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Q96J02

- ITCH_HUMAN

UniProt

Q96J02 - ITCH_HUMAN

Protein

E3 ubiquitin-protein ligase Itchy homolog

Gene

ITCH

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 128 (01 Oct 2014)
      Sequence version 2 (03 Oct 2003)
      Previous versions | rss
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    Functioni

    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. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. 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. 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. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation By similarity. Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. 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. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination.By similarity11 Publications

    Enzyme regulationi

    Activated by NDFIP1- and NDFIP2-binding.By similarity

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei871 – 8711Glycyl thioester intermediatePROSITE-ProRule annotation

    GO - Molecular functioni

    1. CXCR chemokine receptor binding Source: UniProtKB
    2. ligase activity Source: UniProtKB-KW
    3. protein binding Source: IntAct
    4. ribonucleoprotein complex binding Source: UniProtKB
    5. ubiquitin-protein transferase activity Source: UniProtKB

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. defense response to virus Source: UniProtKB-KW
    3. inflammatory response Source: UniProtKB
    4. innate immune response Source: Reactome
    5. negative regulation of alpha-beta T cell proliferation Source: Ensembl
    6. negative regulation of apoptotic process Source: UniProtKB
    7. negative regulation of defense response to virus Source: UniProtKB
    8. negative regulation of JNK cascade Source: BHF-UCL
    9. negative regulation of NF-kappaB transcription factor activity Source: BHF-UCL
    10. negative regulation of type I interferon production Source: Reactome
    11. Notch signaling pathway Source: Reactome
    12. nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Source: Reactome
    13. nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
    14. positive regulation of protein catabolic process Source: Ensembl
    15. positive regulation of T cell anergy Source: Ensembl
    16. protein K29-linked ubiquitination Source: UniProtKB
    17. protein K48-linked ubiquitination Source: UniProtKB
    18. protein K63-linked ubiquitination Source: UniProtKB
    19. protein ubiquitination Source: UniProtKB
    20. protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: RefGenome
    21. regulation of cell growth Source: UniProtKB
    22. regulation of protein deubiquitination Source: BHF-UCL
    23. ubiquitin-dependent protein catabolic process Source: UniProtKB
    24. viral entry into host cell Source: UniProtKB

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    Antiviral defense, Apoptosis, Host-virus interaction, Immunity, Innate immunity, Ubl conjugation pathway

    Enzyme and pathway databases

    ReactomeiREACT_115828. Downregulation of ERBB4 signaling.
    REACT_118614. Activated NOTCH1 Transmits Signal to the Nucleus.
    REACT_25271. Negative regulators of RIG-I/MDA5 signaling.
    REACT_75776. NOD1/2 Signaling Pathway.
    REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
    SignaLinkiQ96J02.
    UniPathwayiUPA00143.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    E3 ubiquitin-protein ligase Itchy homolog (EC:6.3.2.-)
    Short name:
    Itch
    Alternative name(s):
    Atrophin-1-interacting protein 4
    Short name:
    AIP4
    NFE2-associated polypeptide 1
    Short name:
    NAPP1
    Gene namesi
    Name:ITCH
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 20

    Organism-specific databases

    HGNCiHGNC:13890. ITCH.

    Subcellular locationi

    Cell membrane. Cytoplasm By similarity. Nucleus
    Note: Associates with endocytic vesicles. May be recruited to exosomes by NDFIP1.

    GO - Cellular componenti

    1. cell cortex Source: Ensembl
    2. cytoplasm Source: HPA
    3. cytoplasmic vesicle Source: Ensembl
    4. cytosol Source: Reactome
    5. membrane Source: UniProtKB
    6. nucleus Source: HPA
    7. plasma membrane Source: UniProtKB

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Syndromic multisystem autoimmune disease (SMAD) [MIM:613385]: A disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi343 – 3431Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. 1 Publication
    Mutagenesisi420 – 4201Y → F: Greatly reduced phosphorylation on T-cell stimulation and in the presence of FYN. Increased ITCH-mediated Ub conjugation and degradation of JUNB. 1 Publication
    Mutagenesisi455 – 4551Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. 1 Publication
    Mutagenesisi871 – 8711C → A: Loss of ubiquitin protein ligase activity. Results in altered endosomal sorting and reduced degradation of CXCR4. Unable to inhibit MAVS-induced activation of INFB. 3 Publications

    Organism-specific databases

    MIMi613385. phenotype.
    Orphaneti228426. Syndromic multisystem autoimmune disease due to Itch deficiency.
    PharmGKBiPA29934.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed1 Publication
    Chaini2 – 903902E3 ubiquitin-protein ligase Itchy homologPRO_0000120317Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserine1 Publication
    Modified residuei240 – 2401Phosphoserine; by MAPK8By similarity
    Modified residuei263 – 2631Phosphothreonine; by MAPK8By similarity
    Modified residuei273 – 2731Phosphoserine; by MAPK8By similarity
    Modified residuei385 – 3851Phosphothreonine; by SGK32 Publications
    Modified residuei420 – 4201Phosphotyrosine; by FYN2 Publications
    Modified residuei450 – 4501Phosphoserine; by SGK32 Publications

    Post-translational modificationi

    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 By similarity. Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation.By similarity4 Publications
    Ubiquitinated; autopolyubiquitination with 'Lys-63' linkages which does not lead to protein degradation.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ96J02.
    PaxDbiQ96J02.
    PRIDEiQ96J02.

    PTM databases

    PhosphoSiteiQ96J02.

    Expressioni

    Tissue specificityi

    Widely expressed.

    Gene expression databases

    BgeeiQ96J02.
    CleanExiHS_ITCH.
    GenevestigatoriQ96J02.

    Organism-specific databases

    HPAiHPA021126.
    HPA049032.

    Interactioni

    Subunit structurei

    Monomer By similarity. Interacts (via its WW domains) with OCNL, NOTCH1 AND JUN. Interacts (via WW domain 2) with N4BP1; leading to inhibiting its E3 ubiquitin-protein ligase activity. Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes By similarity. Interacts with ARHGEF7. Interacts with RNF11. 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. 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 and PCBP2. Interacts (via WW domains) with TXNIP (via C-terminus). Interacts with p15 BID. Interacts with ERBB4, DTX1, SPG20, SNX9 and SNX18. Interacts (via its WW domains) with ATN1. Interacts with Epstein-Barr virus LMP2A. Interacts (via WW domains) with SGK3. Interacts with OTUD7B.By similarity19 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    BidP704442EBI-1564678,EBI-783400From a different organism.
    CYLDQ9NQC73EBI-1564678,EBI-2117940
    GLI1P081514EBI-1564678,EBI-308084
    LMP2P132852EBI-1564678,EBI-7181113From a different organism.
    NumbQ9QZS3-22EBI-1564678,EBI-3896014From a different organism.
    PI4K2AQ9BTU65EBI-1564678,EBI-3239392
    RNF11Q9Y3C52EBI-1564678,EBI-396669
    SGK3Q96BR15EBI-1564678,EBI-2801236
    SNX9Q9Y5X17EBI-1564678,EBI-77848
    TP73O15350-15EBI-1564678,EBI-389619
    TP73O15350-82EBI-1564678,EBI-5651259

    Protein-protein interaction databases

    BioGridi123747. 131 interactions.
    DIPiDIP-29849N.
    IntActiQ96J02. 29 interactions.
    MINTiMINT-148272.
    STRINGi9606.ENSP00000363998.

    Structurei

    Secondary structure

    1
    903
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi18 – 2912
    Beta strandi41 – 477
    Beta strandi50 – 534
    Beta strandi64 – 7310
    Beta strandi78 – 858
    Beta strandi88 – 903
    Beta strandi93 – 1019
    Helixi102 – 1087
    Turni109 – 1113
    Beta strandi112 – 12615
    Beta strandi130 – 14314
    Beta strandi332 – 3365
    Beta strandi342 – 3465
    Turni347 – 3493
    Beta strandi352 – 3554
    Beta strandi365 – 3684
    Beta strandi374 – 3774
    Beta strandi379 – 3813
    Beta strandi482 – 4887
    Beta strandi494 – 4985
    Turni499 – 5013
    Beta strandi504 – 5074
    Turni509 – 5113
    Helixi528 – 53912
    Turni540 – 5423
    Beta strandi545 – 5517
    Beta strandi554 – 5563
    Helixi557 – 56711
    Helixi572 – 5743
    Beta strandi575 – 5806
    Helixi589 – 60315
    Turni607 – 6093
    Beta strandi611 – 6144
    Beta strandi621 – 6244
    Helixi626 – 6305
    Helixi634 – 65017
    Helixi661 – 6677
    Helixi675 – 6773
    Turni678 – 6803
    Helixi682 – 69211
    Helixi735 – 74713
    Helixi751 – 76414
    Helixi767 – 7704
    Helixi775 – 7839
    Helixi790 – 7956
    Beta strandi798 – 8014
    Helixi807 – 81812
    Helixi821 – 83212
    Helixi842 – 8443
    Beta strandi848 – 8514
    Beta strandi855 – 8584
    Beta strandi867 – 8693
    Helixi870 – 8723
    Beta strandi874 – 8774
    Helixi883 – 89513

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2DMVNMR-A328-357[»]
    2KYKNMR-A359-392[»]
    2NQ3X-ray1.80A1-155[»]
    2P4RX-ray2.00T246-270[»]
    2YSFNMR-A480-512[»]
    3TUGX-ray2.27A524-903[»]
    ProteinModelPortaliQ96J02.
    SMRiQ96J02. Positions 13-145, 326-900.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ96J02.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini5 – 9995C2PROSITE-ProRule annotationAdd
    BLAST
    Domaini326 – 35934WW 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini358 – 39134WW 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini438 – 47134WW 3PROSITE-ProRule annotationAdd
    BLAST
    Domaini478 – 51134WW 4PROSITE-ProRule annotationAdd
    BLAST
    Domaini569 – 903335HECTPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni395 – 47177Required for interaction with FYNAdd
    BLAST
    Regioni574 – 58310MAP kinase docking siteBy similarity

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi252 – 26716Arg/Pro-rich (PRR domain)Add
    BLAST

    Sequence similaritiesi

    Contains 1 C2 domain.PROSITE-ProRule annotation
    Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.PROSITE-ProRule annotation
    Contains 4 WW domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiCOG5021.
    HOVERGENiHBG004134.
    InParanoidiQ96J02.
    KOiK05632.
    OMAiGETTCSE.
    OrthoDBiEOG7RFTGT.
    PhylomeDBiQ96J02.
    TreeFamiTF323658.

    Family and domain databases

    Gene3Di2.60.40.150. 1 hit.
    InterProiIPR000008. C2_dom.
    IPR024928. E3_ub_ligase_SMURF1.
    IPR000569. HECT.
    IPR001202. WW_dom.
    [Graphical view]
    PfamiPF00168. C2. 1 hit.
    PF00632. HECT. 1 hit.
    PF00397. WW. 4 hits.
    [Graphical view]
    PIRSFiPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
    SMARTiSM00239. C2. 1 hit.
    SM00119. HECTc. 1 hit.
    SM00456. WW. 4 hits.
    [Graphical view]
    SUPFAMiSSF49562. SSF49562. 1 hit.
    SSF51045. SSF51045. 4 hits.
    SSF56204. SSF56204. 1 hit.
    PROSITEiPS50004. C2. 1 hit.
    PS50237. HECT. 1 hit.
    PS01159. WW_DOMAIN_1. 4 hits.
    PS50020. WW_DOMAIN_2. 4 hits.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: Q96J02-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ    50
    SKKTEKCNNT NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL 100
    DIYETLKSNN MKLEEVVVTL QLGGDKEPTE TIGDLSICLD GLQLESEVVT 150
    NGETTCSENG VSLCLPRLEC NSAISAHCNL CLPGLSDSPI SASRVAGFTG 200
    ASQNDDGSRS KDETRVSTNG SDDPEDAGAG ENRRVSGNNS PSLSNGGFKP 250
    SRPPRPSRPP PPTPRRPASV NGSPSATSES DGSSTGSLPP TNTNTNTSEG 300
    ATSGLIIPLT ISGGSGPRPL NPVTQAPLPP GWEQRVDQHG RVYYVDHVEK 350
    RTTWDRPEPL PPGWERRVDN MGRIYYVDHF TRTTTWQRPT LESVRNYEQW 400
    QLQRSQLQGA MQQFNQRFIY GNQDLFATSQ SKEFDPLGPL PPGWEKRTDS 450
    NGRVYFVNHN TRITQWEDPR SQGQLNEKPL PEGWEMRFTV DGIPYFVDHN 500
    RRTTTYIDPR TGKSALDNGP QIAYVRDFKA KVQYFRFWCQ QLAMPQHIKI 550
    TVTRKTLFED SFQQIMSFSP QDLRRRLWVI FPGEEGLDYG GVAREWFFLL 600
    SHEVLNPMYC LFEYAGKDNY CLQINPASYI NPDHLKYFRF IGRFIAMALF 650
    HGKFIDTGFS LPFYKRILNK PVGLKDLESI DPEFYNSLIW VKENNIEECD 700
    LEMYFSVDKE ILGEIKSHDL KPNGGNILVT EENKEEYIRM VAEWRLSRGV 750
    EEQTQAFFEG FNEILPQQYL QYFDAKELEV LLCGMQEIDL NDWQRHAIYR 800
    HYARTSKQIM WFWQFVKEID NEKRMRLLQF VTGTCRLPVG GFADLMGSNG 850
    PQKFCIEKVG KENWLPRSHT CFNRLDLPPY KSYEQLKEKL LFAIEETEGF 900
    GQE 903

    Note: No experimental confirmation available.

    Length:903
    Mass (Da):102,803
    Last modified:October 3, 2003 - v2
    Checksum:i6777A2043C7B67BC
    GO
    Isoform 2 (identifier: Q96J02-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S

    Show »
    Length:862
    Mass (Da):98,676
    Checksum:iA3D960E7F4DBF9D3
    GO
    Isoform 3 (identifier: Q96J02-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-110: Missing.
         159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S

    Note: No experimental confirmation available.

    Show »
    Length:752
    Mass (Da):86,498
    Checksum:iB08AB68B285391F8
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti297 – 2971T → I in BAG64996. (PubMed:14702039)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 110110Missing in isoform 3. 1 PublicationVSP_044732Add
    BLAST
    Alternative sequencei159 – 20042NGVSL…AGFTG → S in isoform 2 and isoform 3. 5 PublicationsVSP_008451Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF095745 mRNA. Translation: AAK39399.1.
    AB056663 mRNA. Translation: BAB39389.1.
    AK304090 mRNA. Translation: BAG64996.1.
    AK315212 mRNA. Translation: BAG37647.1.
    AL109923, AL356299 Genomic DNA. Translation: CAI21458.1.
    AL356299, AL109923 Genomic DNA. Translation: CAI17959.1.
    AL356299, AL109923 Genomic DNA. Translation: CAI17960.1.
    AL109923, AL356299 Genomic DNA. Translation: CAI21459.1.
    CH471077 Genomic DNA. Translation: EAW76272.1.
    CH471077 Genomic DNA. Translation: EAW76274.1.
    CH471077 Genomic DNA. Translation: EAW76276.1.
    BC006848 mRNA. Translation: AAH06848.1.
    BC011571 mRNA. Translation: AAH11571.1.
    AF038564 mRNA. Translation: AAC04845.1.
    CCDSiCCDS13234.1. [Q96J02-2]
    CCDS58768.1. [Q96J02-1]
    CCDS58769.1. [Q96J02-3]
    RefSeqiNP_001244066.1. NM_001257137.1. [Q96J02-1]
    NP_001244067.1. NM_001257138.1. [Q96J02-3]
    NP_113671.3. NM_031483.5. [Q96J02-2]
    XP_006723944.1. XM_006723881.1. [Q96J02-2]
    XP_006723945.1. XM_006723882.1. [Q96J02-3]
    UniGeneiHs.632272.

    Genome annotation databases

    EnsembliENST00000262650; ENSP00000262650; ENSG00000078747. [Q96J02-1]
    ENST00000374864; ENSP00000363998; ENSG00000078747. [Q96J02-2]
    ENST00000535650; ENSP00000445608; ENSG00000078747. [Q96J02-3]
    GeneIDi83737.
    KEGGihsa:83737.
    UCSCiuc002xak.3. human. [Q96J02-2]
    uc010geu.2. human. [Q96J02-1]

    Polymorphism databases

    DMDMi37537897.

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF095745 mRNA. Translation: AAK39399.1 .
    AB056663 mRNA. Translation: BAB39389.1 .
    AK304090 mRNA. Translation: BAG64996.1 .
    AK315212 mRNA. Translation: BAG37647.1 .
    AL109923 , AL356299 Genomic DNA. Translation: CAI21458.1 .
    AL356299 , AL109923 Genomic DNA. Translation: CAI17959.1 .
    AL356299 , AL109923 Genomic DNA. Translation: CAI17960.1 .
    AL109923 , AL356299 Genomic DNA. Translation: CAI21459.1 .
    CH471077 Genomic DNA. Translation: EAW76272.1 .
    CH471077 Genomic DNA. Translation: EAW76274.1 .
    CH471077 Genomic DNA. Translation: EAW76276.1 .
    BC006848 mRNA. Translation: AAH06848.1 .
    BC011571 mRNA. Translation: AAH11571.1 .
    AF038564 mRNA. Translation: AAC04845.1 .
    CCDSi CCDS13234.1. [Q96J02-2 ]
    CCDS58768.1. [Q96J02-1 ]
    CCDS58769.1. [Q96J02-3 ]
    RefSeqi NP_001244066.1. NM_001257137.1. [Q96J02-1 ]
    NP_001244067.1. NM_001257138.1. [Q96J02-3 ]
    NP_113671.3. NM_031483.5. [Q96J02-2 ]
    XP_006723944.1. XM_006723881.1. [Q96J02-2 ]
    XP_006723945.1. XM_006723882.1. [Q96J02-3 ]
    UniGenei Hs.632272.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2DMV NMR - A 328-357 [» ]
    2KYK NMR - A 359-392 [» ]
    2NQ3 X-ray 1.80 A 1-155 [» ]
    2P4R X-ray 2.00 T 246-270 [» ]
    2YSF NMR - A 480-512 [» ]
    3TUG X-ray 2.27 A 524-903 [» ]
    ProteinModelPortali Q96J02.
    SMRi Q96J02. Positions 13-145, 326-900.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 123747. 131 interactions.
    DIPi DIP-29849N.
    IntActi Q96J02. 29 interactions.
    MINTi MINT-148272.
    STRINGi 9606.ENSP00000363998.

    PTM databases

    PhosphoSitei Q96J02.

    Polymorphism databases

    DMDMi 37537897.

    Proteomic databases

    MaxQBi Q96J02.
    PaxDbi Q96J02.
    PRIDEi Q96J02.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000262650 ; ENSP00000262650 ; ENSG00000078747 . [Q96J02-1 ]
    ENST00000374864 ; ENSP00000363998 ; ENSG00000078747 . [Q96J02-2 ]
    ENST00000535650 ; ENSP00000445608 ; ENSG00000078747 . [Q96J02-3 ]
    GeneIDi 83737.
    KEGGi hsa:83737.
    UCSCi uc002xak.3. human. [Q96J02-2 ]
    uc010geu.2. human. [Q96J02-1 ]

    Organism-specific databases

    CTDi 83737.
    GeneCardsi GC20P032951.
    H-InvDB HIX0015745.
    HGNCi HGNC:13890. ITCH.
    HPAi HPA021126.
    HPA049032.
    MIMi 606409. gene.
    613385. phenotype.
    neXtProti NX_Q96J02.
    Orphaneti 228426. Syndromic multisystem autoimmune disease due to Itch deficiency.
    PharmGKBi PA29934.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5021.
    HOVERGENi HBG004134.
    InParanoidi Q96J02.
    KOi K05632.
    OMAi GETTCSE.
    OrthoDBi EOG7RFTGT.
    PhylomeDBi Q96J02.
    TreeFami TF323658.

    Enzyme and pathway databases

    UniPathwayi UPA00143 .
    Reactomei REACT_115828. Downregulation of ERBB4 signaling.
    REACT_118614. Activated NOTCH1 Transmits Signal to the Nucleus.
    REACT_25271. Negative regulators of RIG-I/MDA5 signaling.
    REACT_75776. NOD1/2 Signaling Pathway.
    REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
    SignaLinki Q96J02.

    Miscellaneous databases

    ChiTaRSi ITCH. human.
    EvolutionaryTracei Q96J02.
    GenomeRNAii 83737.
    NextBioi 72745.
    PROi Q96J02.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q96J02.
    CleanExi HS_ITCH.
    Genevestigatori Q96J02.

    Family and domain databases

    Gene3Di 2.60.40.150. 1 hit.
    InterProi IPR000008. C2_dom.
    IPR024928. E3_ub_ligase_SMURF1.
    IPR000569. HECT.
    IPR001202. WW_dom.
    [Graphical view ]
    Pfami PF00168. C2. 1 hit.
    PF00632. HECT. 1 hit.
    PF00397. WW. 4 hits.
    [Graphical view ]
    PIRSFi PIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
    SMARTi SM00239. C2. 1 hit.
    SM00119. HECTc. 1 hit.
    SM00456. WW. 4 hits.
    [Graphical view ]
    SUPFAMi SSF49562. SSF49562. 1 hit.
    SSF51045. SSF51045. 4 hits.
    SSF56204. SSF56204. 1 hit.
    PROSITEi PS50004. C2. 1 hit.
    PS50237. HECT. 1 hit.
    PS01159. WW_DOMAIN_1. 4 hits.
    PS50020. WW_DOMAIN_2. 4 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Human ITCH is a co-regulator of the hematopoietic transcription factor NF-E2."
      Chen X., Wen S.-C., Fukuda M.N., Gavva N.R., Hsu D.-W., Akama T.O., Yang-Peng T.L., Shen C.K.J.
      Genomics 73:238-241(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH NFE2.
      Tissue: Leukemia.
    2. "Homo sapiens mRNA for ubiquitin protein ligase Itch, complete cds."
      Miyazaki K., Okamoto Y., Sakamoto M., Nakagawara A.
      Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
    3. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
      Tissue: Trachea.
    4. "The DNA sequence and comparative analysis of human chromosome 20."
      Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E.
      , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
      Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
      Tissue: Kidney and Placenta.
    7. "Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins."
      Wood J.D., Yuan J., Margolis R.L., Colomer V., Duan K., Kushi J., Kaminsky Z., Kleiderlein J.J. Jr., Sharp A.H., Ross C.A.
      Mol. Cell. Neurosci. 11:149-160(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 83-903 (ISOFORM 2), INTERACTION WITH ATN1.
      Tissue: Fetal brain.
    8. "Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases."
      Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G., Ingham R., Ernberg I., Pawson T.
      Mol. Cell. Biol. 20:8526-8535(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 463-470; 503-510; 514-526; 644-665 AND 875-881, INTERACTION WITH LMP2A, MUTAGENESIS OF CYS-871.
      Tissue: B-cell.
    9. "Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH."
      Courbard J.-R., Fiore F., Adelaide J., Borg J.P., Birnbaum D., Ollendorff V.
      J. Biol. Chem. 277:45267-45275(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CBLC, PHOSPHORYLATION.
    10. "The RING-H2 protein RNF11 is differentially expressed in breast tumours and interacts with HECT-type E3 ligases."
      Kitching R., Wong M.J., Koehler D., Burger A.M., Landberg G., Gish G., Seth A.K.
      Biochim. Biophys. Acta 1639:104-112(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH RNF11.
    11. "The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4."
      Marchese A., Raiborg C., Santini F., Keen J.H., Stenmark H., Benovic J.L.
      Dev. Cell 5:709-722(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-871.
    12. "CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4."
      Slagsvold T., Marchese A., Brech A., Stenmark H.
      EMBO J. 25:3738-3749(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-385 AND SER-450, INTERACTION WITH SGK3.
    13. "Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains."
      Chastagner P., Israel A., Brou C.
      EMBO Rep. 7:1147-1153(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH DTX1, UBIQUITINATION OF DTX1.
    14. "Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation."
      Yang C., Zhou W., Jeon M.S., Demydenko D., Harada Y., Zhou H., Liu Y.C.
      Mol. Cell 21:135-141(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT TYR-420, INTERACTION WITH JUNB AND FYN, FUNCTION, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF TYR-343; TYR-420 AND TYR-455.
    15. "Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination."
      Lee T.-L., Shyu Y.-C., Hsu T.-Y., Shen C.-K.J.
      Biochem. Biophys. Res. Commun. 375:326-330(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH NFE2, FUNCTION.
    16. Cited for: AUTOUBIQUITINATION, FUNCTION, IDENTIFICATION BY MASS SPECTROMETRY.
    17. "Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins."
      Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J., Tan S.S.
      J. Biol. Chem. 283:32621-32627(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    18. "AIP4/Itch regulates Notch receptor degradation in the absence of ligand."
      Chastagner P., Israel A., Brou C.
      PLoS ONE 3:E2735-E2735(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, UBIQUITINATION OF NOTCH1.
    19. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
      Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
      Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
    20. "Endogenous spartin (SPG20) is recruited to endosomes and lipid droplets and interacts with the ubiquitin E3 ligases AIP4 and AIP5."
      Edwards T.L., Clowes V.E., Tsang H.T., Connell J.W., Sanderson C.M., Luzio J.P., Reid E.
      Biochem. J. 423:31-39(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SPG20.
    21. "ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways."
      Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E., Abbott D.W.
      Curr. Biol. 19:1255-1263(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, UBIQUITINATION OF RIPK2.
    22. "The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling."
      Shembade N., Parvatiyar K., Harhaj N.S., Harhaj E.W.
      EMBO J. 28:513-522(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH RNF11.
    23. "The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction."
      Bhandari D., Robia S.L., Marchese A.
      Mol. Biol. Cell 20:1324-1339(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CXCR4.
    24. "PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4."
      You F., Sun H., Zhou X., Sun W., Liang S., Zhai Z., Jiang Z.
      Nat. Immunol. 10:1300-1308(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, UBIQUITINATION OF MAVS, INTERACTION WITH PCBP2, MUTAGENESIS OF CYS-871.
    25. Cited for: INVOLVEMENT IN SMAD.
    26. "The E3 ubiquitin ligase Itch regulates sorting nexin 9 through an unconventional substrate recognition domain."
      Baumann C., Lindholm C.K., Rimoldi D., Levy F.
      FEBS J. 277:2803-2814(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SNX9 AND SNX18, UBIQUITINATION OF SNX9.
    27. "The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid."
      Azakir B.A., Desrochers G., Angers A.
      FEBS J. 277:1319-1330(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH P15 BID, UBIQUITINATION OF P15 BID.
    28. "The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation."
      Zhang P., Wang C., Gao K., Wang D., Mao J., An J., Xu C., Wu D., Yu H., Liu J.O., Yu L.
      J. Biol. Chem. 285:8869-8879(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH TXNIP, UBIQUITINATION OF TXNIP.
    29. "Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways."
      Gilmore-Hebert M., Ramabhadran R., Stern D.F.
      Mol. Cancer Res. 8:1388-1398(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH ERBB4, SUBCELLULAR LOCATION.
    30. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    31. Cited for: INTERACTION WITH OTUD7B.
    32. "A novel interaction between atrophin-interacting protein 4 and beta-p21-activated kinase-interactive exchange factor is mediated by an SH3 domain."
      Janz J.M., Sakmar T.P., Min K.C.
      J. Biol. Chem. 282:28893-28903(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 246-270 IN COMPLEX WITH ARHGEF7.
    33. "Solution structure of the second WW domain of ITCHY homolog E3 ubiquitin protein ligase (ITCH)."
      RIKEN structural genomics initiative (RSGI)
      Submitted (OCT-2006) to the PDB data bank
      Cited for: STRUCTURE BY NMR OF 328-357.

    Entry informationi

    Entry nameiITCH_HUMAN
    AccessioniPrimary (citable) accession number: Q96J02
    Secondary accession number(s): A6NEW4
    , B4E234, E1P5P3, F5H217, O43584, Q5QP37, Q5TEL0, Q96F66, Q9BY75, Q9H451, Q9H4U5
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 3, 2003
    Last sequence update: October 3, 2003
    Last modified: October 1, 2014
    This is version 128 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 20
      Human chromosome 20: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    4. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    5. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3