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Q9NZC7

- WWOX_HUMAN

UniProt

Q9NZC7 - WWOX_HUMAN

Protein

WW domain-containing oxidoreductase

Gene

WWOX

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 131 (01 Oct 2014)
      Sequence version 1 (01 Oct 2000)
      Previous versions | rss
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    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)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei260 – 2601SubstrateBy similarity
    Active sitei293 – 2931Proton acceptorBy similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi131 – 1377NADPBy similarity

    GO - Molecular functioni

    1. coenzyme binding Source: UniProtKB
    2. cofactor binding Source: UniProtKB
    3. enzyme binding Source: BHF-UCL
    4. oxidoreductase activity Source: UniProtKB
    5. protein binding Source: UniProtKB
    6. protein dimerization activity Source: UniProtKB

    GO - Biological processi

    1. cellular response to transforming growth factor beta stimulus Source: BHF-UCL
    2. extrinsic apoptotic signaling pathway Source: Ensembl
    3. intrinsic apoptotic signaling pathway by p53 class mediator Source: Ensembl
    4. negative regulation of Wnt signaling pathway Source: UniProtKB
    5. osteoblast differentiation Source: Ensembl
    6. oxidation-reduction process Source: UniProtKB
    7. positive regulation of extrinsic apoptotic signaling pathway Source: BHF-UCL
    8. positive regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: Ensembl
    9. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    10. skeletal system morphogenesis Source: BHF-UCL
    11. steroid metabolic process Source: UniProtKB
    12. Wnt signaling pathway Source: UniProtKB-KW

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Biological processi

    Apoptosis, Wnt signaling pathway

    Keywords - Ligandi

    NADP

    Enzyme and pathway databases

    ReactomeiREACT_116022. Nuclear signaling by ERBB4.
    SignaLinkiQ9NZC7.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    WW domain-containing oxidoreductase (EC:1.1.1.-)
    Alternative name(s):
    Fragile site FRA16D oxidoreductase
    Gene namesi
    Name:WWOX
    Synonyms:FOR, WOX1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 16

    Organism-specific databases

    HGNCiHGNC:12799. WWOX.

    Subcellular locationi

    Cytoplasm. Nucleus. Mitochondrion. Golgi apparatus
    Note: Partially localizes to the mitochondria. Translocates to the nucleus upon genotoxic stress or TNF stimulation By similarity. Translocates to the nucleus in response to TGFB1. Isoform 5 and isoform 6 may localize in the nucleus.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. cytosol Source: BHF-UCL
    3. Golgi apparatus Source: UniProtKB
    4. mitochondrion Source: BHF-UCL
    5. nucleus Source: BHF-UCL

    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. 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.
    Esophageal cancer (ESCR) [MIM:133239]: A 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.
    Note: The disease may be caused by mutations affecting the gene represented in this entry.
    Spinocerebellar ataxia, autosomal recessive, 12 (SCAR12) [MIM:614322]: Spinocerebellar 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.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti47 – 471P → T in SCAR12. 1 Publication
    VAR_070992
    Natural varianti372 – 3721G → R in SCAR12. 1 Publication
    VAR_070993

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi28 – 281K → T: No effect on interaction with TP53. Abolishes interaction with MAPK8; when associated with V-29. 2 Publications
    Mutagenesisi29 – 291D → V: No effect on interaction with TP53. Abolishes interaction with MAPK8; when associated with T-28. 2 Publications
    Mutagenesisi33 – 331Y → F: Loss of phosphorylation. 3 Publications
    Mutagenesisi33 – 331Y → R: Abolishes interaction with TP53, TP73, MAPK8 and ERBB4. Partial loss of interaction with TFAP2C. Loss of phosphorylation. Loss of the proapoptotic activity. 3 Publications
    Mutagenesisi44 – 474WEHP → FEHA: Abolishes interaction with LITAF. 1 Publication
    Mutagenesisi61 – 611Y → R: No effect on interaction with TP73. 2 Publications
    Mutagenesisi85 – 884YLDP → ALDA: No effect on interaction with LITAF. 1 Publication
    Mutagenesisi287 – 2871Y → A: Loss of phosphorylation by TNK2. 2 Publications

    Keywords - Diseasei

    Disease mutation, Neurodegeneration, Tumor suppressor

    Organism-specific databases

    MIMi133239. phenotype.
    614322. phenotype.
    Orphaneti251510. 46,XY partial gonadal dysgenesis.
    284282. Autosomal recessive cerebellar ataxia - epilepsy - intellectual disability.
    PharmGKBiPA37398.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 414414WW domain-containing oxidoreductasePRO_0000054815Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei12 – 121Phosphothreonine2 Publications
    Modified residuei14 – 141Phosphoserine2 Publications
    Modified residuei33 – 331Phosphotyrosine3 Publications
    Modified residuei287 – 2871Phosphotyrosine; by TNK22 Publications

    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

    MaxQBiQ9NZC7.
    PaxDbiQ9NZC7.
    PRIDEiQ9NZC7.

    PTM databases

    PhosphoSiteiQ9NZC7.

    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

    ArrayExpressiQ9NZC7.
    BgeeiQ9NZC7.
    GenevestigatoriQ9NZC7.

    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

    WithEntry#Exp.IntActNotes
    Erbb4Q615273EBI-4320739,EBI-4398741From a different organism.
    FAM189BP814082EBI-4320739,EBI-6366314
    LITAFQ997325EBI-4320739,EBI-725647
    SHISA5Q8N1142EBI-4320739,EBI-2115556
    WBP1Q96G273EBI-4320739,EBI-3867685

    Protein-protein interaction databases

    BioGridi119707. 230 interactions.
    IntActiQ9NZC7. 6 interactions.
    MINTiMINT-1175612.

    Structurei

    Secondary structure

    1
    414
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi63 – 675
    Beta strandi73 – 808
    Beta strandi83 – 864

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1WMVNMR-A51-101[»]
    ProteinModelPortaliQ9NZC7.
    SMRiQ9NZC7. Positions 13-101, 121-376.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9NZC7.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini16 – 4934WW 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini57 – 9034WW 2PROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni125 – 414290Interaction with MAPTBy similarityAdd
    BLAST
    Regioni209 – 27365Mediates targeting to the mitochondriaBy similarityAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi50 – 556Nuclear localization signalBy similarity

    Domaini

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

    Sequence similaritiesi

    Contains 2 WW domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiCOG1028.
    HOVERGENiHBG078800.
    OMAiYSNIHRS.
    OrthoDBiEOG73Z2TK.
    PhylomeDBiQ9NZC7.
    TreeFamiTF105428.

    Family and domain databases

    Gene3Di3.40.50.720. 1 hit.
    InterProiIPR002198. DH_sc/Rdtase_SDR.
    IPR002347. Glc/ribitol_DH.
    IPR016040. NAD(P)-bd_dom.
    IPR001202. WW_dom.
    [Graphical view]
    PfamiPF00106. adh_short. 1 hit.
    PF00397. WW. 2 hits.
    [Graphical view]
    PRINTSiPR00081. GDHRDH.
    SMARTiSM00456. WW. 2 hits.
    [Graphical view]
    SUPFAMiSSF51045. SSF51045. 2 hits.
    PROSITEiPS01159. WW_DOMAIN_1. 2 hits.
    PS50020. WW_DOMAIN_2. 2 hits.
    [Graphical view]

    Sequences (7)i

    Sequence statusi: Complete.

    This entry describes 7 isoformsi produced by alternative splicing. Align

    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

    MAALRYAGLD DTDSEDELPP GWEERTTKDG WVYYANHTEE KTQWEHPKTG    50
    KRKRVAGDLP YGWEQETDEN GQVFFVDHIN KRTTYLDPRL AFTVDDNPTK 100
    PTTRQRYDGS TTAMEILQGR DFTGKVVVVT GANSGIGFET AKSFALHGAH 150
    VILACRNMAR ASEAVSRILE EWHKAKVEAM TLDLALLRSV QHFAEAFKAK 200
    NVPLHVLVCN AATFALPWSL TKDGLETTFQ VNHLGHFYLV QLLQDVLCRS 250
    APARVIVVSS ESHRFTDIND SLGKLDFSRL SPTKNDYWAM LAYNRSKLCN 300
    ILFSNELHRR LSPRGVTSNA VHPGNMMYSN IHRSWWVYTL LFTLARPFTK 350
    SMQQGAATTV YCAAVPELEG LGGMYFNNCC RCMPSPEAQS EETARTLWAL 400
    SERLIQERLG SQSG 414
    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 AAP94227.1 differs from that shown. Reason: Frameshift at position 362.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti47 – 471P → T in SCAR12. 1 Publication
    VAR_070992
    Natural varianti98 – 981P → L.1 Publication
    Corresponds to variant rs144601717 [ dbSNP | Ensembl ].
    VAR_023916
    Natural varianti111 – 1111T → S in a Burkitt lymphoma cell line. 1 Publication
    Corresponds to variant rs114755364 [ dbSNP | Ensembl ].
    VAR_023917
    Natural varianti120 – 1201R → W in a primary colorectal tumor and a histiocytic lymphoma cell line. 1 Publication
    Corresponds to variant rs141361080 [ dbSNP | Ensembl ].
    VAR_023918
    Natural varianti179 – 1791A → T.2 Publications
    Corresponds to variant rs12918952 [ dbSNP | Ensembl ].
    VAR_023919
    Natural varianti216 – 2161L → V.
    Corresponds to variant rs7201683 [ dbSNP | Ensembl ].
    VAR_052323
    Natural varianti272 – 2721L → F.1 Publication
    Corresponds to variant rs186745328 [ dbSNP | Ensembl ].
    VAR_023920
    Natural varianti282 – 2821P → A.1 Publication
    Corresponds to variant rs3764340 [ dbSNP | Ensembl ].
    VAR_023921
    Natural varianti291 – 2911L → P Found in a esophageal cancer sample; somatic mutation. 1 Publication
    VAR_023922
    Natural varianti314 – 3141R → H in a cervical carcinoma cell line. 1 Publication
    Corresponds to variant rs73572838 [ dbSNP | Ensembl ].
    VAR_023923
    Natural varianti372 – 3721G → R in SCAR12. 1 Publication
    VAR_070993
    Isoform 3 (identifier: Q9NZC7-3)
    Natural varianti182 – 1821K → E Found in a primary colorectal tumor and tumor cells.

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei36 – 361N → K in isoform 4. 1 PublicationVSP_016358
    Alternative sequencei37 – 414378Missing in isoform 4. 1 PublicationVSP_016359Add
    BLAST
    Alternative sequencei137 – 414278GFETA…GSQSG → ATGSCHHRVLCCCPRTGGSG RDVLQQLLPLHALTRSSERR DGPDPVGAQREADPRTAWQP VRLSGAQSGWAHTPALCVSP HASARAGPLPNVPPTQIRKS KGNKSSHNRVKNLKYQWEAG NSWGKVSLFWGWARHRSLCF LVVACLKVKTCLVCRFRISL EKHQQFSFFYCYRIA in isoform 6. 1 PublicationVSP_016360Add
    BLAST
    Alternative sequencei138 – 21376FETAK…CNAAT → KASCHVGRTLKHTRVEELSL LPTAINRELPPPCTVLLSQN WRVWEGCTSTTAAAACPHQK LRAKRRPGPCGRSARG in isoform 7. CuratedVSP_016362Add
    BLAST
    Alternative sequencei173 – 352180Missing in isoform 5. 3 PublicationsVSP_016363Add
    BLAST
    Alternative sequencei173 – 18917HKAKV…ALLRS → KTKYHPPPEKCRIKIFH in isoform 3. 1 PublicationVSP_016364Add
    BLAST
    Alternative sequencei190 – 414225Missing in isoform 3. 1 PublicationVSP_016365Add
    BLAST
    Alternative sequencei214 – 414201Missing in isoform 7. CuratedVSP_016366Add
    BLAST
    Alternative sequencei353 – 36311QQGAATTVYCA → VSDCLVEGGHF in isoform 2. 1 PublicationVSP_016367Add
    BLAST
    Alternative sequencei364 – 41451Missing in isoform 2. 1 PublicationVSP_016369Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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_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.2. human. [Q9NZC7-4]
    uc002ffj.2. human. [Q9NZC7-3]
    uc002ffk.3. human. [Q9NZC7-1]
    uc002ffl.3. human. [Q9NZC7-5]
    uc010che.3. human. [Q9NZC7-6]

    Polymorphism databases

    DMDMi74725363.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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 .
    CCDSi CCDS42196.1. [Q9NZC7-1 ]
    CCDS42197.1. [Q9NZC7-3 ]
    RefSeqi NP_057457.1. NM_016373.3. [Q9NZC7-1 ]
    NP_570607.1. NM_130791.3. [Q9NZC7-3 ]
    UniGenei Hs.461453.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1WMV NMR - A 51-101 [» ]
    ProteinModelPortali Q9NZC7.
    SMRi Q9NZC7. Positions 13-101, 121-376.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 119707. 230 interactions.
    IntActi Q9NZC7. 6 interactions.
    MINTi MINT-1175612.

    PTM databases

    PhosphoSitei Q9NZC7.

    Polymorphism databases

    DMDMi 74725363.

    Proteomic databases

    MaxQBi Q9NZC7.
    PaxDbi Q9NZC7.
    PRIDEi Q9NZC7.

    Protocols and materials databases

    DNASUi 51741.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000355860 ; 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 ]
    GeneIDi 51741.
    KEGGi hsa:51741.
    UCSCi uc002ffi.2. human. [Q9NZC7-4 ]
    uc002ffj.2. human. [Q9NZC7-3 ]
    uc002ffk.3. human. [Q9NZC7-1 ]
    uc002ffl.3. human. [Q9NZC7-5 ]
    uc010che.3. human. [Q9NZC7-6 ]

    Organism-specific databases

    CTDi 51741.
    GeneCardsi GC16P078133.
    HGNCi HGNC:12799. WWOX.
    HPAi HPA050992.
    MIMi 133239. phenotype.
    605131. gene.
    614322. phenotype.
    neXtProti NX_Q9NZC7.
    Orphaneti 251510. 46,XY partial gonadal dysgenesis.
    284282. Autosomal recessive cerebellar ataxia - epilepsy - intellectual disability.
    PharmGKBi PA37398.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG1028.
    HOVERGENi HBG078800.
    OMAi YSNIHRS.
    OrthoDBi EOG73Z2TK.
    PhylomeDBi Q9NZC7.
    TreeFami TF105428.

    Enzyme and pathway databases

    Reactomei REACT_116022. Nuclear signaling by ERBB4.
    SignaLinki Q9NZC7.

    Miscellaneous databases

    ChiTaRSi WWOX. human.
    EvolutionaryTracei Q9NZC7.
    GeneWikii WWOX.
    GenomeRNAii 51741.
    NextBioi 55812.
    PROi Q9NZC7.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q9NZC7.
    Bgeei Q9NZC7.
    Genevestigatori Q9NZC7.

    Family and domain databases

    Gene3Di 3.40.50.720. 1 hit.
    InterProi IPR002198. DH_sc/Rdtase_SDR.
    IPR002347. Glc/ribitol_DH.
    IPR016040. NAD(P)-bd_dom.
    IPR001202. WW_dom.
    [Graphical view ]
    Pfami PF00106. adh_short. 1 hit.
    PF00397. WW. 2 hits.
    [Graphical view ]
    PRINTSi PR00081. GDHRDH.
    SMARTi SM00456. WW. 2 hits.
    [Graphical view ]
    SUPFAMi SSF51045. SSF51045. 2 hits.
    PROSITEi PS01159. WW_DOMAIN_1. 2 hits.
    PS50020. WW_DOMAIN_2. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3-24.1, a region frequently affected in breast cancer."
      Bednarek A.K., Laflin K.J., Daniel R.L., Liao Q., Hawkins K.A., Aldaz C.M.
      Cancer Res. 60:2140-2145(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-35, TISSUE SPECIFICITY.
      Tissue: Placenta.
    2. "Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells."
      Ried K., Finnis M., Hobson L., Mangelsdorf M., Dayan S., Nancarrow J.K., Woollatt E., Kremmidiotis G., Gardner A., Venter D., Baker E., Richards R.I.
      Hum. Mol. Genet. 9:1651-1663(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 173-414.
    3. "WWOX, the FRA16D gene, behaves as a suppressor of tumor growth."
      Bednarek A.K., Keck-Waggoner C.L., Daniel R.L., Laflin K.J., Bergsagel P.L., Kiguchi K., Brenner A.J., Aldaz C.M.
      Cancer Res. 61:8068-8073(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 5 AND 6), FUNCTION, TISSUE SPECIFICITY.
    4. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORMS 1; 3 AND 7), VARIANTS LEU-98; SER-111; TRP-120; THR-179; PHE-272; ALA-282 AND HIS-314, DISEASE.
    5. "Cloning of human WOX8 (WWOX v8)."
      Chang N.-S.
      Submitted (DEC-2004) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT THR-179.
      Tissue: Colon adenocarcinoma.
    6. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    7. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
      Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
      Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
    8. "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 5).
      Tissue: Lung.
    9. "An opposing view on WWOX protein function as a tumor suppressor."
      Watanabe A., Hippo Y., Taniguchi H., Iwanari H., Yashiro M., Hirakawa K., Kodama T., Aburatani H.
      Cancer Res. 63:8629-8633(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    10. "JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis."
      Chang N.-S., Doherty J., Ensign A.
      J. Biol. Chem. 278:9195-9202(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MAPK8 AND TP53, MUTAGENESIS OF LYS-28; ASP-29 AND TYR-33.
    11. "Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma."
      Park S.-W., Ludes-Meyers J., Zimonjic D.B., Durkin M.E., Popescu N.C., Aldaz C.M.
      Br. J. Cancer 91:753-759(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISEASE.
    12. "Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor."
      Aqeilan R.I., Palamarchuk A., Weigel R.J., Herrero J.J., Pekarsky Y., Croce C.M.
      Cancer Res. 64:8256-8261(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH TFAP2C AND TFAP2A, DOMAIN.
    13. Cited for: DISEASE.
    14. Cited for: DISEASE.
    15. "WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins."
      Ludes-Meyers J.H., Kil H., Bednarek A.K., Drake J., Bedford M.T., Aldaz C.M.
      Oncogene 23:5049-5055(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LITAF; WBP1; FAM189B AND SCOTIN, MUTAGENESIS OF 44-TRP--PRO-47 AND 85-TYR--PRO-88, DOMAIN, SUBCELLULAR LOCATION.
    16. Cited for: FUNCTION, INTERACTION WITH TP73, DOMAIN, MUTAGENESIS OF TYR-33 AND TYR-61, PHOSPHORYLATION AT TYR-33, SUBCELLULAR LOCATION.
    17. "WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function."
      Aqeilan R.I., Donati V., Palamarchuk A., Trapasso F., Kaou M., Pekarsky Y., Sudol M., Croce C.M.
      Cancer Res. 65:6764-6772(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH ERBB4.
    18. "Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox."
      Mahajan N.P., Whang Y.E., Mohler J.L., Earp H.S.
      Cancer Res. 65:10514-10523(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT TYR-287 BY TNK2, UBIQUITINATION, MUTAGENESIS OF TYR-287, INTERACTION WITH TNK2.
    19. "WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53."
      Chang N.-S., Doherty J., Ensign A., Schultz L., Hsu L.-J., Hong Q.
      J. Biol. Chem. 280:43100-43108(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH MDM2 AND TP53, PHOSPHORYLATION, SUBCELLULAR LOCATION.
    20. Cited for: DISEASE.
    21. "Transforming growth factor beta1 signaling via interaction with cell surface Hyal-2 and recruitment of WWOX/WOX1."
      Hsu L.-J., Schultz L., Hong Q., Van Moer K., Heath J., Li M.-Y., Lai F.-J., Lin S.-R., Lee M.-H., Lo C.-P., Lin Y.-S., Chen S.-T., Chang N.-S.
      J. Biol. Chem. 284:16049-16059(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT TYR-33, SUBCELLULAR LOCATION, INTERACTION WITH HYAL2.
    22. "Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein."
      Bouteille N., Driouch K., Hage P.E., Sin S., Formstecher E., Camonis J., Lidereau R., Lallemand F.
      Oncogene 28:2569-2580(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH DVL1; DVL2 AND DVL3.
    23. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-12 AND SER-14, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    24. "A WWOX-binding molecule, transmembrane protein 207, is related to the invasiveness of gastric signet-ring cell carcinoma."
      Takeuchi T., Adachi Y., Nagayama T.
      Carcinogenesis 33:548-554(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH TMEM207.
    25. "The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration."
      Abdel-Salam G., Thoenes M., Afifi H.H., Koerber F., Swan D., Bolz H.J.
      Orphanet J. Rare Dis. 9:12-12(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN SCAR12.
    26. "Solution structure of the second WW domain of WWOX."
      Kowalski K., Merkel A.L., Colella A., Richards R.I., Booker G.W.
      Submitted (FEB-2009) to the PDB data bank
      Cited for: STRUCTURE BY NMR OF 51-101.
    27. "Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma."
      Kuroki T., Trapasso F., Shiraishi T., Alder H., Mimori K., Mori M., Croce C.M.
      Cancer Res. 62:2258-2260(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT PRO-291.
    28. "The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation."
      Mallaret M., Synofzik M., Lee J., Sagum C.A., Mahajnah M., Sharkia R., Drouot N., Renaud M., Klein F.A., Anheim M., Tranchant C., Mignot C., Mandel J.L., Bedford M., Bauer P., Salih M.A., Schuele R., Schoels L., Aldaz C.M., Koenig M.
      Brain 137:411-419(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS SCAR12 THR-47 AND ARG-372.

    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 historyi
    Integrated into UniProtKB/Swiss-Prot: November 22, 2005
    Last sequence update: October 1, 2000
    Last modified: October 1, 2014
    This is version 131 of the entry and version 1 of the sequence. [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

    Documents

    1. Human chromosome 16
      Human chromosome 16: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3