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Protein

WW domain-containing oxidoreductase

Gene

WWOX

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Putative oxidoreductase. Acts as a tumor suppressor and plays a role in apoptosis. Required for normal bone development (By similarity). May function synergistically with p53/TP53 to control genotoxic stress-induced cell death. Plays a role in TGFB1 signaling and TGFB1-mediated cell death. May also play a role in tumor necrosis factor (TNF)-mediated cell death. Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm.By similarity7 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei260SubstrateBy similarity1
Active sitei293Proton acceptorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi131 – 137NADPBy similarity7

GO - Molecular functioni

  • coenzyme binding Source: UniProtKB
  • cofactor binding Source: UniProtKB
  • enzyme binding Source: BHF-UCL
  • oxidoreductase activity Source: UniProtKB
  • protein dimerization activity Source: UniProtKB
  • RNA polymerase II transcription coactivator activity Source: Ensembl

GO - Biological processi

Keywordsi

Molecular functionOxidoreductase
Biological processApoptosis, Wnt signaling pathway
LigandNADP

Enzyme and pathway databases

ReactomeiR-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-8866904 Negative regulation of activity of TFAP2 (AP-2) family transcription factors
R-HSA-8866907 Activation of the TFAP2 (AP-2) family of transcription factors
SignaLinkiQ9NZC7
SIGNORiQ9NZC7

Names & Taxonomyi

Protein namesi
Recommended name:
WW domain-containing oxidoreductase (EC:1.1.1.-)
Alternative name(s):
Fragile site FRA16D oxidoreductase
Short chain dehydrogenase/reductase family 41C member 1
Gene namesi
Name:WWOX
Synonyms:FOR, SDR41C1, WOX1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

EuPathDBiHostDB:ENSG00000186153.16
HGNCiHGNC:12799 WWOX
MIMi605131 gene
neXtProtiNX_Q9NZC7

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Golgi apparatus, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Defects in WWOX may be involved in several cancer types. The gene spans the second most common chromosomal fragile site (FRA16D) which is frequently altered in cancers (PubMed:10861292). Alteration of the expression and expression of some isoforms is associated with cancers. However, it is still unclear if alteration of WWOX is directly implicated in cancerogenesis or if it corresponds to a secondary effect (PubMed:10861292, PubMed:11572989, PubMed:15266310, PubMed:15073125, PubMed:15131042).5 Publications
Esophageal cancer (ESCR)1 Publication
The disease may be caused by mutations affecting the gene represented in this entry.
Disease descriptionA malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage.
See also OMIM:133239
Spinocerebellar ataxia, autosomal recessive, 12 (SCAR12)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSpinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR12 is additionally characterized by onset of generalized seizures in infancy, and delayed psychomotor development with mental retardation. Some patients may also show spasticity.
See also OMIM:614322
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07099247P → T in SCAR12. 1 PublicationCorresponds to variant dbSNP:rs587777128Ensembl.1
Natural variantiVAR_070993372G → R in SCAR12. 1 PublicationCorresponds to variant dbSNP:rs587777127Ensembl.1
Epileptic encephalopathy, early infantile, 28 (EIEE28)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.
See also OMIM:616211
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07235147P → R in EIEE28. 1 PublicationCorresponds to variant dbSNP:rs730880292Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi28K → T: No effect on interaction with TP53. Abolishes interaction with MAPK8; when associated with V-29. 1 Publication1
Mutagenesisi29D → V: No effect on interaction with TP53. Abolishes interaction with MAPK8; when associated with T-28. 1 Publication1
Mutagenesisi33Y → F: Loss of phosphorylation. 2 Publications1
Mutagenesisi33Y → R: Abolishes interaction with TP53, TP73, MAPK8 and ERBB4. Partial loss of interaction with TFAP2C. Loss of phosphorylation. Loss of the proapoptotic activity. 2 Publications1
Mutagenesisi44 – 47WEHP → FEHA: Abolishes interaction with LITAF. 1 Publication4
Mutagenesisi61Y → R: No effect on interaction with TP73. 1 Publication1
Mutagenesisi85 – 88YLDP → ALDA: No effect on interaction with LITAF. 1 Publication4
Mutagenesisi287Y → A: Loss of phosphorylation by TNK2. 1 Publication1

Keywords - Diseasei

Disease mutation, Epilepsy, Neurodegeneration, Tumor suppressor

Organism-specific databases

DisGeNETi51741
MalaCardsiWWOX
MIMi133239 phenotype
614322 phenotype
616211 phenotype
OpenTargetsiENSG00000186153
Orphaneti251510 46,XY partial gonadal dysgenesis
284282 Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
PharmGKBiPA37398

Polymorphism and mutation databases

BioMutaiWWOX
DMDMi74725363

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000548151 – 414WW domain-containing oxidoreductaseAdd BLAST414

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei12PhosphothreonineCombined sources1
Modified residuei14PhosphoserineCombined sources1
Modified residuei33Phosphotyrosine2 Publications1
Modified residuei287Phosphotyrosine; by TNK21 Publication1

Post-translational modificationi

Phosphorylated upon genotoxic stress. Phosphorylation of Tyr-33 regulates interaction with TP53, TP73 and MAPK8. May also regulate proapoptotic activity. Phosphorylation by TNK2 is associated with polyubiquitination and degradation.3 Publications
Ubiquitinated when phosphorylated by TNK2, leading to its degradation.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9NZC7
MaxQBiQ9NZC7
PaxDbiQ9NZC7
PeptideAtlasiQ9NZC7
PRIDEiQ9NZC7

PTM databases

iPTMnetiQ9NZC7
PhosphoSitePlusiQ9NZC7

Expressioni

Tissue specificityi

Widely expressed. Strongly expressed in testis, prostate, and ovary. Overexpressed in cancer cell lines. Isoform 5 and isoform 6 may only be expressed in tumor cell lines.2 Publications

Gene expression databases

BgeeiENSG00000186153
ExpressionAtlasiQ9NZC7 baseline and differential
GenevisibleiQ9NZC7 HS

Organism-specific databases

HPAiHPA050992

Interactioni

Subunit structurei

Interacts with TP53, p73/TP73 and MAPK8. Interacts with MAPT/TAU, RUNX2 and HYAL2 (By similarity). Forms a ternary complex with TP53 and MDM2. Interacts with ERBB4, LITAF and WBP1. Interacts with DVL1, DVL2 and DVL3. May interact with FAM189B and SCOTIN. Interacts with TNK2. Interacts with TMEM207.By similarity10 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • enzyme binding Source: BHF-UCL
  • protein dimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi119707255 interactors.
IntActiQ9NZC7 119 interactors.
MINTiQ9NZC7
STRINGi9606.ENSP00000457230

Structurei

Secondary structure

1414
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi63 – 67Combined sources5
Beta strandi73 – 80Combined sources8
Beta strandi83 – 86Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1WMVNMR-A51-101[»]
ProteinModelPortaliQ9NZC7
SMRiQ9NZC7
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9NZC7

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini16 – 49WW 1PROSITE-ProRule annotationAdd BLAST34
Domaini57 – 90WW 2PROSITE-ProRule annotationAdd BLAST34

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni125 – 414Interaction with MAPTBy similarityAdd BLAST290
Regioni209 – 273Mediates targeting to the mitochondriaBy similarityAdd BLAST65

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi50 – 55Nuclear localization signalBy similarity6

Domaini

The WW 1 domain mediates interaction with TP53, and probably TP73, TFAP2C, LITAF and WBP1.3 Publications

Sequence similaritiesi

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410INSS Eukaryota
COG5021 LUCA
GeneTreeiENSGT00760000119068
HOVERGENiHBG078800
InParanoidiQ9NZC7
KOiK19329
OMAiAATSIYC
OrthoDBiEOG091G0EI5
PhylomeDBiQ9NZC7
TreeFamiTF105428

Family and domain databases

CDDicd00201 WW, 2 hits
InterProiView protein in InterPro
IPR036291 NAD(P)-bd_dom_sf
IPR002347 SDR_fam
IPR001202 WW_dom
IPR036020 WW_dom_sf
PfamiView protein in Pfam
PF00106 adh_short, 1 hit
PF00397 WW, 2 hits
PRINTSiPR00081 GDHRDH
SMARTiView protein in SMART
SM00456 WW, 2 hits
SUPFAMiSSF51045 SSF51045, 2 hits
SSF51735 SSF51735, 1 hit
PROSITEiView protein in PROSITE
PS01159 WW_DOMAIN_1, 2 hits
PS50020 WW_DOMAIN_2, 2 hits

Sequences (7)i

Sequence statusi: Complete.

This entry describes 7 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NZC7-1) [UniParc]FASTAAdd to basket
Also known as: FOR II, FOR2, WWOXv1, WWOX v8

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.

« Hide

        10         20         30         40         50
MAALRYAGLD DTDSEDELPP GWEERTTKDG WVYYANHTEE KTQWEHPKTG
60 70 80 90 100
KRKRVAGDLP YGWEQETDEN GQVFFVDHIN KRTTYLDPRL AFTVDDNPTK
110 120 130 140 150
PTTRQRYDGS TTAMEILQGR DFTGKVVVVT GANSGIGFET AKSFALHGAH
160 170 180 190 200
VILACRNMAR ASEAVSRILE EWHKAKVEAM TLDLALLRSV QHFAEAFKAK
210 220 230 240 250
NVPLHVLVCN AATFALPWSL TKDGLETTFQ VNHLGHFYLV QLLQDVLCRS
260 270 280 290 300
APARVIVVSS ESHRFTDIND SLGKLDFSRL SPTKNDYWAM LAYNRSKLCN
310 320 330 340 350
ILFSNELHRR LSPRGVTSNA VHPGNMMYSN IHRSWWVYTL LFTLARPFTK
360 370 380 390 400
SMQQGAATTV YCAAVPELEG LGGMYFNNCC RCMPSPEAQS EETARTLWAL
410
SERLIQERLG SQSG
Length:414
Mass (Da):46,677
Last modified:October 1, 2000 - v1
Checksum:iE4D9A649E6CB05DF
GO
Isoform 2 (identifier: Q9NZC7-2) [UniParc]FASTAAdd to basket
Also known as: FOR I, FOR1, WOX2, WWOXv2

The sequence of this isoform differs from the canonical sequence as follows:
     353-363: QQGAATTVYCA → VSDCLVEGGHF
     364-414: Missing.

Show »
Length:363
Mass (Da):41,128
Checksum:iC1BB208B887281C3
GO
Isoform 3 (identifier: Q9NZC7-3) [UniParc]FASTAAdd to basket
Also known as: FOR III, FOR3, WOX3

The sequence of this isoform differs from the canonical sequence as follows:
     173-189: HKAKVEAMTLDLALLRS → KTKYHPPPEKCRIKIFH
     190-414: Missing.

Show »
Length:189
Mass (Da):21,559
Checksum:i82155A9AD7C824C7
GO
Isoform 4 (identifier: Q9NZC7-4) [UniParc]FASTAAdd to basket
Also known as: FOR IV

The sequence of this isoform differs from the canonical sequence as follows:
     36-36: N → K
     37-414: Missing.

Show »
Length:36
Mass (Da):4,150
Checksum:iA6D0FEE1CAE266B2
GO
Isoform 5 (identifier: Q9NZC7-5) [UniParc]FASTAAdd to basket
Also known as: WWOXdelta6-8, WWOXv4

The sequence of this isoform differs from the canonical sequence as follows:
     173-352: Missing.

Show »
Length:234
Mass (Da):26,148
Checksum:iC69FB6B3E87635F4
GO
Isoform 6 (identifier: Q9NZC7-6) [UniParc]FASTAAdd to basket
Also known as: WWOXdelta5-8, WWOXv3

The sequence of this isoform differs from the canonical sequence as follows:
     137-414: GFETAKSFAL...IQERLGSQSG → ATGSCHHRVL...FSFFYCYRIA

Show »
Length:311
Mass (Da):35,042
Checksum:i8EF6B9823F90C9F7
GO
Isoform 7 (identifier: Q9NZC7-7) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     138-213: FETAKSFALH...LHVLVCNAAT → KASCHVGRTL...PGPCGRSARG
     214-414: Missing.

Show »
Length:213
Mass (Da):23,868
Checksum:iA21054FF8214CC7C
GO

Sequence cautioni

The sequence AAP94227 differs from that shown. Reason: Frameshift at position 362.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07235147P → R in EIEE28. 1 PublicationCorresponds to variant dbSNP:rs730880292Ensembl.1
Natural variantiVAR_07099247P → T in SCAR12. 1 PublicationCorresponds to variant dbSNP:rs587777128Ensembl.1
Natural variantiVAR_02391698P → L1 PublicationCorresponds to variant dbSNP:rs144601717Ensembl.1
Natural variantiVAR_023917111T → S in a Burkitt lymphoma cell line. 1 PublicationCorresponds to variant dbSNP:rs114755364Ensembl.1
Natural variantiVAR_023918120R → W in a primary colorectal tumor and a histiocytic lymphoma cell line. 1 PublicationCorresponds to variant dbSNP:rs141361080Ensembl.1
Natural variantiVAR_023919179A → T2 PublicationsCorresponds to variant dbSNP:rs11545029Ensembl.1
Natural variantiVAR_052323216L → V. Corresponds to variant dbSNP:rs7201683Ensembl.1
Natural variantiVAR_023920272L → F1 PublicationCorresponds to variant dbSNP:rs186745328Ensembl.1
Natural variantiVAR_023921282P → A1 PublicationCorresponds to variant dbSNP:rs3764340Ensembl.1
Natural variantiVAR_023922291L → P Found in a esophageal cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs119487098Ensembl.1
Natural variantiVAR_023923314R → H in a cervical carcinoma cell line. 1 PublicationCorresponds to variant dbSNP:rs73572838Ensembl.1
Natural variantiVAR_070993372G → R in SCAR12. 1 PublicationCorresponds to variant dbSNP:rs587777127Ensembl.1
Isoform 3 (identifier: Q9NZC7-3)
Natural varianti182K → E Found in a primary colorectal tumor and tumor cells. 1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01635836N → K in isoform 4. 1 Publication1
Alternative sequenceiVSP_01635937 – 414Missing in isoform 4. 1 PublicationAdd BLAST378
Alternative sequenceiVSP_016360137 – 414GFETA…GSQSG → ATGSCHHRVLCCCPRTGGSG RDVLQQLLPLHALTRSSERR DGPDPVGAQREADPRTAWQP VRLSGAQSGWAHTPALCVSP HASARAGPLPNVPPTQIRKS KGNKSSHNRVKNLKYQWEAG NSWGKVSLFWGWARHRSLCF LVVACLKVKTCLVCRFRISL EKHQQFSFFYCYRIA in isoform 6. 1 PublicationAdd BLAST278
Alternative sequenceiVSP_016362138 – 213FETAK…CNAAT → KASCHVGRTLKHTRVEELSL LPTAINRELPPPCTVLLSQN WRVWEGCTSTTAAAACPHQK LRAKRRPGPCGRSARG in isoform 7. CuratedAdd BLAST76
Alternative sequenceiVSP_016363173 – 352Missing in isoform 5. 3 PublicationsAdd BLAST180
Alternative sequenceiVSP_016364173 – 189HKAKV…ALLRS → KTKYHPPPEKCRIKIFH in isoform 3. 1 PublicationAdd BLAST17
Alternative sequenceiVSP_016365190 – 414Missing in isoform 3. 1 PublicationAdd BLAST225
Alternative sequenceiVSP_016366214 – 414Missing in isoform 7. CuratedAdd BLAST201
Alternative sequenceiVSP_016367353 – 363QQGAATTVYCA → VSDCLVEGGHF in isoform 2. 1 PublicationAdd BLAST11
Alternative sequenceiVSP_016369364 – 414Missing in isoform 2. 1 PublicationAdd BLAST51

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF211943 mRNA Translation: AAF27049.1
AF212843 Genomic DNA Translation: AAF27050.1
AH009490 Genomic DNA Translation: AAF78197.1
AF227526 mRNA Translation: AAF82053.1
AF227527 mRNA Translation: AAF82054.1
AF227528 mRNA Translation: AAF82055.1
AF227529 mRNA Translation: AAF82056.1
AF395123 mRNA Translation: AAK81727.1
AF395124 mRNA Translation: AAK81728.1
AF325432
, AF325423, AF325424, AF325425, AF325426, AF325427, AF325428, AF325430, AF325431 Genomic DNA Translation: AAL05449.1
AF325429
, AF325423, AF325424, AF325425, AF325426, AF325427 Genomic DNA Translation: AAL05450.1
AF325432
, AF325423, AF325424, AF325425, AF325426, AF325433 Genomic DNA Translation: AAL05451.1
AY256821 mRNA Translation: AAP94227.1 Frameshift.
AK290438 mRNA Translation: BAF83127.1
BT007445 mRNA Translation: AAP36113.1
BC003184 mRNA Translation: AAH03184.1
CCDSiCCDS42196.1 [Q9NZC7-1]
CCDS42197.1 [Q9NZC7-3]
RefSeqiNP_001278926.1, NM_001291997.1
NP_057457.1, NM_016373.3 [Q9NZC7-1]
NP_570607.1, NM_130791.3 [Q9NZC7-3]
UniGeneiHs.461453

Genome annotation databases

EnsembliENST00000355860; ENSP00000348119; ENSG00000186153 [Q9NZC7-3]
ENST00000402655; ENSP00000384238; ENSG00000186153 [Q9NZC7-6]
ENST00000406884; ENSP00000384495; ENSG00000186153 [Q9NZC7-5]
ENST00000408984; ENSP00000386161; ENSG00000186153 [Q9NZC7-2]
ENST00000566780; ENSP00000457230; ENSG00000186153 [Q9NZC7-1]
ENST00000569818; ENSP00000454485; ENSG00000186153 [Q9NZC7-4]
GeneIDi51741
KEGGihsa:51741
UCSCiuc002ffi.3 human [Q9NZC7-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiWWOX_HUMAN
AccessioniPrimary (citable) accession number: Q9NZC7
Secondary accession number(s): A8K323
, Q5MYT5, Q96KM3, Q96RF2, Q9BTT8, Q9NPC9, Q9NRF4, Q9NRF5, Q9NRF6, Q9NRK1, Q9NZC5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 22, 2005
Last sequence update: October 1, 2000
Last modified: April 25, 2018
This is version 167 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome