Q8C863 (ITCH_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase Itchy
EC=6.3.2.-

Gene names

Name:

Itch

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	864 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 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. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation. Ubiquitinates SNX9 By similarity. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway By similarity. 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 By similarity. 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. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination By similarity. Ref.5 Ref.8 Ref.11 Ref.12 Ref.13
Enzyme regulation	Activated by NDFIP1- and NDFIP2-binding By similarity.
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Monomer By similarity. Interacts with (via its WW domains) with ATN1. Interacts with ARHGEF7 and 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 (via WW domain 2) with N4BP1; leading to inhibits its E3 ubiquitin-protein ligase activity. 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 with FYN; the interaction phosphorylates ITCH on Tyr-381 decreasing binding of JUNB. Interacts (via WW domains) with TXNIP (via C-terminus). Interacts with ERBB4, DTX1, SPG20, SNX9 and SNX18. Interacts with OTUD7B By similarity. Interacts (via its WW domains) with OCNL, NOTCH1, JUN and JUNB. Interacts with p15 BID and MAPK8. Interacts with NDFIP1 and NDFIP2; the interaction with NDFIP proteins activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes. Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity. Interacts (via WW domains) with SGK3. Ref.4 Ref.5 Ref.6 Ref.7 Ref.9 Ref.10 Ref.11 Ref.13
Subcellular location	Cell membrane By similarity. Cytoplasm. Nucleus. Note: Associates with endocytic vesicles By similarity. May be recruited to exosomes by NDFIP1 By similarity.
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. 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 By similarity. Ref.8 Ref.10 Ref.12 Ref.13
Involvement in disease	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. Ref.1
Sequence similarities	Contains 1 C2 domain. Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. Contains 4 WW domains.
Caution	It is uncertain whether Met-1 or Met-11 is the initiator.
Sequence caution	The sequence AAB99764.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Antiviral defense Apoptosis 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 Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW defense response to virus Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of JNK cascade Inferred from mutant phenotype PubMed 18246070. Source: BHF-UCL negative regulation of NF-kappaB transcription factor activity Inferred from mutant phenotype PubMed 18246070. Source: BHF-UCL negative regulation of alpha-beta T cell proliferation Inferred from mutant phenotype PubMed 14973438. Source: MGI negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of defense response to virus Inferred from mutant phenotype PubMed 19881509. Source: UniProtKB positive regulation of T cell anergy Inferred from mutant phenotype PubMed 14973438. Source: MGI positive regulation of protein catabolic process Inferred from direct assay PubMed 14973438. Source: MGI protein K29-linked ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB protein K48-linked ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB protein K63-linked ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB protein ubiquitination involved in ubiquitin-dependent protein catabolic process Inferred from direct assay PubMed 14973438. Source: MGI regulation of protein deubiquitination Inferred from mutant phenotype PubMed 18246070. Source: BHF-UCL
Cellular_component	cell cortex Inferred from direct assay Ref.9. Source: MGI cytoplasmic vesicle Inferred from direct assay Ref.9. Source: MGI cytosol Traceable author statement. Source: Reactome membrane Inferred from direct assay PubMed 14973438. Source: MGI nucleus Inferred from direct assay PubMed 11555636. Source: MGI plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell ubiquitin ligase complex Inferred from sequence alignment Ref.1. Source: MGI
Molecular_function	ribonucleoprotein complex binding Inferred from electronic annotation. Source: Compara ubiquitin-protein ligase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8C863-1)

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: Major form.

Isoform 2 (identifier: Q8C863-2)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 864

864

E3 ubiquitin-protein ligase Itchy

PRO_0000120318

Regions

Domain

5 – 99

95

C2

Domain

287 – 320

34

WW 1

Domain

319 – 352

34

WW 2

Domain

399 – 432

34

WW 3

Domain

439 – 472

34

WW 4

Domain

530 – 864

335

HECT

Region

356 – 432

77

Required for interaction with FYN By similarity

Region

535 – 544

10

MAP kinase docking site

Compositional bias

211 – 226

16

Arg/Pro-rich (PRR domain)

Sites

Active site

832

1

Glycyl thioester intermediate By similarity

Amino acid modifications

Modified residue

199

1

Phosphoserine; by MAPK8 Ref.10

Modified residue

222

1

Phosphothreonine; by MAPK8 Ref.10

Modified residue

232

1

Phosphoserine; by MAPK8 Ref.10

Modified residue

346

1

Phosphothreonine; by SGK3 By similarity

Modified residue

381

1

Phosphotyrosine; by FYN By similarity

Modified residue

411

1

Phosphoserine; by SGK3 By similarity

Natural variations

Alternative sequence

742 – 759

18

LLCGM…QRHAI → MNFYLLKHTSKYSFRYLF in isoform 2.

VSP_008452

Alternative sequence

760 – 864

105

Missing in isoform 2.

VSP_008453

Experimental info

Mutagenesis

199

1

S → 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. Ref.10

Mutagenesis

199

1

S → D: More sensitive to in vitro proteolysis. Ref.10

Mutagenesis

222

1

T → 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. Ref.10

Mutagenesis

222

1

T → D: Inhibits in vitro interaction between ITCH HECT domain and PRR/WW motifs. More sensitive to in vitro proteolysis. Ref.10

Mutagenesis

232

1

S → 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. Ref.10

Mutagenesis

232

1

S → D: More sensitive to in vitro proteolysis. Ref.10

Mutagenesis

535 – 540

6

RRRLWV → AAALWA: Abolishes interaction with MAPK8. Ref.10

Mutagenesis

535 – 537

3

RRR → AAA: Almost complete loss of interaction with MAPK8.

Mutagenesis

535 – 536

2

RR → AA: Greatly decreased interaction with MAPK8 and ligase activity.

Mutagenesis

832

1

C → A: Loss of ubiquitin protein ligase activity. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

864

Helix Strand Turn

Details...

Beta strand

399 – 401

3

Beta strand

407 – 409

3

Beta strand

411 – 413

3

Beta strand

415 – 419

5

Turn

420 – 423

4

Beta strand

424 – 426

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 3, 2003. Version 2. Checksum: 905FDBE00A1EA7EA	FASTA	864	98,994
	10 20 30 40 50 60 MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 70 80 90 100 110 120 NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL 130 140 150 160 170 180 QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS 190 200 210 220 230 240 EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD 250 260 270 280 290 300 GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH 310 320 330 340 350 360 GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ 370 380 390 400 410 420 WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH 430 440 450 460 470 480 NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG 490 500 510 520 530 540 PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV 550 560 570 580 590 600 IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR 610 620 630 640 650 660 FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC 670 680 690 700 710 720 GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE 730 740 750 760 770 780 GFNEILPQQY LQYFDAKELE VLLCGMQEID LNDWQRHAIY RHYTRTSKQI MWFWQFVKEI 790 800 810 820 830 840 DNEKRMRLLQ FVTGTCRLPV GGFADLMGSN GPQKFCIEKV GKENWLPRSH TCFNRLDLPP 850 860 YKSYEQLKEK LLFAIEETEG FGQE
	Isoform 2 [UniParc]. Checksum: B1820795111F666B	FASTA	759	86,702
	10 20 30 40 50 60 MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 70 80 90 100 110 120 NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL 130 140 150 160 170 180 QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS 190 200 210 220 230 240 EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD 250 260 270 280 290 300 GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH 310 320 330 340 350 360 GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ 370 380 390 400 410 420 WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH 430 440 450 460 470 480 NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG 490 500 510 520 530 540 PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV 550 560 570 580 590 600 IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR 610 620 630 640 650 660 FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC 670 680 690 700 710 720 GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE 730 740 750 GFNEILPQQY LQYFDAKELE VMNFYLLKHT SKYSFRYLF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice." Perry W.L., Hustad C.M., Swing D.A., O'Sullivan T.N., Jenkins N.A., Copeland N.G. Nat. Genet. 18:143-146(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DISEASE. Strain: C3H/HeJ. Tissue: Kidney.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Strain: C57BL/6J. Tissue: Head.
[3]	"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] (ISOFORM 1). Strain: C57BL/6. Tissue: Brain.
[4]	"N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein." Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S. J. Biol. Chem. 277:9307-9317(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NDFIP1.
[5]	"Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation." Fang D., Elly C., Gao B., Fang N., Altman Y., Joazeiro C., Hunter T., Copeland N.G., Jenkins N.A., Liu Y.C. Nat. Immunol. 3:281-287(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH JUN AND JUNB.
[6]	"Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase." Qiu L., Joazeiro C., Fang N., Wang H.-Y., Elly C., Altman Y., Fang D., Hunter T., Liu Y.-C. J. Biol. Chem. 275:35734-35737(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NOTCH1, MUTAGENESIS OF CYS-832.
[7]	"The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch." Traweger A., Fang D., Liu Y.-C., Stelzhammer W., Krizbai I.A., Fresser F., Bauer H.-C., Bauer H. J. Biol. Chem. 277:10201-10208(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH OCNL.
[8]	"Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch." Gao M., Labuda T., Xia Y., Gallagher E., Fang D., Liu Y.C., Karin M. Science 306:271-275(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, FUNCTION, AUTOUBIQUITINATION.
[9]	"Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation." Oliver P.M., Cao X., Worthen G.S., Shi P., Briones N., MacLeod M., White J., Kirby P., Kappler J., Marrack P., Yang B. Immunity 25:929-940(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NDFIP1.
[10]	"Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change." Gallagher E., Gao M., Liu Y.C., Karin M. Proc. Natl. Acad. Sci. U.S.A. 103:1717-1722(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-199; THR-222 AND SER-232, INTERACTION WITH MAPK8, AUTOUBIQUITINATION, SUBUNIT, MUTAGENESIS OF SER-199; THR-222; SER-232 AND 535-ARG--VAL-540.
[11]	"The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch." Oberst A., Malatesta M., Aqeilan R.I., Rossi M., Salomoni P., Murillas R., Sharma P., Kuehn M.R., Oren M., Croce C.M., Bernassola F., Melino G. Proc. Natl. Acad. Sci. U.S.A. 104:11280-11285(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH N4BP1.
[12]	"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.
[13]	"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.
[14]	"Phosphorylation of either Ser16 or Thr30 does not disrupt the structure of the Itch E3 ubiquitin ligase third WW domain." Shaw A.Z., Martin-Malpartida P., Morales B., Yraola F., Royo M., Macias M.J. Proteins 60:558-560(2005) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 399-432 OF WILD TYPE AND IN VITRO WW3-PHOSPHORYLATED FORMS.
[15]	"NMR structural studies of the ItchWW3 domain reveal that phosphorylation at T30 inhibits the interaction with PPxY-containing ligands." Morales B., Ramirez-Espain X., Shaw A.Z., Martin-Malpartida P., Yraola F., Sanchez-Tillo E., Farrera C., Celada A., Royo M., Macias M.J. Structure 15:473-483(2007) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 399-432 OF WILD TYPE AND IN VITRO PHOSPHORYLATED FORMS IN COMPLEX WITH PPXY MOTIFS OF EPSTEIN-BARR VIRUS LMP2A.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF037454 mRNA. Translation: AAB99764.1. Different initiation.
AK048303 mRNA. Translation: BAC33298.1.
BC062934 mRNA. Translation: AAH62934.1.

IPI

IPI00380162.
IPI00380163.

RefSeq

NP_001230641.1. NM_001243712.1.
NP_032421.2. NM_008395.3.

UniGene

Mm.208286.
Mm.490088.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1YIU	NMR	-	A	399-432	[»]
2JO9	NMR	-	A	399-432	[»]
2JOC	NMR	-	A	399-432	[»]

ProteinModelPortal

Q8C863.

SMR

Q8C863. Positions 13-145, 287-858.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29318N.

IntAct

Q8C863. 8 interactions.

MINT

MINT-142559.

STRING

10090.ENSMUSP00000105307.

PTM databases

PhosphoSite

Q8C863.

Proteomic databases

PaxDb

Q8C863.

PRIDE

Q8C863.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000029126; ENSMUSP00000029126; ENSMUSG00000027598.
ENSMUST00000109685; ENSMUSP00000105307; ENSMUSG00000027598.

GeneID

16396.

KEGG

mmu:16396.

UCSC

uc008nkd.1. mouse.

Organism-specific databases

CTD

83737.

MGI

MGI:1202301. Itch.

Phylogenomic databases

eggNOG

COG5021.

GeneTree

ENSGT00570000078756.

HOVERGEN

HBG004134.

InParanoid

Q8C863.

KO

K05632.

OMA

PTETIGD.

OrthoDB

EOG47H5PD.

Enzyme and pathway databases

Reactome

REACT_115202. Signal Transduction.

UniPathway

UPA00143.

Gene expression databases

ArrayExpress

Q8C863.

Bgee

Q8C863.

CleanEx

MM_ITCH.

Genevestigator

Q8C863.

GermOnline

ENSMUSG00000027598. Mus musculus.

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

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Other

ChiTaRS

ITCH. mouse.

EvolutionaryTrace

Q8C863.

NextBio

289541.

SOURCE

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Entry information

Entry name

ITCH_MOUSE

Accession

Primary (citable) accession number: Q8C863
Secondary accession number(s): O54971

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 3, 2003
Last sequence update:	October 3, 2003
Last modified:	May 1, 2013
This is version 110 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program