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E3 ubiquitin-protein ligase Itchy homolog (Itch) (EC 2.3.2.26) (Atrophin-1-interacting protein 4) (AIP4) (HECT-type E3 ubiquitin transferase Itchy homolog) (NFE2-associated polypeptide 1) (NAPP1)

 ITCH_HUMAN              Reviewed;         903 AA.
Q96J02; A6NEW4; B4E234; E1P5P3; F5H217; O43584; Q5QP37; Q5TEL0;
Q96F66; Q9BY75; Q9H451; Q9H4U5;
03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
03-OCT-2003, sequence version 2.
22-NOV-2017, entry version 164.
RecName: Full=E3 ubiquitin-protein ligase Itchy homolog;
Short=Itch;
EC=2.3.2.26 {ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19592251};
AltName: Full=Atrophin-1-interacting protein 4;
Short=AIP4;
AltName: Full=HECT-type E3 ubiquitin transferase Itchy homolog;
AltName: Full=NFE2-associated polypeptide 1;
Short=NAPP1;
Name=ITCH;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND INTERACTION WITH NFE2.
TISSUE=Leukemia;
PubMed=11318614; DOI=10.1006/geno.2001.6512;
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.;
"Human ITCH is a co-regulator of the hematopoietic transcription
factor NF-E2.";
Genomics 73:238-241(2001).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
Miyazaki K., Okamoto Y., Sakamoto M., Nakagawara A.;
"Homo sapiens mRNA for ubiquitin protein ligase Itch, complete cds.";
Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
TISSUE=Trachea;
PubMed=14702039; DOI=10.1038/ng1285;
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.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=11780052; DOI=10.1038/414865a;
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.;
"The DNA sequence and comparative analysis of human chromosome 20.";
Nature 414:865-871(2001).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
TISSUE=Kidney, and Placenta;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[7]
NUCLEOTIDE SEQUENCE [MRNA] OF 83-903 (ISOFORM 2), AND INTERACTION WITH
ATN1.
TISSUE=Fetal brain;
PubMed=9647693; DOI=10.1006/mcne.1998.0677;
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.;
"Atrophin-1, the DRPLA gene product, interacts with two families of WW
domain-containing proteins.";
Mol. Cell. Neurosci. 11:149-160(1998).
[8]
PROTEIN SEQUENCE OF 463-470; 503-510; 514-526; 644-665 AND 875-881,
INTERACTION WITH LMP2A, AND MUTAGENESIS OF CYS-871.
TISSUE=B-cell;
PubMed=11046148; DOI=10.1128/MCB.20.22.8526-8535.2000;
Winberg G., Matskova L., Chen F., Plant P., Rotin D., Gish G.,
Ingham R., Ernberg I., Pawson T.;
"Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3
protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases.";
Mol. Cell. Biol. 20:8526-8535(2000).
[9]
INTERACTION WITH CBLC, AND PHOSPHORYLATION.
PubMed=12226085; DOI=10.1074/jbc.M206460200;
Courbard J.-R., Fiore F., Adelaide J., Borg J.P., Birnbaum D.,
Ollendorff V.;
"Interaction between two ubiquitin-protein isopeptide ligases of
different classes, CBLC and AIP4/ITCH.";
J. Biol. Chem. 277:45267-45275(2002).
[10]
INTERACTION WITH RNF11.
PubMed=14559117; DOI=10.1016/j.bbadis.2003.07.001;
Kitching R., Wong M.J., Koehler D., Burger A.M., Landberg G., Gish G.,
Seth A.K.;
"The RING-H2 protein RNF11 is differentially expressed in breast
tumours and interacts with HECT-type E3 ligases.";
Biochim. Biophys. Acta 1639:104-112(2003).
[11]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, SUBCELLULAR LOCATION,
INTERACTION WITH HGS, AND MUTAGENESIS OF CYS-871.
PubMed=14602072; DOI=10.1016/S1534-5807(03)00321-6;
Marchese A., Raiborg C., Santini F., Keen J.H., Stenmark H.,
Benovic J.L.;
"The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of
the G protein-coupled receptor CXCR4.";
Dev. Cell 5:709-722(2003).
[12]
PHOSPHORYLATION AT THR-385 AND SER-450, AND INTERACTION WITH SGK3.
PubMed=16888620; DOI=10.1038/sj.emboj.7601267;
Slagsvold T., Marchese A., Brech A., Stenmark H.;
"CISK attenuates degradation of the chemokine receptor CXCR4 via the
ubiquitin ligase AIP4.";
EMBO J. 25:3738-3749(2006).
[13]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH DTX1, AND
UBIQUITINATION OF DTX1.
PubMed=17028573; DOI=10.1038/sj.embor.7400822;
Chastagner P., Israel A., Brou C.;
"Itch/AIP4 mediates Deltex degradation through the formation of K29-
linked polyubiquitin chains.";
EMBO Rep. 7:1147-1153(2006).
[14]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH JUNB AND FYN,
PHOSPHORYLATION AT TYR-420, IDENTIFICATION BY MASS SPECTROMETRY, AND
MUTAGENESIS OF TYR-343; TYR-420 AND TYR-455.
PubMed=16387660; DOI=10.1016/j.molcel.2005.11.014;
Yang C., Zhou W., Jeon M.S., Demydenko D., Harada Y., Zhou H.,
Liu Y.C.;
"Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated
tyrosine phosphorylation.";
Mol. Cell 21:135-141(2006).
[15]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND INTERACTION WITH NFE2.
PubMed=18718448; DOI=10.1016/j.bbrc.2008.07.164;
Lee T.-L., Shyu Y.-C., Hsu T.-Y., Shen C.-K.J.;
"Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination.";
Biochem. Biophys. Res. Commun. 375:326-330(2008).
[16]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AUTOUBIQUITINATION, AND
IDENTIFICATION BY MASS SPECTROMETRY.
PubMed=18718449; DOI=10.1016/j.bcp.2008.07.028;
Scialpi F., Malatesta M., Peschiaroli A., Rossi M., Melino G.,
Bernassola F.;
"Itch self-polyubiquitylation occurs through lysine-63 linkages.";
Biochem. Pharmacol. 76:1515-1521(2008).
[17]
SUBCELLULAR LOCATION.
PubMed=18819914; DOI=10.1074/jbc.M804120200;
Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J.,
Tan S.S.;
"Nedd4 family-interacting protein 1 (Ndfip1) is required for the
exosomal secretion of Nedd4 family proteins.";
J. Biol. Chem. 283:32621-32627(2008).
[18]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND UBIQUITINATION OF NOTCH1.
PubMed=18628966; DOI=10.1371/journal.pone.0002735;
Chastagner P., Israel A., Brou C.;
"AIP4/Itch regulates Notch receptor degradation in the absence of
ligand.";
PLoS ONE 3:E2735-E2735(2008).
[19]
ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19413330; DOI=10.1021/ac9004309;
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
Mohammed S.;
"Lys-N and trypsin cover complementary parts of the phosphoproteome in
a refined SCX-based approach.";
Anal. Chem. 81:4493-4501(2009).
[20]
INTERACTION WITH SPART.
PubMed=19580544; DOI=10.1042/BJ20082398;
Edwards T.L., Clowes V.E., Tsang H.T., Connell J.W., Sanderson C.M.,
Luzio J.P., Reid E.;
"Endogenous spartin (SPG20) is recruited to endosomes and lipid
droplets and interacts with the ubiquitin E3 ligases AIP4 and AIP5.";
Biochem. J. 423:31-39(2009).
[21]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND UBIQUITINATION OF RIPK2.
PubMed=19592251; DOI=10.1016/j.cub.2009.06.038;
Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E.,
Abbott D.W.;
"ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence
inflammatory signaling pathways.";
Curr. Biol. 19:1255-1263(2009).
[22]
FUNCTION, AND INTERACTION WITH RNF11.
PubMed=19131965; DOI=10.1038/emboj.2008.285;
Shembade N., Parvatiyar K., Harhaj N.S., Harhaj E.W.;
"The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-
kappaB signalling.";
EMBO J. 28:513-522(2009).
[23]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH CXCR4, AND
UBIQUITINATION.
PubMed=19116316; DOI=10.1091/mbc.E08-03-0308;
Bhandari D., Robia S.L., Marchese A.;
"The E3 ubiquitin ligase atrophin interacting protein 4 binds directly
to the chemokine receptor CXCR4 via a novel WW domain-mediated
interaction.";
Mol. Biol. Cell 20:1324-1339(2009).
[24]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, UBIQUITINATION OF MAVS,
INTERACTION WITH PCBP2, AND MUTAGENESIS OF CYS-871.
PubMed=19881509; DOI=10.1038/ni.1815;
You F., Sun H., Zhou X., Sun W., Liang S., Zhai Z., Jiang Z.;
"PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin
ligase AIP4.";
Nat. Immunol. 10:1300-1308(2009).
[25]
INVOLVEMENT IN ADMFD.
PubMed=20170897; DOI=10.1016/j.ajhg.2010.01.028;
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.;
"Human ITCH E3 ubiquitin ligase deficiency causes syndromic
multisystem autoimmune disease.";
Am. J. Hum. Genet. 86:447-453(2010).
[26]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH SNX9 AND
SNX18, AND UBIQUITINATION OF SNX9.
PubMed=20491914; DOI=10.1111/j.1742-4658.2010.07698.x;
Baumann C., Lindholm C.K., Rimoldi D., Levy F.;
"The E3 ubiquitin ligase Itch regulates sorting nexin 9 through an
unconventional substrate recognition domain.";
FEBS J. 277:2803-2814(2010).
[27]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH P15 BID, AND
UBIQUITINATION OF P15 BID.
PubMed=20392206; DOI=10.1111/j.1742-4658.2010.07562.x;
Azakir B.A., Desrochers G., Angers A.;
"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.";
FEBS J. 277:1319-1330(2010).
[28]
FUNCTION, CATALYTIC ACTIVITY, PATHWAY, INTERACTION WITH TXNIP, AND
UBIQUITINATION OF TXNIP.
PubMed=20068034; DOI=10.1074/jbc.M109.063321;
Zhang P., Wang C., Gao K., Wang D., Mao J., An J., Xu C., Wu D.,
Yu H., Liu J.O., Yu L.;
"The ubiquitin ligase itch regulates apoptosis by targeting
thioredoxin-interacting protein for ubiquitin-dependent degradation.";
J. Biol. Chem. 285:8869-8879(2010).
[29]
IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH ERBB4, AND
SUBCELLULAR LOCATION.
PubMed=20858735; DOI=10.1158/1541-7786.MCR-10-0042;
Gilmore-Hebert M., Ramabhadran R., Stern D.F.;
"Interactions of ErbB4 and Kap1 connect the growth factor and DNA
damage response pathways.";
Mol. Cancer Res. 8:1388-1398(2010).
[30]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[31]
INTERACTION WITH ARRDC1; ARRDC2 AND ARRDC3, AND DOMAIN.
PubMed=21191027; DOI=10.1128/JVI.02045-10;
Rauch S., Martin-Serrano J.;
"Multiple interactions between the ESCRT machinery and arrestin-
related proteins: implications for PPXY-dependent budding.";
J. Virol. 85:3546-3556(2011).
[32]
FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, PATHWAY, INTERACTION
WITH PI4K2A, SUBCELLULAR LOCATION, UBIQUITINATION, AND MUTAGENESIS OF
CYS-871.
PubMed=23146885; DOI=10.1038/embor.2012.164;
Mossinger J., Wieffer M., Krause E., Freund C., Gerth F., Krauss M.,
Haucke V.;
"Phosphatidylinositol 4-kinase IIalpha function at endosomes is
regulated by the ubiquitin ligase Itch.";
EMBO Rep. 13:1087-1094(2012).
[33]
INTERACTION WITH OTUD7B.
PubMed=22179831; DOI=10.1038/onc.2011.587;
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.;
"Deubiquitination of EGFR by Cezanne-1 contributes to cancer
progression.";
Oncogene 31:4599-4608(2012).
[34]
INTERACTION WITH ARRDC4.
PubMed=23236378; DOI=10.1371/journal.pone.0050557;
Shea F.F., Rowell J.L., Li Y., Chang T.H., Alvarez C.E.;
"Mammalian alpha arrestins link activated seven transmembrane
receptors to Nedd4 family e3 ubiquitin ligases and interact with beta
arrestins.";
PLoS ONE 7:E50557-E50557(2012).
[35]
FUNCTION, AND INTERACTION WITH ARRDC1 AND ARRDC3.
PubMed=23886940; DOI=10.1242/jcs.130500;
Puca L., Chastagner P., Meas-Yedid V., Israel A., Brou C.;
"Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate
Notch degradation in mammals.";
J. Cell Sci. 126:4457-4468(2013).
[36]
FUNCTION, CATALYTIC ACTIVITY, ENZYME REGULATION, PATHWAY, INTERACTION
WITH DTX3L, IDENTIFICATION IN A COMPLEX WITH DTX3L; STAM AND HGS,
SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-871.
PubMed=24790097; DOI=10.1091/mbc.E13-10-0612;
Holleman J., Marchese A.;
"The ubiquitin ligase deltex-3l regulates endosomal sorting of the G
protein-coupled receptor CXCR4.";
Mol. Biol. Cell 25:1892-1904(2014).
[37]
FUNCTION IN UBIQUITINATION OF BRAT1, CATALYTIC ACTIVITY, ENZYME
REGULATION, AND PATHWAY.
PubMed=25631046; DOI=10.1074/jbc.M114.613687;
Low L.H., Chow Y.L., Li Y., Goh C.P., Putz U., Silke J., Ouchi T.,
Howitt J., Tan S.S.;
"Nedd4 family interacting protein 1 (Ndfip1) is required for
ubiquitination and nuclear trafficking of BRCA1-associated ATM
activator 1 (BRAT1) during the DNA damage response.";
J. Biol. Chem. 290:7141-7150(2015).
[38]
INTERACTION WITH UBE2L3.
PubMed=25632008; DOI=10.4049/jimmunol.1402742;
Kathania M., Zeng M., Yadav V.N., Moghaddam S.J., Yang B.,
Venuprasad K.;
"Ndfip1 regulates itch ligase activity and airway inflammation via
UbcH7.";
J. Immunol. 194:2160-2167(2015).
[39]
X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 246-270 IN COMPLEX WITH
ARHGEF7.
PubMed=17652093; DOI=10.1074/jbc.M702678200;
Janz J.M., Sakmar T.P., Min K.C.;
"A novel interaction between atrophin-interacting protein 4 and beta-
p21-activated kinase-interactive exchange factor is mediated by an SH3
domain.";
J. Biol. Chem. 282:28893-28903(2007).
[40]
STRUCTURE BY NMR OF 328-357.
RIKEN structural genomics initiative (RSGI);
"Solution structure of the second WW domain of ITCHY homolog E3
ubiquitin protein ligase (ITCH).";
Submitted (OCT-2006) to the PDB data bank.
-!- 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 (PubMed:14602072, PubMed:17028573, PubMed:16387660,
PubMed:18718448, PubMed:18718449, PubMed:11046148,
PubMed:19592251, PubMed:19116316, PubMed:19881509,
PubMed:20491914, PubMed:20392206, PubMed:20068034,
PubMed:23146885, PubMed:24790097, PubMed:25631046). Catalyzes
'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation
(PubMed:17028573, PubMed:18718448, PubMed:19131965,
PubMed:19881509). Involved in the control of inflammatory
signaling pathways (PubMed:19131965). Essential component of a
ubiquitin-editing protein complex, comprising also TNFAIP3,
TAX1BP1 and RNF11, that ensures the transient nature of
inflammatory signaling pathways (PubMed:19131965). Promotes the
association of the complex after TNF stimulation
(PubMed:19131965). Once the complex is formed, TNFAIP3
deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and
catalyzes the formation of 'Lys-48'-polyubiquitin chains
(PubMed:19131965). This leads to RIPK1 proteasomal degradation and
consequently termination of the TNF- or LPS-mediated activation of
NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked
conjugation and influences NOD2-dependent signal transduction
pathways (PubMed:19592251). Regulates the transcriptional activity
of several transcription factors, and probably plays an important
role in the regulation of immune response (PubMed:18718448,
PubMed:20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is
implicated in the control of the development of hematopoietic
lineages (PubMed:18718448). Mediates JUN ubiquitination and
degradation (By similarity). Mediates JUNB ubiquitination and
degradation (PubMed:16387660). Critical regulator of type 2 helper
T (Th2) cell cytokine production by inducing JUNB ubiquitination
and degradation (By similarity). Involved in the negative
regulation of MAVS-dependent cellular antiviral responses
(PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked
conjugation resulting in MAVS proteasomal degradation
(PubMed:19881509). Following ligand stimulation, regulates sorting
of Wnt receptor FZD4 to the degradative endocytic pathway probably
by modulating PI42KA activity (PubMed:23146885). Ubiquitinates
PI4K2A and negatively regulates its catalytic activity
(PubMed:23146885). 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
(PubMed:14602072, PubMed:23146885). Targets DTX1 for lysosomal
degradation and controls NOTCH1 degradation, in the absence of
ligand, through 'Lys-29'-linked polyubiquitination
(PubMed:17028573, PubMed:18628966, PubMed:23886940). Ubiquitinates
SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through 'Lys-48'-
linked conjugation (By similarity). Involved in the regulation of
apoptosis and reactive oxygen species levels through the
ubiquitination and proteasomal degradation of TXNIP
(PubMed:20068034). 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
(PubMed:25631046). {ECO:0000250|UniProtKB:Q8C863,
ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660,
ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966,
ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449,
ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19131965,
ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509,
ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206,
ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885,
ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:24790097,
ECO:0000269|PubMed:25631046}.
-!- CATALYTIC ACTIVITY: S-ubiquitinyl-[E2 ubiquitin-conjugating
enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-
conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor
protein]-L-lysine. {ECO:0000269|PubMed:14602072,
ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573,
ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448,
ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316,
ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509,
ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206,
ECO:0000269|PubMed:20491914, ECO:0000269|PubMed:23146885,
ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25631046}.
-!- ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding
(PubMed:25631046). Activated by PI4K2A-binding (PubMed:23146885).
Inhibited by DTX3L-binding (PubMed:24790097). Inhibited by N4BP1
binding (By similarity). {ECO:0000250|UniProtKB:Q8C863,
ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097,
ECO:0000269|PubMed:25631046}.
-!- PATHWAY: Protein modification; protein ubiquitination.
{ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660,
ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966,
ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449,
ECO:0000269|PubMed:19116316, ECO:0000269|PubMed:19592251,
ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034,
ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914,
ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097,
ECO:0000269|PubMed:25631046}.
-!- SUBUNIT: Monomer. Interacts (via WW domains) with OCNL (By
similarity). Interacts (via WW domains) with NOTCH1 (By
similarity). Interacts (via WW domains) with JUN (By similarity).
Interacts with JUNB; the interaction promotes ITCH-mediated
ubiquitination and degradation of JUNB (PubMed:16387660).
Interacts with FYN; the interaction phosphorylates ITCH on Tyr-420
decreasing binding of JUNB (PubMed:16387660). Interacts (via WW
domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-
protein ligase activity (By similarity). 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 (PubMed:17652093). Interacts with RNF11
(PubMed:14559117, PubMed:19131965). 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
(PubMed:11318614, PubMed:18718448). Interacts (via WW domains)
with CXCR4 (via C-terminus); the interaction depends on CXCR4
phosphorylation (PubMed:19116316). Found in a complex with E3
ligase DTX3L and ESCRT-0 components HGS and STAM
(PubMed:24790097). Interacts with DTX3L (via C-terminus); the
interaction is increased upon CXCL12 stimulation and inhibits ITCH
catalytic activity (the interaction is direct) (PubMed:24790097).
Interacts with HGS (PubMed:14602072). Interacts (via WW domains)
with PCBP2 within a complex containing ITCH, MAVS and PCBP2
(PubMed:19881509). Interacts (via WW domains) with TXNIP (via C-
terminus) (PubMed:20068034). Interacts with p15 BID
(PubMed:20392206). Interacts with ERBB4 (PubMed:20858735).
Interacts with DTX1 (PubMed:17028573). Interacts with SPART
(PubMed:19580544). Interacts with SNX9 and SNX18
(PubMed:20491914). Interacts (via its WW domains) with ATN1
(PubMed:9647693). Interacts (via WW domains) with SGK3
(PubMed:16888620). Interacts with CBLC (PubMed:12226085).
Interacts with OTUD7B (PubMed:22179831). 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 (PubMed:23236378). Part of a complex
containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with
UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008).
Interacts with MAPK8/JNK1 (By similarity). 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 (PubMed:21191027,
PubMed:23886940). Interacts (via WW domains) with ARRDC2
(PubMed:21191027). Interacts (via WW domains) with ARRDC3
(PubMed:21191027, PubMed:23886940). {ECO:0000250|UniProtKB:Q8C863,
ECO:0000269|PubMed:11318614, ECO:0000269|PubMed:12226085,
ECO:0000269|PubMed:14559117, ECO:0000269|PubMed:14602072,
ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16888620,
ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:17652093,
ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:19116316,
ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:19580544,
ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034,
ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:20491914,
ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:21191027,
ECO:0000269|PubMed:22179831, ECO:0000269|PubMed:23146885,
ECO:0000269|PubMed:23236378, ECO:0000269|PubMed:23886940,
ECO:0000269|PubMed:24790097, ECO:0000269|PubMed:25632008,
ECO:0000269|PubMed:9647693}.
-!- SUBUNIT: (Microbial infection) Interacts with Epstein-Barr virus
LMP2A. {ECO:0000269|PubMed:11046148}.
-!- INTERACTION:
P70444:Bid (xeno); NbExp=2; IntAct=EBI-1564678, EBI-783400;
Q9NQC7:CYLD; NbExp=3; IntAct=EBI-1564678, EBI-2117940;
Q15303:ERBB4; NbExp=3; IntAct=EBI-6672198, EBI-80371;
Q15303-3:ERBB4; NbExp=2; IntAct=EBI-6672198, EBI-15692884;
P08151:GLI1; NbExp=4; IntAct=EBI-1564678, EBI-308084;
P13285:LMP2 (xeno); NbExp=3; IntAct=EBI-1564678, EBI-7181113;
O75113:N4BP1; NbExp=3; IntAct=EBI-1564678, EBI-5278391;
Q9QZS3-2:Numb (xeno); NbExp=2; IntAct=EBI-1564678, EBI-3896014;
Q9BTU6:PI4K2A; NbExp=5; IntAct=EBI-1564678, EBI-3239392;
Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-1564678, EBI-396669;
Q96BR1:SGK3; NbExp=5; IntAct=EBI-1564678, EBI-2801236;
Q9Y5X1:SNX9; NbExp=7; IntAct=EBI-1564678, EBI-77848;
Q13625:TP53BP2; NbExp=2; IntAct=EBI-1564678, EBI-77642;
Q9H3D4:TP63; NbExp=2; IntAct=EBI-1564678, EBI-2337775;
O15350:TP73; NbExp=3; IntAct=EBI-1564678, EBI-389606;
O15350-1:TP73; NbExp=5; IntAct=EBI-1564678, EBI-389619;
O15350-8:TP73; NbExp=2; IntAct=EBI-1564678, EBI-5651259;
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14602072};
Peripheral membrane protein {ECO:0000305|PubMed:14602072};
Cytoplasmic side {ECO:0000305|PubMed:14602072}. Cytoplasm
{ECO:0000269|PubMed:14602072}. Nucleus
{ECO:0000269|PubMed:20858735}. Early endosome membrane
{ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:23146885,
ECO:0000269|PubMed:24790097}; Peripheral membrane protein
{ECO:0000305|PubMed:14602072, ECO:0000305|PubMed:23146885,
ECO:0000305|PubMed:24790097}; Cytoplasmic side
{ECO:0000305|PubMed:14602072, ECO:0000305|PubMed:23146885,
ECO:0000305|PubMed:24790097}. Endosome membrane
{ECO:0000269|PubMed:23146885}; Peripheral membrane protein
{ECO:0000305|PubMed:23146885}; Cytoplasmic side
{ECO:0000305|PubMed:23146885}. Note=May be recruited to exosomes
by NDFIP1 (PubMed:18819914). Localizes to plasma membrane upon
CXCL12 stimulation where it co-localizes with CXCL4
(PubMed:14602072). Localization to early endosomes is increased
upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4
(PubMed:24790097). {ECO:0000269|PubMed:14602072,
ECO:0000269|PubMed:18819914, ECO:0000269|PubMed:24790097}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1;
IsoId=Q96J02-1; Sequence=Displayed;
Note=No experimental confirmation available.;
Name=2;
IsoId=Q96J02-2; Sequence=VSP_008451;
Name=3;
IsoId=Q96J02-3; Sequence=VSP_044732, VSP_008451;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Widely expressed.
-!- DOMAIN: The WW domains mediate interaction with PPxY motif-
containing proteins. {ECO:0000269|PubMed:21191027}.
-!- PTM: 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.
{ECO:0000250, ECO:0000269|PubMed:12226085,
ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:16888620,
ECO:0000269|PubMed:18718449}.
-!- PTM: Monoubiquitinated (PubMed:19116316). Autopolyubiquitinated
with 'Lys-63' linkages which does not lead to protein degradation
(PubMed:18718449, PubMed:23146885, PubMed:24790097).
{ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19116316,
ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24790097}.
-!- DISEASE: Autoimmune disease, multisystem, with facial dysmorphism
(ADMFD) [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. {ECO:0000269|PubMed:20170897}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-----------------------------------------------------------------------
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EMBL; AF095745; AAK39399.1; -; mRNA.
EMBL; AB056663; BAB39389.1; -; mRNA.
EMBL; AK304090; BAG64996.1; -; mRNA.
EMBL; AK315212; BAG37647.1; -; mRNA.
EMBL; AL109923; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AL356299; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471077; EAW76272.1; -; Genomic_DNA.
EMBL; CH471077; EAW76274.1; -; Genomic_DNA.
EMBL; CH471077; EAW76276.1; -; Genomic_DNA.
EMBL; BC006848; AAH06848.1; -; mRNA.
EMBL; BC011571; AAH11571.1; -; mRNA.
EMBL; AF038564; AAC04845.1; -; mRNA.
CCDS; CCDS13234.1; -. [Q96J02-2]
CCDS; CCDS58768.1; -. [Q96J02-1]
CCDS; CCDS58769.1; -. [Q96J02-3]
RefSeq; NP_001244066.1; NM_001257137.2. [Q96J02-1]
RefSeq; NP_001244067.1; NM_001257138.2. [Q96J02-3]
RefSeq; NP_001311126.1; NM_001324197.1. [Q96J02-1]
RefSeq; NP_001311127.1; NM_001324198.1. [Q96J02-2]
RefSeq; NP_113671.3; NM_031483.6. [Q96J02-2]
RefSeq; XP_016883578.1; XM_017028089.1. [Q96J02-1]
RefSeq; XP_016883580.1; XM_017028091.1. [Q96J02-3]
UniGene; Hs.632272; -.
PDB; 2DMV; NMR; -; A=328-357.
PDB; 2KYK; NMR; -; A=359-392.
PDB; 2NQ3; X-ray; 1.80 A; A=1-155.
PDB; 2P4R; X-ray; 2.00 A; T=246-270.
PDB; 2YSF; NMR; -; A=480-512.
PDB; 3TUG; X-ray; 2.27 A; A=524-903.
PDB; 4ROF; X-ray; 2.03 A; A/B=436-474.
PDB; 5C7M; X-ray; 3.03 A; A=524-899.
PDB; 5CQ2; X-ray; 1.40 A; A=433-521.
PDB; 5DWS; X-ray; 1.65 A; A/C/E/G=436-474.
PDB; 5DZD; X-ray; 1.57 A; A/B=475-514.
PDB; 5SXP; X-ray; 1.65 A; F/G=249-269.
PDBsum; 2DMV; -.
PDBsum; 2KYK; -.
PDBsum; 2NQ3; -.
PDBsum; 2P4R; -.
PDBsum; 2YSF; -.
PDBsum; 3TUG; -.
PDBsum; 4ROF; -.
PDBsum; 5C7M; -.
PDBsum; 5CQ2; -.
PDBsum; 5DWS; -.
PDBsum; 5DZD; -.
PDBsum; 5SXP; -.
ProteinModelPortal; Q96J02; -.
SMR; Q96J02; -.
BioGrid; 123747; 183.
CORUM; Q96J02; -.
DIP; DIP-29849N; -.
ELM; Q96J02; -.
IntAct; Q96J02; 38.
MINT; MINT-148272; -.
STRING; 9606.ENSP00000363998; -.
iPTMnet; Q96J02; -.
PhosphoSitePlus; Q96J02; -.
BioMuta; ITCH; -.
DMDM; 37537897; -.
EPD; Q96J02; -.
MaxQB; Q96J02; -.
PaxDb; Q96J02; -.
PeptideAtlas; Q96J02; -.
PRIDE; Q96J02; -.
Ensembl; ENST00000262650; ENSP00000262650; ENSG00000078747. [Q96J02-1]
Ensembl; ENST00000374864; ENSP00000363998; ENSG00000078747. [Q96J02-2]
Ensembl; ENST00000535650; ENSP00000445608; ENSG00000078747. [Q96J02-3]
GeneID; 83737; -.
KEGG; hsa:83737; -.
UCSC; uc002xak.3; human. [Q96J02-1]
CTD; 83737; -.
DisGeNET; 83737; -.
EuPathDB; HostDB:ENSG00000078747.12; -.
GeneCards; ITCH; -.
H-InvDB; HIX0015745; -.
HGNC; HGNC:13890; ITCH.
HPA; HPA021126; -.
HPA; HPA049032; -.
MalaCards; ITCH; -.
MIM; 606409; gene.
MIM; 613385; phenotype.
neXtProt; NX_Q96J02; -.
OpenTargets; ENSG00000078747; -.
Orphanet; 228426; Syndromic multisystem autoimmune disease due to Itch deficiency.
PharmGKB; PA29934; -.
eggNOG; KOG0940; Eukaryota.
eggNOG; COG5021; LUCA.
GeneTree; ENSGT00760000118966; -.
HOVERGEN; HBG004134; -.
InParanoid; Q96J02; -.
KO; K05632; -.
OMA; SLIWVKE; -.
OrthoDB; EOG091G0SS8; -.
PhylomeDB; Q96J02; -.
TreeFam; TF323658; -.
BRENDA; 6.3.2.19; 2681.
Reactome; R-HSA-1253288; Downregulation of ERBB4 signaling.
Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
Reactome; R-HSA-5610780; Degradation of GLI1 by the proteasome.
Reactome; R-HSA-5632684; Hedgehog 'on' state.
Reactome; R-HSA-8939236; RUNX1 regulates transcription of genes involved in differentiation of HSCs.
Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
SignaLink; Q96J02; -.
SIGNOR; Q96J02; -.
UniPathway; UPA00143; -.
ChiTaRS; ITCH; human.
EvolutionaryTrace; Q96J02; -.
GenomeRNAi; 83737; -.
PRO; PR:Q96J02; -.
Proteomes; UP000005640; Chromosome 20.
Bgee; ENSG00000078747; -.
CleanEx; HS_ITCH; -.
Genevisible; Q96J02; HS.
GO; GO:0005938; C:cell cortex; IEA:Ensembl.
GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
GO; GO:0016020; C:membrane; IDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
GO; GO:0043234; C:protein complex; IDA:UniProtKB.
GO; GO:1990763; F:arrestin family protein binding; IPI:UniProtKB.
GO; GO:0045236; F:CXCR chemokine receptor binding; IPI:UniProtKB.
GO; GO:0016874; F:ligase activity; IEA:Ensembl.
GO; GO:0043021; F:ribonucleoprotein complex binding; IPI:UniProtKB.
GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
GO; GO:0044389; F:ubiquitin-like protein ligase binding; IPI:UniProtKB.
GO; GO:0019787; F:ubiquitin-like protein transferase activity; TAS:Reactome.
GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
GO; GO:0006954; P:inflammatory response; NAS:UniProtKB.
GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
GO; GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IEA:Ensembl.
GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
GO; GO:0050687; P:negative regulation of defense response to virus; IMP:UniProtKB.
GO; GO:0046329; P:negative regulation of JNK cascade; ISS:BHF-UCL.
GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:BHF-UCL.
GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome.
GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
GO; GO:0045732; P:positive regulation of protein catabolic process; IEA:Ensembl.
GO; GO:2000646; P:positive regulation of receptor catabolic process; IMP:UniProtKB.
GO; GO:0002669; P:positive regulation of T cell anergy; IEA:Ensembl.
GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
GO; GO:0051865; P:protein autoubiquitination; IMP:UniProtKB.
GO; GO:0035519; P:protein K29-linked ubiquitination; IDA:UniProtKB.
GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:GO_Central.
GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; TAS:Reactome.
GO; GO:0090085; P:regulation of protein deubiquitination; ISS:BHF-UCL.
GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:MGI.
GO; GO:0046718; P:viral entry into host cell; TAS:UniProtKB.
CDD; cd00078; HECTc; 1.
CDD; cd00201; WW; 4.
Gene3D; 2.60.40.150; -; 1.
InterPro; IPR000008; C2_dom.
InterPro; IPR035892; C2_domain_sf.
InterPro; IPR024928; E3_ub_ligase_SMURF1.
InterPro; IPR000569; HECT_dom.
InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
InterPro; IPR001202; WW_dom.
InterPro; IPR036020; WW_dom_sf.
Pfam; PF00168; C2; 1.
Pfam; PF00632; HECT; 1.
Pfam; PF00397; WW; 4.
PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
SMART; SM00239; C2; 1.
SMART; SM00119; HECTc; 1.
SMART; SM00456; WW; 4.
SUPFAM; SSF49562; SSF49562; 1.
SUPFAM; SSF51045; SSF51045; 4.
SUPFAM; SSF56204; SSF56204; 1.
PROSITE; PS50004; C2; 1.
PROSITE; PS50237; HECT; 1.
PROSITE; PS01159; WW_DOMAIN_1; 4.
PROSITE; PS50020; WW_DOMAIN_2; 4.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; Antiviral defense;
Apoptosis; Cell membrane; Complete proteome; Cytoplasm;
Direct protein sequencing; Endosome; Host-virus interaction; Immunity;
Innate immunity; Membrane; Nucleus; Phosphoprotein;
Reference proteome; Repeat; Transferase; Ubl conjugation;
Ubl conjugation pathway.
INIT_MET 1 1 Removed. {ECO:0000244|PubMed:19413330}.
CHAIN 2 903 E3 ubiquitin-protein ligase Itchy
homolog.
/FTId=PRO_0000120317.
DOMAIN 5 99 C2. {ECO:0000255|PROSITE-
ProRule:PRU00041}.
DOMAIN 326 359 WW 1. {ECO:0000255|PROSITE-
ProRule:PRU00224}.
DOMAIN 358 391 WW 2. {ECO:0000255|PROSITE-
ProRule:PRU00224}.
DOMAIN 438 471 WW 3. {ECO:0000255|PROSITE-
ProRule:PRU00224}.
DOMAIN 478 511 WW 4. {ECO:0000255|PROSITE-
ProRule:PRU00224}.
DOMAIN 569 903 HECT. {ECO:0000255|PROSITE-
ProRule:PRU00104}.
REGION 395 471 Required for interaction with FYN.
{ECO:0000269|PubMed:16387660}.
REGION 574 583 MAP kinase docking site. {ECO:0000250}.
COMPBIAS 252 267 Arg/Pro-rich (PRR domain).
ACT_SITE 871 871 Glycyl thioester intermediate.
{ECO:0000255|PROSITE-ProRule:PRU00104}.
MOD_RES 2 2 N-acetylserine.
{ECO:0000244|PubMed:19413330}.
MOD_RES 240 240 Phosphoserine; by MAPK8.
{ECO:0000250|UniProtKB:Q8C863}.
MOD_RES 263 263 Phosphothreonine; by MAPK8.
{ECO:0000250|UniProtKB:Q8C863}.
MOD_RES 273 273 Phosphoserine; by MAPK8.
{ECO:0000250|UniProtKB:Q8C863}.
MOD_RES 385 385 Phosphothreonine; by SGK3.
{ECO:0000269|PubMed:16888620}.
MOD_RES 420 420 Phosphotyrosine; by FYN.
{ECO:0000269|PubMed:16387660}.
MOD_RES 450 450 Phosphoserine; by SGK3.
{ECO:0000269|PubMed:16888620}.
VAR_SEQ 1 110 Missing (in isoform 3).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_044732.
VAR_SEQ 159 200 NGVSLCLPRLECNSAISAHCNLCLPGLSDSPISASRVAGFT
G -> S (in isoform 2 and isoform 3).
{ECO:0000303|PubMed:11318614,
ECO:0000303|PubMed:14702039,
ECO:0000303|PubMed:15489334,
ECO:0000303|PubMed:9647693,
ECO:0000303|Ref.2}.
/FTId=VSP_008451.
MUTAGEN 343 343 Y->F: No effect on phosphorylation on T-
cell stimulation nor in the presence of
FYN. {ECO:0000269|PubMed:16387660}.
MUTAGEN 420 420 Y->F: Greatly reduced phosphorylation on
T-cell stimulation and in the presence of
FYN. Increased ITCH-mediated Ub
conjugation and degradation of JUNB.
{ECO:0000269|PubMed:16387660}.
MUTAGEN 455 455 Y->F: No effect on phosphorylation on T-
cell stimulation nor in the presence of
FYN. {ECO:0000269|PubMed:16387660}.
MUTAGEN 871 871 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. {ECO:0000269|PubMed:11046148,
ECO:0000269|PubMed:14602072,
ECO:0000269|PubMed:19881509,
ECO:0000269|PubMed:23146885,
ECO:0000269|PubMed:24790097}.
CONFLICT 297 297 T -> I (in Ref. 3; BAG64996).
{ECO:0000305}.
STRAND 18 29 {ECO:0000244|PDB:2NQ3}.
STRAND 41 47 {ECO:0000244|PDB:2NQ3}.
STRAND 50 53 {ECO:0000244|PDB:2NQ3}.
STRAND 64 73 {ECO:0000244|PDB:2NQ3}.
STRAND 78 85 {ECO:0000244|PDB:2NQ3}.
STRAND 88 90 {ECO:0000244|PDB:2NQ3}.
STRAND 93 101 {ECO:0000244|PDB:2NQ3}.
HELIX 102 108 {ECO:0000244|PDB:2NQ3}.
TURN 109 111 {ECO:0000244|PDB:2NQ3}.
STRAND 112 126 {ECO:0000244|PDB:2NQ3}.
STRAND 130 143 {ECO:0000244|PDB:2NQ3}.
STRAND 332 336 {ECO:0000244|PDB:2DMV}.
STRAND 342 346 {ECO:0000244|PDB:2DMV}.
TURN 347 349 {ECO:0000244|PDB:2DMV}.
STRAND 352 355 {ECO:0000244|PDB:2DMV}.
STRAND 365 368 {ECO:0000244|PDB:2KYK}.
STRAND 374 377 {ECO:0000244|PDB:2KYK}.
STRAND 379 381 {ECO:0000244|PDB:2KYK}.
STRAND 444 448 {ECO:0000244|PDB:5CQ2}.
STRAND 454 458 {ECO:0000244|PDB:5CQ2}.
TURN 459 462 {ECO:0000244|PDB:5CQ2}.
STRAND 463 467 {ECO:0000244|PDB:5CQ2}.
HELIX 469 471 {ECO:0000244|PDB:5DWS}.
STRAND 484 488 {ECO:0000244|PDB:5CQ2}.
STRAND 494 498 {ECO:0000244|PDB:5CQ2}.
TURN 499 502 {ECO:0000244|PDB:5CQ2}.
STRAND 503 507 {ECO:0000244|PDB:5CQ2}.
TURN 509 511 {ECO:0000244|PDB:5CQ2}.
HELIX 528 539 {ECO:0000244|PDB:3TUG}.
TURN 540 542 {ECO:0000244|PDB:3TUG}.
STRAND 545 551 {ECO:0000244|PDB:3TUG}.
STRAND 554 556 {ECO:0000244|PDB:3TUG}.
HELIX 557 567 {ECO:0000244|PDB:3TUG}.
HELIX 572 574 {ECO:0000244|PDB:3TUG}.
STRAND 575 580 {ECO:0000244|PDB:3TUG}.
HELIX 589 603 {ECO:0000244|PDB:3TUG}.
TURN 607 609 {ECO:0000244|PDB:3TUG}.
STRAND 611 614 {ECO:0000244|PDB:3TUG}.
STRAND 621 624 {ECO:0000244|PDB:3TUG}.
HELIX 626 630 {ECO:0000244|PDB:3TUG}.
HELIX 634 650 {ECO:0000244|PDB:3TUG}.
HELIX 661 667 {ECO:0000244|PDB:3TUG}.
HELIX 675 677 {ECO:0000244|PDB:3TUG}.
TURN 678 680 {ECO:0000244|PDB:3TUG}.
HELIX 682 692 {ECO:0000244|PDB:3TUG}.
HELIX 696 699 {ECO:0000244|PDB:5C7M}.
STRAND 704 709 {ECO:0000244|PDB:5C7M}.
STRAND 716 721 {ECO:0000244|PDB:5C7M}.
HELIX 724 726 {ECO:0000244|PDB:5C7M}.
TURN 731 733 {ECO:0000244|PDB:5C7M}.
HELIX 735 747 {ECO:0000244|PDB:3TUG}.
HELIX 751 764 {ECO:0000244|PDB:3TUG}.
HELIX 767 770 {ECO:0000244|PDB:3TUG}.
HELIX 775 783 {ECO:0000244|PDB:3TUG}.
HELIX 790 795 {ECO:0000244|PDB:3TUG}.
STRAND 798 801 {ECO:0000244|PDB:3TUG}.
HELIX 807 818 {ECO:0000244|PDB:3TUG}.
HELIX 821 832 {ECO:0000244|PDB:3TUG}.
HELIX 842 844 {ECO:0000244|PDB:3TUG}.
STRAND 848 851 {ECO:0000244|PDB:3TUG}.
STRAND 855 858 {ECO:0000244|PDB:3TUG}.
STRAND 867 869 {ECO:0000244|PDB:3TUG}.
HELIX 870 872 {ECO:0000244|PDB:3TUG}.
STRAND 874 877 {ECO:0000244|PDB:3TUG}.
HELIX 883 895 {ECO:0000244|PDB:3TUG}.
SEQUENCE 903 AA; 102803 MW; 6777A2043C7B67BC CRC64;
MSDSGSQLGS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT
NSPKWKQPLT VIVTPVSKLH FRVWSHQTLK SDVLLGTAAL DIYETLKSNN MKLEEVVVTL
QLGGDKEPTE TIGDLSICLD GLQLESEVVT NGETTCSENG VSLCLPRLEC NSAISAHCNL
CLPGLSDSPI SASRVAGFTG ASQNDDGSRS KDETRVSTNG SDDPEDAGAG ENRRVSGNNS
PSLSNGGFKP SRPPRPSRPP PPTPRRPASV NGSPSATSES DGSSTGSLPP TNTNTNTSEG
ATSGLIIPLT ISGGSGPRPL NPVTQAPLPP GWEQRVDQHG RVYYVDHVEK RTTWDRPEPL
PPGWERRVDN MGRIYYVDHF TRTTTWQRPT LESVRNYEQW QLQRSQLQGA MQQFNQRFIY
GNQDLFATSQ SKEFDPLGPL PPGWEKRTDS NGRVYFVNHN TRITQWEDPR SQGQLNEKPL
PEGWEMRFTV DGIPYFVDHN RRTTTYIDPR TGKSALDNGP QIAYVRDFKA KVQYFRFWCQ
QLAMPQHIKI TVTRKTLFED SFQQIMSFSP QDLRRRLWVI FPGEEGLDYG GVAREWFFLL
SHEVLNPMYC LFEYAGKDNY CLQINPASYI NPDHLKYFRF IGRFIAMALF HGKFIDTGFS
LPFYKRILNK PVGLKDLESI DPEFYNSLIW VKENNIEECD LEMYFSVDKE ILGEIKSHDL
KPNGGNILVT EENKEEYIRM VAEWRLSRGV EEQTQAFFEG FNEILPQQYL QYFDAKELEV
LLCGMQEIDL NDWQRHAIYR HYARTSKQIM WFWQFVKEID NEKRMRLLQF VTGTCRLPVG
GFADLMGSNG PQKFCIEKVG KENWLPRSHT CFNRLDLPPY KSYEQLKEKL LFAIEETEGF
GQE


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