UniProt Accession

 ITCH_HUMAN; Q96J02; A6NEW4; B4E234; E1P5P3; F5H217; O43584; Q5QP37; Q5TEL0; Q96F66; Q9BY75; Q9H451; Q9H4U5 

Genbank Protein ID

 AF095745; AB056663; AK304090; AK315212; AL109923; AL356299; AL356299; AL109923; AL356299; AL109923; AL109923; AL356299; CH471077; CH471077; CH471077; BC006848; BC011571; AF038564 

Genbank Nucleotide ID

 AAK39399.1; BAB39389.1; BAG64996.1; BAG37647.1; CAI21458.1; CAI21458.1; CAI17959.1; CAI17959.1; CAI17960.1; CAI17960.1; CAI21459.1; CAI21459.1; EAW76272.1; EAW76274.1; EAW76276.1; AAH06848.1; AAH11571.1; AAC04845.1 

Protein Name

 E3 ubiquitin-protein ligase Itchy homolog 

Protein Synonyms/Alias

 Itch; Atrophin-1-interacting protein 4; AIP4; NFE2-associated polypeptide 1; NAPP1 

Gene Name

 ITCH 

Gene Synonyms/Alias

  

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
34	AKLKENKKNWFGPSP	ubiquitination	[1, 2, 3, 4]
66	NTNSPKWKQPLTVIV	ubiquitination	[1, 3, 4, 5]
350	YYVDHVEKRTTWDRP	ubiquitination	[3, 5, 6, 7]
432	LFATSQSKEFDPLGP	ubiquitination	[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]
446	PLPPGWEKRTDSNGR	ubiquitination	[1, 2, 3, 4, 5, 6, 9, 12, 13]
478	SQGQLNEKPLPEGWE	ubiquitination	[1, 2, 3, 4, 5, 7, 8, 9, 10, 11]
513	YIDPRTGKSALDNGP	ubiquitination	[1, 2, 3, 4, 7, 10]
858	PQKFCIEKVGKENWL	ubiquitination	[3]
861	FCIEKVGKENWLPRS	ubiquitination	[1, 3, 8]
881	RLDLPPYKSYEQLKE	ubiquitination	[1]

Reference

 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [4] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
 Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
 Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]
 [5] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [6] Proteome-wide identification of ubiquitylation sites by conjugation of engineered lysine-less ubiquitin.
 Oshikawa K, Matsumoto M, Oyamada K, Nakayama KI.
 J Proteome Res. 2012 Feb 3;11(2):796-807. [PMID: 22053931]
 [7] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
 Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
 Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965]
 [8] A data set of human endogenous protein ubiquitination sites.
 Shi Y, Chan DW, Jung SY, Malovannaya A, Wang Y, Qin J.
 Mol Cell Proteomics. 2011 May;10(5):M110.002089. [PMID: 20972266]
 [9] Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level.
 Danielsen JM, Sylvestersen KB, Bekker-Jensen S, Szklarczyk D, Poulsen JW, Horn H, Jensen LJ, Mailand N, Nielsen ML.
 Mol Cell Proteomics. 2011 Mar;10(3):M110.003590. [PMID: 21139048]
 [10] Global identification of modular cullin-RING ligase substrates.
 Emanuele MJ, Elia AE, Xu Q, Thoma CR, Izhar L, Leng Y, Guo A, Chen YN, Rush J, Hsu PW, Yen HC, Elledge SJ.
 Cell. 2011 Oct 14;147(2):459-74. [PMID: 21963094]
 [11] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [12] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [13] Global analysis of lysine ubiquitination by ubiquitin remnant immunoaffinity profiling.
 Xu G, Paige JS, Jaffrey SR.
 Nat Biotechnol. 2010 Aug;28(8):868-73. [PMID: 20639865] 

Functional Description

 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. 

Sequence Annotation

 DOMAIN 5 99 C2.
 DOMAIN 326 359 WW 1.
 DOMAIN 358 391 WW 2.
 DOMAIN 438 471 WW 3.
 DOMAIN 478 511 WW 4.
 DOMAIN 569 903 HECT.
 REGION 395 471 Required for interaction with FYN.
 REGION 574 583 MAP kinase docking site (By similarity).
 ACT_SITE 871 871 Glycyl thioester intermediate (By
 MOD_RES 2 2 N-acetylserine.
 MOD_RES 240 240 Phosphoserine; by MAPK8 (By similarity).
 MOD_RES 263 263 Phosphothreonine; by MAPK8 (By
 MOD_RES 273 273 Phosphoserine; by MAPK8 (By similarity).
 MOD_RES 385 385 Phosphothreonine; by SGK3.
 MOD_RES 420 420 Phosphotyrosine; by FYN.
 MOD_RES 450 450 Phosphoserine; by SGK3.  

Keyword

 3D-structure; Acetylation; Alternative splicing; Antiviral defense; Apoptosis; Cell membrane; Complete proteome; Cytoplasm; Direct protein sequencing; Host-virus interaction; Immunity; Innate immunity; Ligase; Membrane; Nucleus; Phosphoprotein; Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 903 AA 

Protein Sequence

Gene Ontology

 GO:0005938; C:cell cortex; IEA:Compara.
 GO:0031410; C:cytoplasmic vesicle; IEA:Compara.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005634; C:nucleus; IBA:RefGenome.
 GO:0005886; C:plasma membrane; IDA:UniProtKB.
 GO:0043021; F:ribonucleoprotein complex binding; IPI:UniProtKB.
 GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
 GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
 GO:0006954; P:inflammatory response; NAS:UniProtKB.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IEA:Compara.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:0050687; P:negative regulation of defense response to virus; IMP:UniProtKB.
 GO:0046329; P:negative regulation of JNK cascade; ISS:BHF-UCL.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:BHF-UCL.
 GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
 GO:0007219; P:Notch signaling pathway; TAS:Reactome.
 GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
 GO:0045732; P:positive regulation of protein catabolic process; IEA:Compara.
 GO:0002669; P:positive regulation of T cell anergy; IEA:Compara.
 GO:0035519; P:protein K29-linked ubiquitination; IDA:UniProtKB.
 GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
 GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
 GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:RefGenome.
 GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
 GO:0090085; P:regulation of protein deubiquitination; ISS:BHF-UCL.
 GO:0046718; P:viral entry into host cell; TAS:UniProtKB. 

Interpro

 IPR000008; C2_Ca-dep.
 IPR008973; C2_Ca/lipid-bd_dom_CaLB.
 IPR018029; C2_membr_targeting.
 IPR024928; E3_ub_ligase_SMURF1.
 IPR000569; HECT.
 IPR001202; WW_dom. 

Pfam

 PF00168; C2
 PF00632; HECT
 PF00397; WW 

SMART

 SM00239; C2
 SM00119; HECTc
 SM00456; WW 

PROSITE

 PS50004; C2
 PS50237; HECT
 PS01159; WW_DOMAIN_1
 PS50020; WW_DOMAIN_2 

PRINTS