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Q96J02 (ITCH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 126. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase Itchy homolog

Short name=Itch
EC=6.3.2.-
Alternative name(s):
Atrophin-1-interacting protein 4
Short name=AIP4
NFE2-associated polypeptide 1
Short name=NAPP1
Gene names
Name:ITCH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length903 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.11 Ref.13 Ref.14 Ref.15 Ref.16 Ref.18 Ref.21 Ref.22 Ref.24 Ref.27 Ref.28

Enzyme regulation

Activated by NDFIP1- and NDFIP2-binding By similarity.

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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. Ref.1 Ref.7 Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.20 Ref.22 Ref.23 Ref.24 Ref.26 Ref.27 Ref.28 Ref.29 Ref.31

Subcellular location

Cell membrane. Cytoplasm By similarity. Nucleus. Note: Associates with endocytic vesicles. May be recruited to exosomes by NDFIP1. Ref.11 Ref.17 Ref.29

Tissue specificity

Widely expressed.

Post-translational modification

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. Ref.13 Ref.16 Ref.18 Ref.21 Ref.24 Ref.26 Ref.27 Ref.28

Involvement in disease

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. Ref.25

Sequence similarities

Contains 1 C2 domain.

Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.

Contains 4 WW domains.

Ontologies

Keywords
   Biological processAntiviral defense
Apoptosis
Host-virus interaction
Immunity
Innate immunity
Ubl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   Coding sequence diversityAlternative splicing
   DomainRepeat
   Molecular functionLigase
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processNotch signaling pathway

Traceable author statement. Source: Reactome

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

defense response to virus

Inferred from electronic annotation. Source: UniProtKB-KW

inflammatory response

Non-traceable author statement PubMed 9462742. Source: UniProtKB

innate immune response

Traceable author statement. Source: Reactome

negative regulation of JNK cascade

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of NF-kappaB transcription factor activity

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of alpha-beta T cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of apoptotic process

Inferred from mutant phenotype Ref.28. Source: UniProtKB

negative regulation of defense response to virus

Inferred from mutant phenotype Ref.24. Source: UniProtKB

negative regulation of type I interferon production

Traceable author statement. Source: Reactome

nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway

Traceable author statement. Source: Reactome

nucleotide-binding oligomerization domain containing signaling pathway

Traceable author statement. Source: Reactome

positive regulation of T cell anergy

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein catabolic process

Inferred from electronic annotation. Source: Ensembl

protein K29-linked ubiquitination

Inferred from direct assay Ref.13Ref.18. Source: UniProtKB

protein K48-linked ubiquitination

Inferred from direct assay Ref.24. Source: UniProtKB

protein K63-linked ubiquitination

Inferred from direct assay Ref.15Ref.21. Source: UniProtKB

protein ubiquitination

Inferred from direct assay PubMed 17592138. Source: UniProtKB

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of cell growth

Non-traceable author statement PubMed 9462742. Source: UniProtKB

regulation of protein deubiquitination

Inferred from sequence or structural similarity. Source: BHF-UCL

ubiquitin-dependent protein catabolic process

Non-traceable author statement PubMed 9462742. Source: UniProtKB

viral entry into host cell

Traceable author statement PubMed 12450395. Source: UniProtKB

   Cellular_componentcell cortex

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from direct assay. Source: HPA

cytoplasmic vesicle

Inferred from electronic annotation. Source: Ensembl

cytosol

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay. Source: HPA

plasma membrane

Inferred from direct assay Ref.11. Source: UniProtKB

   Molecular_functionCXCR chemokine receptor binding

Inferred from physical interaction Ref.23. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 22057290. Source: IntAct

ribonucleoprotein complex binding

Inferred from physical interaction Ref.24. Source: UniProtKB

ubiquitin-protein transferase activity

Inferred from direct assay PubMed 17592138. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q96J02-1)

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.
Note: No experimental confirmation available.
Isoform 2 (identifier: Q96J02-2)

The sequence of this isoform differs from the canonical sequence as follows:
     159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S
Isoform 3 (identifier: Q96J02-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-110: Missing.
     159-200: NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFTG → S
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.19
Chain2 – 903902E3 ubiquitin-protein ligase Itchy homolog
PRO_0000120317

Regions

Domain5 – 9995C2
Domain326 – 35934WW 1
Domain358 – 39134WW 2
Domain438 – 47134WW 3
Domain478 – 51134WW 4
Domain569 – 903335HECT
Region395 – 47177Required for interaction with FYN
Region574 – 58310MAP kinase docking site By similarity
Compositional bias252 – 26716Arg/Pro-rich (PRR domain)

Sites

Active site8711Glycyl thioester intermediate By similarity

Amino acid modifications

Modified residue21N-acetylserine Ref.19
Modified residue2401Phosphoserine; by MAPK8 By similarity
Modified residue2631Phosphothreonine; by MAPK8 By similarity
Modified residue2731Phosphoserine; by MAPK8 By similarity
Modified residue3851Phosphothreonine; by SGK3 Ref.12
Modified residue4201Phosphotyrosine; by FYN Ref.14
Modified residue4501Phosphoserine; by SGK3 Ref.12

Natural variations

Alternative sequence1 – 110110Missing in isoform 3.
VSP_044732
Alternative sequence159 – 20042NGVSL…AGFTG → S in isoform 2 and isoform 3.
VSP_008451

Experimental info

Mutagenesis3431Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. Ref.14
Mutagenesis4201Y → F: Greatly reduced phosphorylation on T-cell stimulation and in the presence of FYN. Increased ITCH-mediated Ub conjugation and degradation of JUNB. Ref.14
Mutagenesis4551Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. Ref.14
Mutagenesis8711C → 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. Ref.8 Ref.11 Ref.24
Sequence conflict2971T → I in BAG64996. Ref.3

Secondary structure

..................................................................................................... 903
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 3, 2003. Version 2.
Checksum: 6777A2043C7B67BC

FASTA903102,803
        10         20         30         40         50         60 
MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 

        70         80         90        100        110        120 
NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL DIYETLKSNN MKLEEVVVTL 

       130        140        150        160        170        180 
QLGGDKEPTE TIGDLSICLD GLQLESEVVT NGETTCSENG VSLCLPRLEC NSAISAHCNL 

       190        200        210        220        230        240 
CLPGLSDSPI SASRVAGFTG ASQNDDGSRS KDETRVSTNG SDDPEDAGAG ENRRVSGNNS 

       250        260        270        280        290        300 
PSLSNGGFKP SRPPRPSRPP PPTPRRPASV NGSPSATSES DGSSTGSLPP TNTNTNTSEG 

       310        320        330        340        350        360 
ATSGLIIPLT ISGGSGPRPL NPVTQAPLPP GWEQRVDQHG RVYYVDHVEK RTTWDRPEPL 

       370        380        390        400        410        420 
PPGWERRVDN MGRIYYVDHF TRTTTWQRPT LESVRNYEQW QLQRSQLQGA MQQFNQRFIY 

       430        440        450        460        470        480 
GNQDLFATSQ SKEFDPLGPL PPGWEKRTDS NGRVYFVNHN TRITQWEDPR SQGQLNEKPL 

       490        500        510        520        530        540 
PEGWEMRFTV DGIPYFVDHN RRTTTYIDPR TGKSALDNGP QIAYVRDFKA KVQYFRFWCQ 

       550        560        570        580        590        600 
QLAMPQHIKI TVTRKTLFED SFQQIMSFSP QDLRRRLWVI FPGEEGLDYG GVAREWFFLL 

       610        620        630        640        650        660 
SHEVLNPMYC LFEYAGKDNY CLQINPASYI NPDHLKYFRF IGRFIAMALF HGKFIDTGFS 

       670        680        690        700        710        720 
LPFYKRILNK PVGLKDLESI DPEFYNSLIW VKENNIEECD LEMYFSVDKE ILGEIKSHDL 

       730        740        750        760        770        780 
KPNGGNILVT EENKEEYIRM VAEWRLSRGV EEQTQAFFEG FNEILPQQYL QYFDAKELEV 

       790        800        810        820        830        840 
LLCGMQEIDL NDWQRHAIYR HYARTSKQIM WFWQFVKEID NEKRMRLLQF VTGTCRLPVG 

       850        860        870        880        890        900 
GFADLMGSNG PQKFCIEKVG KENWLPRSHT CFNRLDLPPY KSYEQLKEKL LFAIEETEGF 


GQE 

« Hide

Isoform 2 [UniParc].

Checksum: A3D960E7F4DBF9D3
Show »

FASTA86298,676
Isoform 3 [UniParc].

Checksum: B08AB68B285391F8
Show »

FASTA75286,498

References

« Hide 'large scale' references
[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. expand/collapse author list , 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. expand/collapse author list , 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]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
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]"Itch self-polyubiquitylation occurs through lysine-63 linkages."
Scialpi F., Malatesta M., Peschiaroli A., Rossi M., Melino G., Bernassola F.
Biochem. Pharmacol. 76:1515-1521(2008) [PubMed] [Europe PMC] [Abstract]
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]"Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease."
Lohr N.J., Molleston J.P., Strauss K.A., Torres-Martinez W., Sherman E.A., Squires R.H., Rider N.L., Chikwava K.R., Cummings O.W., Morton D.H., Puffenberger E.G.
Am. J. Hum. Genet. 86:447-453(2010) [PubMed] [Europe PMC] [Abstract]
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]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[31]"Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression."
Pareja F., Ferraro D.A., Rubin C., Cohen-Dvashi H., Zhang F., Aulmann S., Ben-Chetrit N., Pines G., Navon R., Crosetto N., Kostler W., Carvalho S., Lavi S., Schmitt F., Dikic I., Yakhini Z., Sinn P., Mills G.B., Yarden Y.
Oncogene 31:4599-4608(2012) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS13234.1. [Q96J02-2]
CCDS58768.1. [Q96J02-1]
CCDS58769.1. [Q96J02-3]
RefSeqNP_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]
UniGeneHs.632272.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2DMVNMR-A328-357[»]
2KYKNMR-A359-392[»]
2NQ3X-ray1.80A1-155[»]
2P4RX-ray2.00T246-270[»]
2YSFNMR-A480-512[»]
3TUGX-ray2.27A524-903[»]
ProteinModelPortalQ96J02.
SMRQ96J02. Positions 13-145, 326-900.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid123747. 128 interactions.
DIPDIP-29849N.
IntActQ96J02. 28 interactions.
MINTMINT-148272.
STRING9606.ENSP00000363998.

PTM databases

PhosphoSiteQ96J02.

Polymorphism databases

DMDM37537897.

Proteomic databases

MaxQBQ96J02.
PaxDbQ96J02.
PRIDEQ96J02.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000262650; ENSP00000262650; ENSG00000078747. [Q96J02-1]
ENST00000374864; ENSP00000363998; ENSG00000078747. [Q96J02-2]
ENST00000535650; ENSP00000445608; ENSG00000078747. [Q96J02-3]
GeneID83737.
KEGGhsa:83737.
UCSCuc002xak.3. human. [Q96J02-2]
uc010geu.2. human. [Q96J02-1]

Organism-specific databases

CTD83737.
GeneCardsGC20P032951.
H-InvDBHIX0015745.
HGNCHGNC:13890. ITCH.
HPAHPA021126.
HPA049032.
MIM606409. gene.
613385. phenotype.
neXtProtNX_Q96J02.
Orphanet228426. Syndromic multisystem autoimmune disease due to Itch deficiency.
PharmGKBPA29934.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5021.
HOVERGENHBG004134.
InParanoidQ96J02.
KOK05632.
OMAGETTCSE.
OrthoDBEOG7RFTGT.
PhylomeDBQ96J02.
TreeFamTF323658.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.
SignaLinkQ96J02.
UniPathwayUPA00143.

Gene expression databases

BgeeQ96J02.
CleanExHS_ITCH.
GenevestigatorQ96J02.

Family and domain databases

Gene3D2.60.40.150. 1 hit.
InterProIPR000008. C2_dom.
IPR024928. E3_ub_ligase_SMURF1.
IPR000569. HECT.
IPR001202. WW_dom.
[Graphical view]
PfamPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 4 hits.
[Graphical view]
PIRSFPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMARTSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]
SUPFAMSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 4 hits.
SSF56204. SSF56204. 1 hit.
PROSITEPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSITCH. human.
EvolutionaryTraceQ96J02.
GenomeRNAi83737.
NextBio72745.
PROQ96J02.
SOURCESearch...

Entry information

Entry nameITCH_HUMAN
AccessionPrimary (citable) accession number: Q96J02
Secondary accession number(s): A6NEW4 expand/collapse secondary AC list , B4E234, E1P5P3, F5H217, O43584, Q5QP37, Q5TEL0, Q96F66, Q9BY75, Q9H451, Q9H4U5
Entry history
Integrated into UniProtKB/Swiss-Prot: October 3, 2003
Last sequence update: October 3, 2003
Last modified: July 9, 2014
This is version 126 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 20

Human chromosome 20: entries, gene names and cross-references to MIM