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Q96J02

- ITCH_HUMAN

UniProt

Q96J02 - ITCH_HUMAN

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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

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.11 Publications

Enzyme regulationi

Activated by NDFIP1- and NDFIP2-binding By similarity.

Pathwayi

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei871 – 8711Glycyl thioester intermediate By similarity

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
Complete GO annotation...

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 NDFIP1.3 Publications

GO - Cellular componenti

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

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.
Note: The disease is caused by mutations affecting the gene represented in this entry.1 Publication

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 MAPK8 By similarity
Modified residuei263 – 2631Phosphothreonine; by MAPK8 By similarity
Modified residuei273 – 2731Phosphoserine; by MAPK8 By similarity
Modified residuei385 – 3851Phosphothreonine; by SGK31 Publication
Modified residuei420 – 4201Phosphotyrosine; by FYN1 Publication
Modified residuei450 – 4501Phosphoserine; by SGK31 Publication

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.
Ubiquitinated; autopolyubiquitination with 'Lys-63' linkages which does not lead to protein degradation.8 Publications

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.18 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. 129 interactions.
DIPiDIP-29849N.
IntActiQ96J02. 28 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.

Miscellaneous databases

EvolutionaryTraceiQ96J02.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini5 – 9995C2Add
BLAST
Domaini326 – 35934WW 1Add
BLAST
Domaini358 – 39134WW 2Add
BLAST
Domaini438 – 47134WW 3Add
BLAST
Domaini478 – 51134WW 4Add
BLAST
Domaini569 – 903335HECTAdd
BLAST

Region

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

Compositional bias

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

Sequence similaritiesi

Contains 1 C2 domain.
Contains 4 WW domains.

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

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 110110Missing in isoform 3. VSP_044732Add
BLAST
Alternative sequencei159 – 20042NGVSL…AGFTG → S in isoform 2 and isoform 3. VSP_008451Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti297 – 2971T → I in BAG64996. 1 Publication

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. 129 interactions.
DIPi DIP-29849N.
IntActi Q96J02. 28 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

« Hide 'large scale' publications
  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: September 3, 2014
This is version 127 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

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