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Protein Page:
ITCH (human)
p Phosphorylation
ac Acetylation
me Methylation
m1 Mono-methylation
m2 Di-methylation
m3 Tri-methylation
ub Ubiquitination
sm Sumoylation
ne Neddylation
gl O-GlcNAc
ga O-GalNAc
pa Palmitoylation
ad Adenylylation
sn S-Nitrosylation
ca Caspase cleavage
sc Succinylation

Overview
ITCH 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. 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. Monomer Interacts (via its WW domains) with OCNL, NOTCH1 AND JUN. 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. 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 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. Widely expressed. 2 isoforms of the human protein are produced by alternative splicing. Note: This description may include information from UniProtKB.
Protein type: Ubiquitin conjugating system; Ubiquitin ligase; EC 6.3.2.-; Ligase; EC 6.3.2.19
Cellular Component: membrane; cytoplasm; plasma membrane; cytoplasmic vesicle; cell cortex; cytosol; nucleus
Molecular Function: ribonucleoprotein binding; protein binding; CXCR chemokine receptor binding; ubiquitin-protein ligase activity; ligase activity
Biological Process: ubiquitin-dependent protein catabolic process; negative regulation of JNK cascade; entry of virus into host cell; Notch signaling pathway; apoptosis; protein ubiquitination during ubiquitin-dependent protein catabolic process; protein ubiquitination; negative regulation of defense response to virus; inhibition of NF-kappaB transcription factor; positive regulation of protein catabolic process; negative regulation of alpha-beta T cell proliferation; innate immune response; regulation of cell growth; inflammatory response; negative regulation of interferon type I production; positive regulation of T cell anergy; defense response to virus; negative regulation of apoptosis
Reference #:  Q96J02 (UniProtKB)
Alt. Names/Synonyms: AIF4; AIP4; atrophin-1 interacting protein 4; Atrophin-1-interacting protein 4; dJ468O1.1; dJ468O1.1 (atrophin 1 interacting protein 4 (AIP4)); E3 ubiquitin-protein ligase Itchy homolog; ITCH; itchy E3 ubiquitin protein ligase homolog (mouse); itchy homolog E3 ubiquitin protein ligase; NAPP1; NFE2-associated polypeptide 1; ubiquitin protein ligase ITCH
Gene Symbols: ITCH
Molecular weight: 102,803 Da
Basal Isoelectric point: 5.94  Predict pI for various phosphorylation states
CST Pathways:  Apoptosis Regulation  |  NF-kB Signaling
Protein-Specific Antibodies or siRNAs from Cell Signaling Technology® Total Proteins
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ITCH

Protein Structure Not Found.


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Sites Implicated In
molecular association, regulation: Y420‑p

Modification Sites and Domains Show Modification Legend
Click here to view phosphorylation modifications only

Modification Sites in Parent Protein, Orthologs, and Isoforms Show Modification Legend
 

Show Multiple Sequence Alignment


 SS 

SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.


 MS 

MS: The number of records in which this modification site was assigned using ONLY proteomic discovery-mode mass spectrometry.


       human

► Hide Isoforms
 
0 1 S10-p DSGSQLGsMGSLTMK
0 1 S18 MGSLTMKSQLQITVI
0 1 S26 QLQITVISAKLKENK
0 2 K34-ub AKLKENKkNWFGPSP
0 1 K53-m1 TVDGQSKkTEKCNNT
0 2 K66-ub NTNSPKWkQPLTVIV
0 1 K90-ub VWSHQTLkSDVLLGT
0 1 K107-ub LDIYETLkSNNMKLE
1 0 S202 VAGFTGASQNDDGSR
0 1 T214-p GSRSKDEtRVstNGs
0 2 S217-p SKDEtRVstNGsDDP
0 2 T218-p KDEtRVstNGsDDPE
0 3 S221-p tRVstNGsDDPEDAG
0 28 R233 DAGAGENRRVSGNNS
1 0 S240 RRVSGNNSPSLSNGG
1 0 T263 PSRPPPPTPRRPASV
1 0 S273 RPASVNGSPSATSES
0 4 Y343-p VDQHGRVyyVDHVEK
0 1 Y344-p DQHGRVyyVDHVEKR
0 1 K350 yyVDHVEKRTTWDRP
0 3 Y375-p VDNMGRIyYVDHFTR
1 0 T385-p DHFTRTTtWQRPTLE
0 1 S393-p WQRPTLEsVRNyEQW
0 5 Y397-p TLEsVRNyEQWQLQR
1 95 Y420-p QFNQRFIyGNQDLFA
0 96 K432-ub LFATSQSkEFDPLGP
0 44 K446-ub PLPPGWEkRTDsNGR
3 0 S450-p GWEkRTDsNGRVYFV
2 0 T464 VNHNTRITQWEDPRS
0 34 K478-ub SQGQLNEkPLPEGWE
0 1 Y495-p FTVDGIPyFVDHNRR
0 1 T503-p FVDHNRRtttyIDPR
0 1 T504-p VDHNRRtttyIDPRT
0 1 T505-p DHNRRtttyIDPRTG
0 1 Y506-p HNRRtttyIDPRTGk
0 3 K513-ub yIDPRTGkSALDNGP
0 1 S514 IDPRTGkSALDNGPQ
0 11 Y589-p PGEEGLDyGGVAREW
0 2 K861-ub FCIEKVGkENWLPRS
  ITCH iso2  
S10 DSGSQLGSMGSLTMK
S18 MGSLTMKSQLQITVI
S26 QLQITVISAKLKENK
K34 AKLKENKKNWFGPSP
K53 TVDGQSKKTEKCNNT
K66 NTNSPKWKQPLTVIV
K90 VWSHQTLKSDVLLGT
K107 LDIYETLKSNNMKLE
S161-p TTCSESAsQNDDGSR
T173 GSRSKDETRVSTNGS
S176 SKDETRVSTNGSDDP
T177 KDETRVSTNGSDDPE
S180 TRVSTNGSDDPEDAG
R192 DAGAGENRRVSGNNS
S199 RRVSGNNSPSLSNGG
T222 PSRPPPPTPRRPASV
S232 RPASVNGSPSATSES
Y302 VDQHGRVYYVDHVEK
Y303 DQHGRVYYVDHVEKR
K309 YYVDHVEKRTTWDRP
Y334 VDNMGRIYYVDHFTR
T344 DHFTRTTTWQRPTLE
S352 WQRPTLESVRNYEQW
Y356 TLESVRNYEQWQLQR
Y379 QFNQRFIYGNQDLFA
K391 LFATSQSKEFDPLGP
K405 PLPPGWEKRTDSNGR
S409 GWEKRTDSNGRVYFV
T423 VNHNTRITQWEDPRS
K437 SQGQLNEKPLPEGWE
Y454 FTVDGIPYFVDHNRR
T462 FVDHNRRTTTYIDPR
T463 VDHNRRTTTYIDPRT
T464 DHNRRTTTYIDPRTG
Y465 HNRRTTTYIDPRTGK
K472 YIDPRTGKSALDNGP
S473 IDPRTGKSALDNGPQ
Y548 PGEEGLDYGGVAREW
K820 FCIEKVGKENWLPRS
  mouse

 
S10 DSGPQLDSMGSLTMK
S18-p MGSLTMKsQLQITVI
S26-p QLQITVIsAKLKENK
K34 AKLKENKKNWFGPSP
K53 TVDGQSKKTEKCNNT
K66-ub NTNSPKWkQPLTVIV
K90 VWSHQTLKSDVLLGT
K107 LDIYETLKSNNMKLE
T161 TSCSESTTQNDDGCR
T173 GCRTRDDTRVStNGs
S176 TRDDTRVStNGsEDP
T177-p RDDTRVStNGsEDPE
S180-p TRVStNGsEDPEVAA
K192-ub VAASGENkRANGNNs
S199-p kRANGNNsPSLSNGG
T222-p PSRPPPPtPRRPASV
S232-p RPASVNGsPSTNSDS
Y304 VDQHGRVYYVDHVEk
Y305 DQHGRVYYVDHVEkR
K311-ub YYVDHVEkRTTWDRP
Y336 VDNMGRIYYVDHFTR
T346 DHFTRTTTWQRPTLE
S354 WQRPTLESVRNYEQW
Y358 TLESVRNYEQWQLQR
Y381 QFNQRFIYGNQDLFA
K393-ub LFATSQNkEFDPLGP
K407-ub PLPPGWEkRTDsNGR
S411-p GWEkRTDsNGRVYFV
T425-p VNHNTRItQWEDPRS
K439-ub SQGQLNEkPLPEGWE
Y456 FTVDGIPYFVDHNRR
A464 FVDHNRRATTYIDPR
T465 VDHNRRATTYIDPRT
T466 DHNRRATTYIDPRTG
Y467 HNRRATTYIDPRTGk
K474-ub YIDPRTGksALDNGP
S475-p IDPRTGksALDNGPQ
Y550 PGEEGLDYGGVAREW
K822 FCIEKVGKENWLPRS
  rat

 
- under review  
S8 MGSLTMKSQLQITVI
S16 QLQITVISAKLKENK
K24 AKLKENKKNWFGPSP
K43 TVDGQSKKTEKCNNT
K56 NTNSPKWKQPLTVIV
K80 VWSHQTLKSDVLLGT
K97 LDIYETLKSNNMKLE
T151 TSCSEGATQNDAGCR
T163 GCRPKDETRVSTNGS
S166 PKDETRVSTNGSEDP
T167 KDETRVSTNGSEDPE
S170 TRVSTNGSEDPEVAA
K182-ub VAASGENkRANGNNS
S189 kRANGNNSPSLSNGG
T212 PSRPPPPTPRRPASV
S222 RPASVNGSPSTNSDS
Y294 VDQHGRAYYVDHVEK
Y295 DQHGRAYYVDHVEKR
K301 YYVDHVEKRTTRDRP
Y326 VDNMGRIYYVDHFTR
T336 DHFTRTTTWQRPTLE
S344 WQRPTLESVRNYEQW
Y348 TLESVRNYEQWQLQR
F371 QFNQRFIFGNQDLFA
K383-ub LFATSQNkEFDPLGP
K397-ub PLPPGWEkRTDSNGR
S401 GWEkRTDSNGRVYFV
T415 VNHNTRITQWEDPRS
K429-ub SQGQLNEkPLPEGWE
Y446 FTVDGIPYFVDHNRR
A454 FVDHNRRATTYIDPR
T455 VDHNRRATTYIDPRT
T456 DHNRRATTYIDPRTG
Y457 HNRRATTYIDPRTGK
K464 YIDPRTGKSALDNGP
S465 IDPRTGKSALDNGPQ
Y540-p PGEEGLDyGGVAREW
K812 FCIEKVGKENWLPRS
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