affecting the turnover of the activated TGF-beta type I receptor
  • directly interacts with the amino-terminal half of nonvisual arrestin-2 (ARRB2)via its WW domains (activation of CXCR4 promotes this interaction that is consistent with a time when AIP4 co-localizes with arrestin-2 on endocytic vesicles)
  • interacting with GLI1 and NUMB
  • binding partner of USP9X (transient overexpression of FAM/USP9X resulted in the deubiquitylation of ITCH)
  • interact with DTX3 and partially colocalize to endocytic vesicles, and ITCH targets DTX for lysosomal degradation
  • interacting with SPG20 (spartin acts as an adaptor for WWP1 and ITCH)
  • interacting with TXNIP, thus regulating intracellular reactive oxygene species levels and apoptosis
  • interacting with atrophin-1
  • upon phosphorylation, can interact directly with CXCR4 and promotes its ubiquitination and degradation
  • interacting with DRPLA, LMP2A, OCNL, NOTCH1, JUN, JUNB, ARHGEF7, RNF11, NFE2, FYN
  • cooperation between USP8, ITCH, and the ESCRT-0 machinery in shaping receptor progression through the sorting endosome
  • ITCH, a WW-domain containing protein, and LITAF strongly interact and this interaction depends on the two PPXY motifs in the N-terminus of LITAF
  • LAPTM5 is a substrate of the ITCH-mediated degradation and its protein level is negatively regulated by ITCH
  • interaction between ITCH and STAM and the ligase activity of ITCH are essential for ERK-1/2 activation
  • NEDD4, NEDD4L and ITCH mediate poly-ubiquitination of AMOT/p130
  • NDFIP1 is an adaptor for the E3 ubiquitin ligase ITCH
  • DVL1-binding protein (ITCH ubiquitinates the phosphorylated form of DVL1 and promotes its degradation via the proteasome pathway, thereby inhibiting canonical Wnt signaling
  • a ubiquitin-regulated signaling network centered on ITCH and BIRC2 controls the strength of NOD2 signaling
  • ITCH interacts with and targets pluripotency-associated transcription factor POU5F1 for ubiquitination
  • interacts with mutant GBA variants and mediates their lysine 48 polyubiquitination and degradation
  • AMOT promotes the ubiquitination of YAP1 by ITCH and prevents ITCH from binding to large tumor suppressor 1
  • bind and ubiquitinate AMOT at residue Lys-481
  • interacts with the deubiquitinating enzyme and is required for deubiquitination of TRAF6, thus limiting TNFSF11-induced osteoclast formation
  • binds and ubiquitinates AMOT130, resulting in a reduction in AMOT130 residence at actin fibers and a significant enhancement of the stability of AMOT130 protein
  • PDYN acts as a neuromodulator to inhibit ITCH in the dorsal horn of the spinal cord
  • acts as an E3 ubiquitin ligase for SMAD7 polyubiquitination, and is an important regulator of SMAD7 activity and a positive regulator of TGFB1 signaling and of TGFB1-mediated biological processes
  • NDFIP1 acts as an adaptor for UBE2L3 and ITCH
  • TAX1BP1 functions as an adaptor molecule for ITCH to target MAVS during RNA virus infection and thus restrict virus-induced apoptosis
  • mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level
  • YOD1 stabilizes ITCH and facilitates ITCH-mediated LATS1/2 ubiquitination and degradation, which results in increased YAP/TAZ level
  • contributes to the differential ubiquitination of isoforms of the endocytic scaffold protein intersectin1 (ITSN1)
  • regulates ITCH-mediated M1 ubiquitination of Influenza A Virus
  • cell & other
    Other ubiquitinated
    phosphorylation by JNK1 increases ITCH catalytic activity whereas phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation
    is processed by caspases in cells from patients with chronic lymphocyte leukemia
    corresponding disease(s) ITCHD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in anaplastic thyroid carcinoma
    Variant & Polymorphism
    Candidate gene
    Therapy target
  • absent in the non-agouti-lethal 18H or Itchy mice, which develop a severe immunological disease, including lung and stomach inflammation and hyperplasia of lymphoid and hematopoietic cells
  • Itch(-/-) mice develop an autoimmune disease phenotype characterized by itchy skin and multiorgan inflammation
  • adult Itch(-/-) mice had normal bone volume, but they had significantly increased LPS-induced osteoclastogenesis and bone resorption