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Protein

E3 ubiquitin-protein ligase Itchy

Gene

Itch

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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 (PubMed:15358865, PubMed:16446428, PubMed:17592138, PubMed:18628966, PubMed:20392206, PubMed:25632008). It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (By similarity). Involved in the control of inflammatory signaling pathways (By similarity). 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 (By similarity). Promotes the association of the complex after TNF stimulation (By similarity). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (By similarity). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (By similarity). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (By similarity). Regulates the transcriptional activity of several transcription factors involved in immune response (PubMed:15358865, PubMed:11828324). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (By similarity). Mediates JUN ubiquitination and degradation (PubMed:15358865). Mediates JUNB ubiquitination and degradation (PubMed:11828324, PubMed:15358865). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (PubMed:11828324). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (By similarity). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (By similarity). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (By similarity). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (By similarity). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (By similarity). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:18628966). Ubiquitinates SNX9 (By similarity). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (PubMed:25632008). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (By similarity). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (By similarity).HMP:6 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.6 Publications

Enzyme regulationi

Activated by NDFIP1- and NDFIP2-binding (PubMed:25632008). Activated by PI4K2A-binding (By similarity). Inhibited by DTX3L-binding (By similarity). Inhibited by N4BP1 binding (PubMed:17592138).HMP:2 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.6 Publications
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei832Glycyl thioester intermediateIEP:1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionTransferase
Biological processAntiviral defense, Apoptosis, Immunity, Innate immunity, Ubl conjugation pathway

Enzyme and pathway databases

BRENDAi6.3.2.19. 3474.
ReactomeiR-MMU-1253288. Downregulation of ERBB4 signaling.
R-MMU-168638. NOD1/2 Signaling Pathway.
R-MMU-2122948. Activated NOTCH1 Transmits Signal to the Nucleus.
R-MMU-5610780. Degradation of GLI1 by the proteasome.
R-MMU-5632684. Hedgehog 'on' state.
R-MMU-8939236. RUNX1 regulates transcription of genes involved in differentiation of HSCs.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase Itchy (EC:2.3.2.266 Publications)
Alternative name(s):
HECT-type E3 ubiquitin transferase Itchy homolog
Gene namesi
Name:Itch
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:1202301. Itch.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Endosome, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Defects in Itch are the cause of the itchy phenotype which is an inflammatory and immunological condition characterized by inflammation in the lung and stomach, hyperplasia in lymphoid and hematopoietic cells and constant itching in the skin.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi199S → A: No loss of MAPK8-mediated phosphorylation and no effect on ligase activity. Almost complete inactivation of ligase activity; when associated with A-232. Greatly reduced MAPK8-mediated phosphorylation; when associated with A-222 or A-232. Completely abolishes MAPK8-mediated phosphorylation; when associated with A-222 and A-232. 1 Publication1
Mutagenesisi199S → D: More sensitive to in vitro proteolysis. 1 Publication1
Mutagenesisi222T → A: No loss of MAPK8-mediated phosphorylation. Greatly reduced MAPK8-mediated phosphorylation; when associated with A-199 or A-232. Completely abolishes MAPK8-mediated phosphorylation; when associated with A-199 and A-232. 1 Publication1
Mutagenesisi222T → D: Inhibits in vitro interaction between ITCH HECT domain and PRR/WW motifs. More sensitive to in vitro proteolysis. 1 Publication1
Mutagenesisi232S → A: No loss of MAPK8-mediated phosphorylation and no effect on ligase activity. Almost complete inactivation of ligase activity; when associated with A-199. Greatly reduced MAPK8-mediated phosphorylation; when associated with A-199 or A-222. Completely abolishes MAPK8-mediated phosphorylation; when associated with A-199 and A-222. 1 Publication1
Mutagenesisi232S → D: More sensitive to in vitro proteolysis. 1 Publication1
Mutagenesisi535 – 540RRRLWV → AAALWA: Abolishes interaction with MAPK8. 1 Publication6
Mutagenesisi535 – 537RRR → AAA: Almost complete loss of interaction with MAPK8. 3
Mutagenesisi535 – 536RR → AA: Greatly decreased interaction with MAPK8 and ligase activity. 2
Mutagenesisi832C → A: Loss of ubiquitin protein ligase activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedHMP:
ChainiPRO_00001203182 – 864E3 ubiquitin-protein ligase ItchyAdd BLAST863

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineHMP:1
Modified residuei199Phosphoserine; by MAPK81 Publication1
Modified residuei222Phosphothreonine; by MAPK81 Publication1
Modified residuei232Phosphoserine; by MAPK81 Publication1
Modified residuei346Phosphothreonine; by SGK3HMP:1
Modified residuei381Phosphotyrosine; by FYNHMP:1
Modified residuei411Phosphoserine; by SGK3HMP:1

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. Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation.4 Publications
Monoubiquitinated. Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation.HMP:

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ8C863.
PaxDbiQ8C863.
PeptideAtlasiQ8C863.
PRIDEiQ8C863.

PTM databases

iPTMnetiQ8C863.
PhosphoSitePlusiQ8C863.

Expressioni

Tissue specificityi

Detected in uterus (at protein level) (PubMed:23146885). Widely expressed (PubMed:9462742).2 Publications

Gene expression databases

BgeeiENSMUSG00000027598.
CleanExiMM_ITCH.
GenevisibleiQ8C863. MM.

Interactioni

Subunit structurei

Monomer. Interacts (via WW domains) with OCNL (PubMed:11782481). Interacts (via WW domains) with NOTCH1 (PubMed:10940313, PubMed:18628966). Interacts (via WW domains) JUN (PubMed:11828324). Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB (PubMed:11828324). Interacts with FYN; the interaction phosphorylates ITCH on Tyr-381 decreasing binding of JUNB (By similarity). Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity (PubMed:17592138). Interacts with NDFIP1 and NDFIP2; the interaction with NDFIP proteins activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (PubMed:11748237, PubMed:17137798, PubMed:25632008). Interacts with ARHGEF7 (By similarity). Interacts with RNF11 (By similarity). 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 (By similarity). Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation (By similarity). Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM (By similarity). Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct) (By similarity). Interacts with HGS (By similarity). Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2 (By similarity). Interacts (via WW domains) with TXNIP (via C-terminus) (By similarity). Interacts with p15 BID (PubMed:20392206). Interacts with ERBB4 (By similarity).Interacts with DTX1 (By similarity). Interacts with SPART (By similarity). Interacts with SNX9 and SNX18 (By similarity). Interacts (via its WW domains) with ATN1 (By similarity). Interacts (via WW domains) with SGK3 (By similarity). Interacts with CBLC (By similarity). Interacts with OTUD7B (By similarity). Interacts (via WW domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity and promotes ITCH catalytic activity (PubMed:23146885). Interacts with ARRDC4 (By similarity). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (PubMed:25632008). Interacts with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008). Interacts with MAPK8/JNK1 (PubMed:16446428). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); the interaction is direct and participates to the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor (By similarity). Interacts (via WW domains) with ARRDC2 (By similarity). Interacts (via WW domains) with ARRDC3 (By similarity).HMP:10 Publications
(Microbial infection) Interacts with Epstein-Barr virus LMP2A.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200813. 23 interactors.
DIPiDIP-29318N.
ELMiQ8C863.
IntActiQ8C863. 12 interactors.
MINTiMINT-142559.
STRINGi10090.ENSMUSP00000029126.

Structurei

Secondary structure

1864
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi293 – 297ND:5
Beta strandi303 – 307ND:5
Turni308 – 311ND:4
Beta strandi312 – 316ND:5
Beta strandi325 – 329ND:5
Beta strandi335 – 339ND:5
Turni340 – 342ND:3
Beta strandi345 – 348ND:4
Helixi352 – 370ND:19
Helixi372 – 375ND:4
Beta strandi399 – 401ND:3
Beta strandi407 – 409ND:3
Beta strandi411 – 413ND:3
Beta strandi415 – 419ND:5
Turni420 – 423ND:4
Beta strandi424 – 426ND:3
Helixi489 – 503ND:15
Beta strandi505 – 512ND:8
Helixi518 – 528ND:11
Helixi531 – 534ND:4
Beta strandi536 – 541ND:6
Helixi550 – 564ND:15
Helixi568 – 570ND:3
Beta strandi573 – 575ND:3
Beta strandi582 – 585ND:4
Helixi587 – 591ND:5
Helixi595 – 612ND:18
Helixi622 – 628ND:7
Helixi635 – 641ND:7
Helixi643 – 649ND:7
Helixi712 – 725ND:14
Helixi728 – 731ND:4
Helixi736 – 744ND:9
Helixi751 – 756ND:6
Helixi771 – 779ND:9
Helixi782 – 793ND:12
Helixi803 – 805ND:3
Beta strandi815 – 819ND:5
Beta strandi823 – 825ND:3
Beta strandi828 – 830ND:3
Helixi831 – 833ND:3
Beta strandi835 – 838ND:4
Helixi844 – 856ND:13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1YIUNMR-A399-432[»]
2JO9NMR-A399-432[»]
2JOCNMR-A399-432[»]
5XMCX-ray2.60A143-864[»]
ProteinModelPortaliQ8C863.
SMRiQ8C863.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8C863.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini5 – 99C2IEP:Add BLAST95
Domaini287 – 320WW 1IEP:Add BLAST34
Domaini319 – 352WW 2IEP:Add BLAST34
Domaini399 – 432WW 3IEP:Add BLAST34
Domaini439 – 472WW 4IEP:Add BLAST34
Domaini530 – 864HECTIEP:Add BLAST335

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni356 – 432Required for interaction with FYNHMP:Add BLAST77
Regioni535 – 544MAP kinase docking site10

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi211 – 226Arg/Pro-rich (PRR domain)Add BLAST16

Domaini

The WW domains mediate interaction with PPxY motif-containing proteins.HMP:

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0940. Eukaryota.
COG5021. LUCA.
GeneTreeiENSGT00760000118966.
HOVERGENiHBG004134.
InParanoidiQ8C863.
KOiK05632.
OMAiSLIWVKE.
OrthoDBiEOG091G0SS8.
PhylomeDBiQ8C863.
TreeFamiTF323658.

Family and domain databases

CDDicd00078. HECTc. 1 hit.
cd00201. WW. 4 hits.
Gene3Di2.60.40.150. 1 hit.
InterProiView protein in InterPro
IPR000008. C2_dom.
IPR035892. C2_domain_sf.
IPR024928. E3_ub_ligase_SMURF1.
IPR000569. HECT_dom.
IPR035983. Hect_E3_ubiquitin_ligase.
IPR001202. WW_dom.
IPR036020. WW_dom_sf.
PfamiView protein in Pfam
PF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 3 hits.
PIRSFiPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMARTiView protein in SMART
SM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 4 hits.
SSF56204. SSF56204. 1 hit.
PROSITEiView protein in PROSITE
PS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8C863-1) [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

        10         20         30         40         50
MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ
60 70 80 90 100
SKKTEKCNNT NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL
110 120 130 140 150
DIYETLKSNN MKLEEVVMTL QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT
160 170 180 190 200
NGETSCSEST TQNDDGCRTR DDTRVSTNGS EDPEVAASGE NKRANGNNSP
210 220 230 240 250
SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD GSSTGSLPPT
260 270 280 290 300
NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH
310 320 330 340 350
GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP
360 370 380 390 400
TLESVRNYEQ WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP
410 420 430 440 450
LPPGWEKRTD SNGRVYFVNH NTRITQWEDP RSQGQLNEKP LPEGWEMRFT
460 470 480 490 500
VDGIPYFVDH NRRATTYIDP RTGKSALDNG PQIAYVRDFK AKVQYFRFWC
510 520 530 540 550
QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV IFPGEEGLDY
560 570 580 590 600
GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR
610 620 630 640 650
FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI
660 670 680 690 700
WVKENNIEEC GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR
710 720 730 740 750
MVAEWRLSRG VEEQTQAFFE GFNEILPQQY LQYFDAKELE VLLCGMQEID
760 770 780 790 800
LNDWQRHAIY RHYTRTSKQI MWFWQFVKEI DNEKRMRLLQ FVTGTCRLPV
810 820 830 840 850
GGFADLMGSN GPQKFCIEKV GKENWLPRSH TCFNRLDLPP YKSYEQLKEK
860
LLFAIEETEG FGQE
Note: Major form.
Length:864
Mass (Da):98,994
Last modified:October 3, 2003 - v2
Checksum:i905FDBE00A1EA7EA
GO
Isoform 2 (identifier: Q8C863-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     742-759: LLCGMQEIDLNDWQRHAI → MNFYLLKHTSKYSFRYLF
     760-864: Missing.

Show »
Length:759
Mass (Da):86,702
Checksum:iB1820795111F666B
GO

Sequence cautioni

The sequence AAB99764 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.IKR:

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_008452742 – 759LLCGM…QRHAI → MNFYLLKHTSKYSFRYLF in isoform 2. IBD:Add BLAST18
Alternative sequenceiVSP_008453760 – 864Missing in isoform 2. IBD:Add BLAST105

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF037454 mRNA. Translation: AAB99764.1. Different initiation.
AK048303 mRNA. Translation: BAC33298.1.
BC062934 mRNA. Translation: AAH62934.1.
CCDSiCCDS38293.1. [Q8C863-1]
RefSeqiNP_001230641.1. NM_001243712.1. [Q8C863-1]
NP_032421.2. NM_008395.3. [Q8C863-1]
UniGeneiMm.208286.
Mm.490088.

Genome annotation databases

EnsembliENSMUST00000029126; ENSMUSP00000029126; ENSMUSG00000027598. [Q8C863-1]
ENSMUST00000109685; ENSMUSP00000105307; ENSMUSG00000027598. [Q8C863-1]
GeneIDi16396.
KEGGimmu:16396.
UCSCiuc008nkd.1. mouse. [Q8C863-2]
uc008nke.2. mouse. [Q8C863-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiITCH_MOUSE
AccessioniPrimary (citable) accession number: Q8C863
Secondary accession number(s): O54971
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 3, 2003
Last sequence update: October 3, 2003
Last modified: November 22, 2017
This is version 156 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Caution

It is uncertain whether Met-1 or Met-11 is the initiator.IKR:

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references