Q96J02 (ITCH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	903 AA.
Sequence status	Complete.
Protein existence	Evidence 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.20 Ref.21 Ref.23 Ref.26 Ref.27
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.19 Ref.21 Ref.22 Ref.23 Ref.25 Ref.26 Ref.27 Ref.28 Ref.30
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.28
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.20 Ref.23 Ref.25 Ref.26 Ref.27
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.24
Sequence similarities	Contains 1 C2 domain. Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. Contains 4 WW domains.

Ontologies

Keywords
Biological process	Antiviral defense Apoptosis Host-virus interaction Immunity Innate immunity Ubl conjugation pathway
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Molecular function	Ligase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Notch 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: Compara negative regulation of apoptotic process Inferred from mutant phenotype Ref.27. Source: UniProtKB negative regulation of defense response to virus Inferred from mutant phenotype Ref.23. Source: UniProtKB negative regulation of type I interferon production 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: Compara positive regulation of protein catabolic process Inferred from electronic annotation. Source: Compara protein K29-linked ubiquitination Inferred from direct assay Ref.13Ref.18. Source: UniProtKB protein K48-linked ubiquitination Inferred from direct assay Ref.23. Source: UniProtKB protein K63-linked ubiquitination Inferred from direct assay Ref.15Ref.20. 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 viral entry into host cell Traceable author statement PubMed 12450395. Source: UniProtKB
Cellular_component	cell cortex Inferred from electronic annotation. Source: Compara cytoplasmic vesicle Inferred from electronic annotation. Source: Compara cytosol Traceable author statement. Source: Reactome nucleus Inferred from Biological aspect of Ancestor. Source: RefGenome plasma membrane Inferred from direct assay Ref.11. Source: UniProtKB
Molecular_function	ribonucleoprotein complex binding Inferred from physical interaction Ref.23. Source: UniProtKB ubiquitin-protein ligase activity Inferred from direct assay PubMed 17592138. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GLI1	P08151	4	EBI-1564678,EBI-308084
Numb	Q9QZS3-2	2	EBI-1564678,EBI-3896014	From a different organism.
RNF11	Q9Y3C5	2	EBI-1564678,EBI-396669

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 903

903

E3 ubiquitin-protein ligase Itchy homolog

PRO_0000120317

Regions

Domain

5 – 99

95

C2

Domain

326 – 359

34

WW 1

Domain

358 – 391

34

WW 2

Domain

438 – 471

34

WW 3

Domain

478 – 511

34

WW 4

Domain

569 – 903

335

HECT

Region

395 – 471

77

Required for interaction with FYN

Region

574 – 583

10

MAP kinase docking site By similarity

Compositional bias

252 – 267

16

Arg/Pro-rich (PRR domain)

Sites

Active site

871

1

Glycyl thioester intermediate By similarity

Amino acid modifications

Modified residue

240

1

Phosphoserine; by MAPK8 By similarity

Modified residue

263

1

Phosphothreonine; by MAPK8 By similarity

Modified residue

273

1

Phosphoserine; by MAPK8 By similarity

Modified residue

385

1

Phosphothreonine; by SGK3 Ref.12

Modified residue

420

1

Phosphotyrosine; by FYN Ref.14

Modified residue

450

1

Phosphoserine; by SGK3 Ref.12

Natural variations

Alternative sequence

1 – 110

110

Missing in isoform 3.

VSP_044732

Alternative sequence

159 – 200

42

NGVSL…AGFTG → S in isoform 2 and isoform 3.

VSP_008451

Experimental info

Mutagenesis

343

1

Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. Ref.14

Mutagenesis

420

1

Y → 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

Mutagenesis

455

1

Y → F: No effect on phosphorylation on T-cell stimulation nor in the presence of FYN. Ref.14

Mutagenesis

871

1

C → 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.23

Sequence conflict

297

1

T → I in BAG64996. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

903

Helix Strand Turn

Details...

Beta strand

18 – 29

12

Beta strand

41 – 47

7

Beta strand

50 – 53

4

Beta strand

64 – 73

10

Beta strand

78 – 85

8

Beta strand

88 – 90

3

Beta strand

93 – 101

9

Helix

102 – 108

7

Turn

109 – 111

3

Beta strand

112 – 126

15

Beta strand

130 – 143

14

Beta strand

332 – 336

5

Beta strand

342 – 346

5

Turn

347 – 349

3

Beta strand

352 – 355

4

Beta strand

365 – 368

4

Beta strand

374 – 377

4

Beta strand

379 – 381

3

Beta strand

482 – 488

7

Beta strand

494 – 498

5

Turn

499 – 501

3

Beta strand

504 – 507

4

Turn

509 – 511

3

Helix

528 – 539

12

Turn

540 – 542

3

Beta strand

545 – 551

7

Beta strand

554 – 556

3

Helix

557 – 567

11

Helix

572 – 574

3

Beta strand

575 – 580

6

Helix

589 – 603

15

Turn

607 – 609

3

Beta strand

611 – 614

4

Beta strand

621 – 624

4

Helix

626 – 630

5

Helix

634 – 650

17

Helix

661 – 667

7

Helix

675 – 677

3

Turn

678 – 680

3

Helix

682 – 692

11

Helix

735 – 747

13

Helix

751 – 764

14

Helix

767 – 770

4

Helix

775 – 783

9

Helix

790 – 795

6

Beta strand

798 – 801

4

Helix

807 – 818

12

Helix

821 – 832

12

Helix

842 – 844

3

Beta strand

848 – 851

4

Beta strand

855 – 858

4

Beta strand

867 – 869

3

Helix

870 – 872

3

Beta strand

874 – 877

4

Helix

883 – 895

13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 3, 2003. Version 2. Checksum: 6777A2043C7B67BC	FASTA	903	102,803
	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
	Isoform 2 [UniParc]. Checksum: A3D960E7F4DBF9D3	FASTA	862	98,676
	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 NGETTCSESA SQNDDGSRSK DETRVSTNGS 190 200 210 220 230 240 DDPEDAGAGE NRRVSGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSATSESD 250 260 270 280 290 300 GSSTGSLPPT NTNTNTSEGA TSGLIIPLTI SGGSGPRPLN PVTQAPLPPG WEQRVDQHGR 310 320 330 340 350 360 VYYVDHVEKR TTWDRPEPLP PGWERRVDNM GRIYYVDHFT RTTTWQRPTL ESVRNYEQWQ 370 380 390 400 410 420 LQRSQLQGAM QQFNQRFIYG NQDLFATSQS KEFDPLGPLP PGWEKRTDSN GRVYFVNHNT 430 440 450 460 470 480 RITQWEDPRS QGQLNEKPLP EGWEMRFTVD GIPYFVDHNR RTTTYIDPRT GKSALDNGPQ 490 500 510 520 530 540 IAYVRDFKAK VQYFRFWCQQ LAMPQHIKIT VTRKTLFEDS FQQIMSFSPQ DLRRRLWVIF 550 560 570 580 590 600 PGEEGLDYGG VAREWFFLLS HEVLNPMYCL FEYAGKDNYC LQINPASYIN PDHLKYFRFI 610 620 630 640 650 660 GRFIAMALFH GKFIDTGFSL PFYKRILNKP VGLKDLESID PEFYNSLIWV KENNIEECDL 670 680 690 700 710 720 EMYFSVDKEI LGEIKSHDLK PNGGNILVTE ENKEEYIRMV AEWRLSRGVE EQTQAFFEGF 730 740 750 760 770 780 NEILPQQYLQ YFDAKELEVL LCGMQEIDLN DWQRHAIYRH YARTSKQIMW FWQFVKEIDN 790 800 810 820 830 840 EKRMRLLQFV TGTCRLPVGG FADLMGSNGP QKFCIEKVGK ENWLPRSHTC FNRLDLPPYK 850 860 SYEQLKEKLL FAIEETEGFG QE
	Isoform 3 [UniParc]. Checksum: B08AB68B285391F8	FASTA	752	86,498
	10 20 30 40 50 60 MKLEEVVVTL QLGGDKEPTE TIGDLSICLD GLQLESEVVT NGETTCSESA SQNDDGSRSK 70 80 90 100 110 120 DETRVSTNGS DDPEDAGAGE NRRVSGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN 130 140 150 160 170 180 GSPSATSESD GSSTGSLPPT NTNTNTSEGA TSGLIIPLTI SGGSGPRPLN PVTQAPLPPG 190 200 210 220 230 240 WEQRVDQHGR VYYVDHVEKR TTWDRPEPLP PGWERRVDNM GRIYYVDHFT RTTTWQRPTL 250 260 270 280 290 300 ESVRNYEQWQ LQRSQLQGAM QQFNQRFIYG NQDLFATSQS KEFDPLGPLP PGWEKRTDSN 310 320 330 340 350 360 GRVYFVNHNT RITQWEDPRS QGQLNEKPLP EGWEMRFTVD GIPYFVDHNR RTTTYIDPRT 370 380 390 400 410 420 GKSALDNGPQ IAYVRDFKAK VQYFRFWCQQ LAMPQHIKIT VTRKTLFEDS FQQIMSFSPQ 430 440 450 460 470 480 DLRRRLWVIF PGEEGLDYGG VAREWFFLLS HEVLNPMYCL FEYAGKDNYC LQINPASYIN 490 500 510 520 530 540 PDHLKYFRFI GRFIAMALFH GKFIDTGFSL PFYKRILNKP VGLKDLESID PEFYNSLIWV 550 560 570 580 590 600 KENNIEECDL EMYFSVDKEI LGEIKSHDLK PNGGNILVTE ENKEEYIRMV AEWRLSRGVE 610 620 630 640 650 660 EQTQAFFEGF NEILPQQYLQ YFDAKELEVL LCGMQEIDLN DWQRHAIYRH YARTSKQIMW 670 680 690 700 710 720 FWQFVKEIDN EKRMRLLQFV TGTCRLPVGG FADLMGSNGP QKFCIEKVGK ENWLPRSHTC 730 740 750 FNRLDLPPYK SYEQLKEKLL FAIEETEGFG QE

References

	« Hide 'large scale' referencesShow '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. , 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]	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. , 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, 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]	"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.
[20]	"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.
[21]	"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.
[22]	"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.
[23]	"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.
[24]	"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.
[25]	"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.
[26]	"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.
[27]	"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.
[28]	"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.
[29]	"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].
[30]	"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.
[31]	"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.
[32]	"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.

IPI

IPI00061780.
IPI00176010.
IPI01010870.

RefSeq

NP_001244066.1. NM_001257137.1.
NP_001244067.1. NM_001257138.1.
NP_113671.3. NM_031483.5.

UniGene

Hs.632272.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

Q96J02.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29849N.

IntAct

Q96J02. 11 interactions.

MINT

MINT-148272.

STRING

9606.ENSP00000363998.

PTM databases

PhosphoSite

Q96J02.

Polymorphism databases

DMDM

37537897.

Proteomic databases

PaxDb

Q96J02.

PRIDE

Q96J02.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000262650; ENSP00000262650; ENSG00000078747.
ENST00000374864; ENSP00000363998; ENSG00000078747.
ENST00000535650; ENSP00000445608; ENSG00000078747.

GeneID

83737.

KEGG

hsa:83737.

UCSC

uc010geu.1. human.

Organism-specific databases

CTD

83737.

GeneCards

GC20P032951.

H-InvDB

HIX0015745.

HGNC

HGNC:13890. ITCH.

HPA

HPA021126.

MIM

606409. gene.
613385. phenotype.

neXtProt

NX_Q96J02.

Orphanet

228426. Syndromic multisystem autoimmune disease due to Itch deficiency.

PharmGKB

PA29934.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5021.

HOVERGEN

HBG004134.

InParanoid

Q96J02.

KO

K05632.

OMA

PTETIGD.

Enzyme and pathway databases

Pathway_Interaction_DB

nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_111102. Signal Transduction.
REACT_6900. Immune System.

UniPathway

UPA00143.

Gene expression databases

ArrayExpress

Q96J02.

Bgee

Q96J02.

CleanEx

HS_ITCH.

Genevestigator

Q96J02.

Family and domain databases

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.
[Graphical view]

Pfam

PF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 4 hits.
[Graphical view]

PIRSF

PIRSF001569. E3_ub_ligase_SMURF1. 1 hit.

SMART

SM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]

SUPFAM

SSF49562. C2_CaLB. 1 hit.
SSF56204. HECT. 1 hit.
SSF51045. WW_Rsp5_WWP. 4 hits.

PROSITE

PS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

ITCH. human.

EvolutionaryTrace

Q96J02.

GenomeRNAi

83737.

NextBio

72745.

SOURCE

Search...

Entry information

Entry name

ITCH_HUMAN

Accession

Primary (citable) accession number: Q96J02
Secondary accession number(s): A6NEW4 , 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:	May 1, 2013
This is version 114 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.