WWP2_MOUSE
ID WWP2_MOUSE Reviewed; 870 AA.
AC Q9DBH0; Q8BTG4; Q923F6;
DT 20-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=NEDD4-like E3 ubiquitin-protein ligase WWP2;
DE EC=2.3.2.26;
DE AltName: Full=HECT-type E3 ubiquitin transferase WWP2;
DE AltName: Full=WW domain-containing protein 2;
GN Name=Wwp2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Brain, Liver, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Brain, and Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION IN UBIQUITINATION OF RPB1, AND INTERACTION WITH RBP1.
RX PubMed=17526739; DOI=10.1128/mcb.01667-06;
RA Li H., Zhang Z., Wang B., Zhang J., Zhao Y., Jin Y.;
RT "Wwp2-mediated ubiquitination of the RNA polymerase II large subunit in
RT mouse embryonic pluripotent stem cells.";
RL Mol. Cell. Biol. 27:5296-5305(2007).
RN [4]
RP FUNCTION IN UBIQUITINATION OF SLC11A2, AND INTERACTION WITH SLC11A2.
RX PubMed=18776082; DOI=10.1182/blood-2008-04-150953;
RA Foot N.J., Dalton H.E., Shearwin-Whyatt L.M., Dorstyn L., Tan S.S.,
RA Yang B., Kumar S.;
RT "Regulation of the divalent metal ion transporter DMT1 and iron homeostasis
RT by a ubiquitin-dependent mechanism involving Ndfips and WWP2.";
RL Blood 112:4268-4275(2008).
RN [5]
RP FUNCTION IN UBIQUITINATION OF EGR2, AND INTERACTION WITH EGR2.
RX PubMed=19651900; DOI=10.1128/mcb.00407-09;
RA Chen A., Gao B., Zhang J., McEwen T., Ye S.Q., Zhang D., Fang D.;
RT "The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell
RT death by catalyzing EGR2 ubiquitination.";
RL Mol. Cell. Biol. 29:5348-5356(2009).
RN [6]
RP FUNCTION IN UBIQUITINATION OF POU5F1, AND AUTOUBIQUITINATION.
RX PubMed=19997087; DOI=10.1038/cr.2009.136;
RA Liao B., Jin Y.;
RT "Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a
RT dosage-dependent manner.";
RL Cell Res. 20:332-344(2010).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an
CC E2 ubiquitin-conjugating enzyme in the form of a thioester and then
CC directly transfers the ubiquitin to targeted substrates.
CC Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it
CC to proteasomal degradation; regulates POU5F1 protein level during
CC differentiation of embryonal carcinoma cells (ECCs) but not in
CC undifferentiated ECCs and embryonic stem cells (ESCs). Ubiquitinates
CC EGR2 and promotes it to proteasomal degradation; in T-cells the
CC ubiquitination inhibits activation-induced cell death. Ubiquitinates
CC SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and
CC NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.
CC {ECO:0000269|PubMed:17526739, ECO:0000269|PubMed:18776082,
CC ECO:0000269|PubMed:19651900, ECO:0000269|PubMed:19997087}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.26;
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000250}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1.
CC Interacts with ERBB4, NDFIP1 and NDFIP2. Interacts with ARRDC4 (By
CC similarity). Interacts with POU5F1, RBP1, EGR2 and SLC11A2. Interacts
CC (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1
CC (By similarity). Interacts (via WW domains) with ARRDC2 and ARRDC3 (By
CC similarity). {ECO:0000250|UniProtKB:O00308,
CC ECO:0000269|PubMed:17526739, ECO:0000269|PubMed:18776082,
CC ECO:0000269|PubMed:19651900}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:O00308}.
CC -!- DOMAIN: The C2 domain is involved in autoinhibition of the catalytic
CC activity by interacting with the HECT domain. {ECO:0000250}.
CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing
CC proteins. {ECO:0000250|UniProtKB:O00308}.
CC -!- PTM: Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex,
CC leading to its degradation by the proteasome (By similarity).
CC {ECO:0000250}.
CC -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-thioester
CC formation.
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DR EMBL; AK004962; BAB23702.1; -; mRNA.
DR EMBL; AK088936; BAC40661.1; -; mRNA.
DR EMBL; AK090392; BAC41195.1; -; mRNA.
DR EMBL; BC004712; AAH04712.1; -; mRNA.
DR EMBL; BC039921; AAH39921.1; -; mRNA.
DR EMBL; BC048184; AAH48184.1; -; mRNA.
DR CCDS; CCDS40467.1; -.
DR RefSeq; NP_080106.1; NM_025830.3.
DR RefSeq; XP_006531362.1; XM_006531299.3.
DR AlphaFoldDB; Q9DBH0; -.
DR SMR; Q9DBH0; -.
DR BioGRID; 211793; 17.
DR IntAct; Q9DBH0; 1.
DR STRING; 10090.ENSMUSP00000132224; -.
DR iPTMnet; Q9DBH0; -.
DR PhosphoSitePlus; Q9DBH0; -.
DR EPD; Q9DBH0; -.
DR jPOST; Q9DBH0; -.
DR MaxQB; Q9DBH0; -.
DR PaxDb; Q9DBH0; -.
DR PRIDE; Q9DBH0; -.
DR ProteomicsDB; 275223; -.
DR Antibodypedia; 29892; 214 antibodies from 25 providers.
DR DNASU; 66894; -.
DR Ensembl; ENSMUST00000166615; ENSMUSP00000132224; ENSMUSG00000031930.
DR GeneID; 66894; -.
DR KEGG; mmu:66894; -.
DR UCSC; uc009nhv.1; mouse.
DR CTD; 11060; -.
DR MGI; MGI:1914144; Wwp2.
DR VEuPathDB; HostDB:ENSMUSG00000031930; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000160726; -.
DR HOGENOM; CLU_002173_0_1_1; -.
DR InParanoid; Q9DBH0; -.
DR OMA; FNAFITG; -.
DR OrthoDB; 167687at2759; -.
DR PhylomeDB; Q9DBH0; -.
DR TreeFam; TF323658; -.
DR Reactome; R-MMU-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-MMU-9013406; RHOQ GTPase cycle.
DR Reactome; R-MMU-9013409; RHOJ GTPase cycle.
DR Reactome; R-MMU-9013420; RHOU GTPase cycle.
DR Reactome; R-MMU-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 66894; 6 hits in 74 CRISPR screens.
DR ChiTaRS; Wwp2; mouse.
DR PRO; PR:Q9DBH0; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q9DBH0; protein.
DR Bgee; ENSMUSG00000031930; Expressed in head bone and 316 other tissues.
DR ExpressionAtlas; Q9DBH0; baseline and differential.
DR Genevisible; Q9DBH0; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005576; C:extracellular region; IEA:GOC.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IGI:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:BHF-UCL.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0006858; P:extracellular transport; ISO:MGI.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:0051224; P:negative regulation of protein transport; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:0032410; P:negative regulation of transporter activity; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; IMP:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; IDA:BHF-UCL.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; ISO:MGI.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:MGI.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; ISO:MGI.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IGI:MGI.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 4.
DR Gene3D; 2.60.40.150; -; 1.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR001202; WW_dom.
DR InterPro; IPR036020; WW_dom_sf.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 4.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 4.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 4.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 4.
DR PROSITE; PS50020; WW_DOMAIN_2; 4.
PE 1: Evidence at protein level;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; Transferase;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..870
FT /note="NEDD4-like E3 ubiquitin-protein ligase WWP2"
FT /id="PRO_0000120339"
FT DOMAIN 1..117
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 300..333
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 330..363
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 405..437
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 444..477
FT /note="WW 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 536..870
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 150..300
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 151..191
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 198..250
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 258..294
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 838
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00308"
SQ SEQUENCE 870 AA; 98761 MW; 72B34A1B727A7FB3 CRC64;
MASASSSRAG VALPFEKSQL TLKVVSAKPK VHNRQPRINS YVEVAVDGLP SETKKTGKRI
GSSELLWNEI IVLNVTAQSH LDLKVWSCHT LRNELLGTAS VNLSNVLKNN GGKMENTQLT
LNLQTENKGS VVSGGELTIF LDGPTVDLGS VPNGSAVTDG SQPPSRESSG TAIAPETRHQ
PPSTNCFGGR SRTHRHSGGS ARTATAASEQ SPGARNRHRQ PVKNSSSSGL ANGTVNEEPT
PASEPEESSV VGVTSLPAAA LSVSSNPNTT SLPAQSTPAE GEEASTSGTQ QLPAAAQAPD
ALPAGWEQRE LPNGRVYYVD HNTKTTTWER PLPPGWEKRT DPRGRFYYVD HNTRTTTWQR
PTAEYVRNYE QWQSQRNQLQ GAMQHFSQRF LYQSSSASTD HDPLGPLPPG WEKRQDNGRV
YYVNHNTRTT QWEDPRTQGM IQEPALPPGW EMKYTSEGVR YFVDHNTRTT TFKDPRPGFE
SGTKQGSPGA YDRSFRWKYH QFRFLCHSNA LPSHVKISVS RQTLFEDSFQ QIMNMKPYDL
RRRLYIIMRG EEGLDYGGIA REWFFLLSHE VLNPMYCLFE YAGKNNYCLQ INPASSINPD
HLTYFRFIGR FIAMALYHGK FIDTGFTLPF YKRMLNKRPT LKDLESIDPE FYNSIVWIKE
NNLEECGLEL FFIQDMEILG KVTTHELKEG GENIRVTEEN KEEYIMLLTD WRFTRGVEEQ
TKAFLDGFNE VAPLEWLRYF DEKELELMLC GMQEIDMSDW QKNAIYRHYT KSSKQIQWFW
QVVKEMDNEK RIRLLQFVTG TCRLPVGGFA ELIGSNGPQK FCIDRVGKET WLPRSHTCFN
RLDLPPYKSY EQLKEKLLYA IEETEGFGQE
