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    ITCH itchy E3 ubiquitin protein ligase [ Homo sapiens (human) ]

    Gene ID: 83737, updated on 8-Jul-2021

    Summary

    Official Symbol
    ITCHprovided by HGNC
    Official Full Name
    itchy E3 ubiquitin protein ligaseprovided by HGNC
    Primary source
    HGNC:HGNC:13890
    See related
    Ensembl:ENSG00000078747 MIM:606409
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    AIF4; AIP4; ADMFD; NAPP1
    Summary
    This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
    Expression
    Ubiquitous expression in testis (RPKM 12.7), esophagus (RPKM 11.6) and 25 other tissues See more
    Orthologs
    NEW
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    Try the new Transcript table

    Genomic context

    See ITCH in Genome Data Viewer
    Location:
    20q11.22
    Exon count:
    31
    Annotation release Status Assembly Chr Location
    109.20210514 current GRCh38.p13 (GCF_000001405.39) 20 NC_000020.11 (34363273..34511773)
    105.20201022 previous assembly GRCh37.p13 (GCF_000001405.25) 20 NC_000020.10 (32951079..33099578)

    Chromosome 20 - NC_000020.11Genomic Context describing neighboring genes Neighboring gene agouti signaling protein Neighboring gene exportin for tRNA pseudogene 1 Neighboring gene density regulated re-initiation and release factor pseudogene Neighboring gene adenosylhomocysteinase Neighboring gene uncharacterized LOC107985381 Neighboring gene cell division cycle 42 pseudogene 1 Neighboring gene microRNA 644a Neighboring gene ferredoxin 1 pseudogene 1 Neighboring gene dynein light chain roadblock-type 1 Neighboring gene microtubule associated protein 1 light chain 3 alpha

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    HIV-1 interactions

    Protein interactions

    Protein Gene Interaction Pubs
    Nef nef HIV-1 Nef co-localizes with CXCR4, AIP4, NEDD4, CD63/LAMP-1-positive vesicles, and HRS/VPS27-positive ESCRT-0 structures in HeLa cells PubMed
    nef The Lys residues (K327/331/333) in the C-terminal tail of CXCR4 and the catalytic Cys830 in the HECT domain of AIP4 are critically required for HIV-1 Nef-mediated downregulation of CXCR4 PubMed
    nef HIV-1 Nef dramatically enhances the binding of AIP4 with CXCR4 and alanine substitutions at positions Q297 and N329 of AIP4 eliminate this binding PubMed
    nef HIV-1 Nef-mediated CXCR4 downregulation is dependent on ubiquitinylation, which is mediated by the E3 ubiquitin ligase AIP4 PubMed
    nef HIV-1 Nef co-localizes with E3 ubiquitin ligases AIP4 and NEDD4. HIV-1 Nef induced degradation of GNAI2 involves AIP4 and NEDD4 through recruitment of AIP4 and NEDD4 by Nef PubMed
    Vif vif HIV-1 Vif, through amino acids 20-128, binds to the WW domains of hNedd4 and AIP4, two HECT E3 ubiquitin ligases PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables CXCR chemokine receptor binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables arrestin family protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables ligase activity IEA
    Inferred from Electronic Annotation
    more info
     
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables ribonucleoprotein complex binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables ubiquitin protein ligase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    enables ubiquitin protein ligase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables ubiquitin protein ligase activity IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    enables ubiquitin protein ligase activity TAS
    Traceable Author Statement
    more info
     
    enables ubiquitin-like protein ligase binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables ubiquitin-like protein transferase activity TAS
    Traceable Author Statement
    more info
     
    enables ubiquitin-protein transferase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables ubiquitin-protein transferase activity IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    enables ubiquitin-protein transferase activity NAS
    Non-traceable Author Statement
    more info
    PubMed 
    Process Evidence Code Pubs
    involved_in apoptotic process IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in defense response to virus IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in inflammatory response NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in innate immune response IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of JNK cascade ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in negative regulation of NF-kappaB transcription factor activity ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in negative regulation of alpha-beta T cell proliferation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of apoptotic process IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in negative regulation of defense response to virus IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in negative regulation of type I interferon production TAS
    Traceable Author Statement
    more info
     
    involved_in nucleotide-binding oligomerization domain containing signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in positive regulation of T cell anergy IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in positive regulation of protein catabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in positive regulation of receptor catabolic process IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in proteasome-mediated ubiquitin-dependent protein catabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in proteasome-mediated ubiquitin-dependent protein catabolic process IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in protein K29-linked ubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in protein K29-linked ubiquitination IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein K48-linked ubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in protein K48-linked ubiquitination IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein K63-linked ubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in protein K63-linked ubiquitination IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein autoubiquitination IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in protein polyubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in protein ubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in protein ubiquitination IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein ubiquitination IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in regulation of cell growth NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in regulation of hematopoietic stem cell differentiation TAS
    Traceable Author Statement
    more info
     
    involved_in regulation of protein deubiquitination ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    acts_upstream_of_or_within ubiquitin-dependent protein catabolic process IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in ubiquitin-dependent protein catabolic process IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in ubiquitin-dependent protein catabolic process NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in viral entry into host cell TAS
    Traceable Author Statement
    more info
    PubMed 
    Component Evidence Code Pubs
    located_in cell cortex IEA
    Inferred from Electronic Annotation
    more info
     
    is_active_in cytoplasm IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    located_in cytoplasmic vesicle IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in cytosol TAS
    Traceable Author Statement
    more info
     
    colocalizes_with early endosome IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in early endosome membrane IEA
    Inferred from Electronic Annotation
    more info
     
    located_in extracellular exosome HDA PubMed 
    located_in intracellular membrane-bounded organelle IDA
    Inferred from Direct Assay
    more info
     
    located_in membrane HDA PubMed 
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
     
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    PubMed 
    part_of protein-containing complex IDA
    Inferred from Direct Assay
    more info
    PubMed 

    General protein information

    Preferred Names
    E3 ubiquitin-protein ligase Itchy homolog
    Names
    HECT-type E3 ubiquitin transferase Itchy homolog
    NFE2-associated polypeptide 1
    atrophin-1 interacting protein 4
    itchy E3 ubiquitin protein ligase homolog
    NP_001244066.1
    NP_001244067.1
    NP_001311126.1
    NP_001311127.1
    NP_113671.3
    XP_005260627.1
    XP_011527381.1
    XP_016883578.1
    XP_016883579.1
    XP_016883580.1
    XP_016883581.1
    XP_024307773.1

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_023206.1 RefSeqGene

      Range
      4980..153137
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_354

    mRNA and Protein(s)

    1. NM_001257137.3NP_001244066.1  E3 ubiquitin-protein ligase Itchy homolog isoform 1

      See identical proteins and their annotated locations for NP_001244066.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1). Both variants 1 and 4 encode the same isoform (1).
      Source sequence(s)
      AA730741, AL109923, AL356299, AL705688, BC011571, BG928040
      Consensus CDS
      CCDS58768.1
      UniProtKB/Swiss-Prot
      Q96J02
      Related
      ENSP00000262650.5, ENST00000262650.10
      Conserved Domains (3) summary
      cd04021
      Location:17140
      C2_E3_ubiquitin_ligase; C2 domain present in E3 ubiquitin ligase
      COG5021
      Location:359903
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:328357
      WW; WW domain
    2. NM_001257138.3NP_001244067.1  E3 ubiquitin-protein ligase Itchy homolog isoform 3

      See identical proteins and their annotated locations for NP_001244067.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks two internal exons and initiates translation at a downstream, in-frame start codon, compared to variant 1. The encoded isoform (3) is shorter than isoform 1.
      Source sequence(s)
      AA730741, AF038564, AK304090, AL109923, AL356299, AL705688, BG928040
      Consensus CDS
      CCDS58769.1
      UniProtKB/Swiss-Prot
      Q96J02
      Related
      ENSP00000445608.1, ENST00000535650.7
      Conserved Domains (3) summary
      COG5021
      Location:208752
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:177206
      WW; WW domain
      cl14603
      Location:130
      C2; C2 domain
    3. NM_001324197.2NP_001311126.1  E3 ubiquitin-protein ligase Itchy homolog isoform 1

      Status: REVIEWED

      Source sequence(s)
      AL109923, AL356299, BG928040
      Consensus CDS
      CCDS58768.1
      UniProtKB/Swiss-Prot
      Q96J02
      Related
      ENSP00000499786.1, ENST00000665346.1
      Conserved Domains (3) summary
      cd04021
      Location:17140
      C2_E3_ubiquitin_ligase; C2 domain present in E3 ubiquitin ligase
      COG5021
      Location:359903
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:328357
      WW; WW domain
    4. NM_001324198.2NP_001311127.1  E3 ubiquitin-protein ligase Itchy homolog isoform 2

      Status: REVIEWED

      Source sequence(s)
      AL109923, AL356299, BG928040
      Consensus CDS
      CCDS13234.1
      UniProtKB/Swiss-Prot
      Q96J02
      Related
      ENSP00000499685.1, ENST00000660337.1
      Conserved Domains (3) summary
      cd04021
      Location:17140
      C2_E3_ubiquitin_ligase; C2 domain present in E3 ubiquitin ligase
      COG5021
      Location:318862
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:287316
      WW; WW domain
    5. NM_031483.7NP_113671.3  E3 ubiquitin-protein ligase Itchy homolog isoform 2

      See identical proteins and their annotated locations for NP_113671.3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an exon in the 5' coding region, but maintains the reading frame, compared to variant 1. The encoded isoform (2) is shorter than isoform 1. Both variants 2 and 5 encode the same isoform (2).
      Source sequence(s)
      AA730741, AK315212, AL109923, AL356299, AL705688, BG928040
      Consensus CDS
      CCDS13234.1
      UniProtKB/Swiss-Prot
      Q96J02
      Related
      ENSP00000363998.4, ENST00000374864.10
      Conserved Domains (3) summary
      cd04021
      Location:17140
      C2_E3_ubiquitin_ligase; C2 domain present in E3 ubiquitin ligase
      COG5021
      Location:318862
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:287316
      WW; WW domain

    RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20210514

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p13 Primary Assembly

    Genomic

    1. NC_000020.11 Reference GRCh38.p13 Primary Assembly

      Range
      34363273..34511773
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_017028090.1XP_016883579.1  E3 ubiquitin-protein ligase Itchy homolog isoform X2

      Related
      ENSP00000499526.1, ENST00000670516.1
    2. XM_005260570.1XP_005260627.1  E3 ubiquitin-protein ligase Itchy homolog isoform X4

      Conserved Domains (2) summary
      COG5021
      Location:148692
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:117146
      WW; WW domain
    3. XM_017028091.1XP_016883580.1  E3 ubiquitin-protein ligase Itchy homolog isoform X3

      UniProtKB/Swiss-Prot
      Q96J02
      Conserved Domains (3) summary
      COG5021
      Location:208752
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:177206
      WW; WW domain
      cl14603
      Location:130
      C2; C2 domain
    4. XM_017028092.2XP_016883581.1  E3 ubiquitin-protein ligase Itchy homolog isoform X6

    5. XM_024452005.1XP_024307773.1  E3 ubiquitin-protein ligase Itchy homolog isoform X1

      Conserved Domains (3) summary
      cd04021
      Location:17140
      C2_E3_ubiquitin_ligase; C2 domain present in E3 ubiquitin ligase
      COG5021
      Location:359903
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:328357
      WW; WW domain
    6. XM_017028089.1XP_016883578.1  E3 ubiquitin-protein ligase Itchy homolog isoform X1

      UniProtKB/Swiss-Prot
      Q96J02
      Conserved Domains (3) summary
      cd04021
      Location:17140
      C2_E3_ubiquitin_ligase; C2 domain present in E3 ubiquitin ligase
      COG5021
      Location:359903
      HUL4; Ubiquitin-protein ligase [Posttranslational modification, protein turnover, chaperones]
      pfam00397
      Location:328357
      WW; WW domain
    7. XM_011529079.1XP_011527381.1  E3 ubiquitin-protein ligase Itchy homolog isoform X5

      Conserved Domains (4) summary
      smart00456
      Location:268299
      WW; Domain with 2 conserved Trp (W) residues
      smart00119
      Location:361689
      HECTc; Domain Homologous to E6-AP Carboxyl Terminus with
      cd00078
      Location:337690
      HECTc; HECT domain; C-terminal catalytic domain of a subclass of Ubiquitin-protein ligase (E3). It binds specific ubiquitin-conjugating enzymes (E2), accepts ubiquitin from E2, transfers ubiquitin to substrate lysine side chains, and transfers additional ...
      pfam00397
      Location:229258
      WW; WW domain

    RNA

    1. XR_001754418.1 RNA Sequence

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