ID   EYA3_MOUSE              Reviewed;         510 AA.
AC   P97480; G5E8I5; P97768;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   03-OCT-2012, sequence version 2.
DT   02-SEP-2026, entry version 184.
DE   RecName: Full=Protein phosphatase EYA3 {ECO:0000305};
DE            EC=3.1.3.48 {ECO:0000269|PubMed:14628042, ECO:0000269|PubMed:14628052, ECO:0000269|PubMed:14628053};
DE   AltName: Full=Eyes absent homolog 3;
GN   Name=Eya3;
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 [MRNA] (ISOFORM 1).
RC   TISSUE=Embryo;
RX   PubMed=9049631; DOI=10.1101/gr.7.2.128;
RA   Zimmerman J.E., Bui Q.T., Steingrimsson E., Nagle D.L., Fu W., Genin A.,
RA   Spinner N.B., Copeland N.G., Jenkins N.A., Bucan M., Bonini N.M.;
RT   "Cloning and characterization of two vertebrate homologs of the Drosophila
RT   eyes absent gene.";
RL   Genome Res. 7:128-141(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC   TISSUE=Embryo;
RX   PubMed=9006082; DOI=10.1242/dev.124.1.219;
RA   Xu P.-X., Woo I., Her H., Beier D.R., Maas R.L.;
RT   "Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for
RT   expression in lens and nasal placode.";
RL   Development 124:219-231(1997).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA   Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA   Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA   Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA   Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA   Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA   Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of the
RT   mouse.";
RL   PLoS Biol. 7:E1000112-E1000112(2009).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 350-468.
RC   TISSUE=Embryo;
RX   PubMed=9887327; DOI=10.1093/hmg/8.1.11;
RA   Borsani G., DeGrandi A., Ballabio A., Bulfone A., Bernard L., Banfi S.,
RA   Gattuso C., Mariani M., Dixon M., Donnai D., Metcalfe K., Winter R.,
RA   Robertson M., Axton R., Brown A., van Heyningen V., Hanson I.;
RT   "EYA4, a novel vertebrate gene related to Drosophila eyes absent.";
RL   Hum. Mol. Genet. 8:11-23(1999).
RN   [6]
RP   FUNCTION, INTERACTION WITH SIX2; SIX4 AND SIX5, AND SUBCELLULAR LOCATION.
RX   PubMed=10490620; DOI=10.1128/mcb.19.10.6815;
RA   Ohto H., Kamada S., Tago K., Tominaga S., Ozaki H., Sato S., Kawakami K.;
RT   "Cooperation of six and eya in activation of their target genes through
RT   nuclear translocation of Eya.";
RL   Mol. Cell. Biol. 19:6815-6824(1999).
RN   [7]
RP   INTERACTION WITH SIX1; SIX2; SIX4 AND SIX5.
RX   PubMed=12215533; DOI=10.1128/mcb.22.19.6759-6766.2002;
RA   Ikeda K., Watanabe Y., Ohto H., Kawakami K.;
RT   "Molecular interaction and synergistic activation of a promoter by Six,
RT   Eya, and Dach proteins mediated through CREB binding protein.";
RL   Mol. Cell. Biol. 22:6759-6766(2002).
RN   [8]
RP   CATALYTIC ACTIVITY, INTERACTION WITH DACH1 AND SIX1, AND MUTAGENESIS OF
RP   ASP-246.
RX   PubMed=14628042; DOI=10.1038/nature02083;
RA   Li X., Oghi K.A., Zhang J., Krones A., Bush K.T., Glass C.K., Nigam S.K.,
RA   Aggarwal A.K., Maas R., Rose D.W., Rosenfeld M.G.;
RT   "Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional
RT   effects in mammalian organogenesis.";
RL   Nature 426:247-254(2003).
RN   [9]
RP   ERRATUM OF PUBMED:14628042.
RA   Li X., Oghi K.A., Zhang J., Krones A., Bush K.T., Glass C.K., Nigam S.K.,
RA   Aggarwal A.K., Maas R., Rose D.W., Rosenfeld M.G.;
RL   Nature 427:265-265(2004).
RN   [10]
RP   CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-246;
RP   ASP-248; THR-250; THR-419; GLY-473; ASP-474 AND GLU-478.
RX   PubMed=14628052; DOI=10.1038/nature02093;
RA   Rayapureddi J.P., Kattamuri C., Steinmetz B.D., Frankfort B.J.,
RA   Ostrin E.J., Mardon G., Hegde R.S.;
RT   "Eyes absent represents a class of protein tyrosine phosphatases.";
RL   Nature 426:295-298(2003).
RN   [11]
RP   CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-246; THR-420; LYS-449; ASP-474
RP   AND GLU-478.
RX   PubMed=14628053; DOI=10.1038/nature02097;
RA   Tootle T.L., Silver S.J., Davies E.L., Newman V., Latek R.R., Mills I.A.,
RA   Selengut J.D., Parlikar B.E., Rebay I.;
RT   "The transcription factor Eyes absent is a protein tyrosine phosphatase.";
RL   Nature 426:299-302(2003).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA   Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT   "Large-scale phosphorylation analysis of mouse liver.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN   [13]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Lung, Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
CC   -!- FUNCTION: Tyrosine phosphatase that specifically dephosphorylates 'Tyr-
CC       142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone
CC       H2AX plays a central role in DNA repair and acts as a mark that
CC       distinguishes between apoptotic and repair responses to genotoxic
CC       stress. Promotes efficient DNA repair by dephosphorylating H2AX,
CC       promoting the recruitment of DNA repair complexes containing MDC1 (By
CC       similarity). Its function as histone phosphatase probably explains its
CC       role in transcription regulation during organogenesis. The phosphatase
CC       activity has been shown in vitro. Coactivates SIX1. Seems to coactivate
CC       SIX2, SIX4 and SIX5. The repression of precursor cell proliferation in
CC       myoblasts by SIX1 is switched to activation through recruitment of EYA3
CC       to the SIX1-DACH1 complex and seems to be dependent on EYA3 phosphatase
CC       activity. May be involved in development of the eye. May play a role in
CC       mediating the induction and differentiation of cranial placodes.
CC       {ECO:0000250|UniProtKB:Q99504, ECO:0000269|PubMed:10490620}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] +
CC         phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC         COMP:20101, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858,
CC         ChEBI:CHEBI:61978; EC=3.1.3.48;
CC         Evidence={ECO:0000269|PubMed:14628042, ECO:0000269|PubMed:14628052,
CC         ECO:0000269|PubMed:14628053};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:O00167};
CC       Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000250|UniProtKB:O00167};
CC   -!- SUBUNIT: Interacts with SIX1 and DACH1, and probably SIX2, SIX4 and
CC       SIX5. {ECO:0000269|PubMed:10490620, ECO:0000269|PubMed:12215533,
CC       ECO:0000269|PubMed:14628042}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10490620}. Nucleus
CC       {ECO:0000269|PubMed:10490620, ECO:0000269|PubMed:14628052}.
CC       Note=Localizes at sites of DNA damage at double-strand breaks (DSBs).
CC       {ECO:0000250|UniProtKB:Q99504}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P97480-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P97480-2; Sequence=VSP_001494;
CC   -!- TISSUE SPECIFICITY: Expressed in branchial arches, CNS and developing
CC       eye.
CC   -!- PTM: Ser-203 phosphorylation is required for localization at sites of
CC       DNA damage and directing interaction with H2AX. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the HAD-like hydrolase superfamily. EYA family.
CC       {ECO:0000305}.
CC   -!- CAUTION: According to PubMed:14628042 also shows serine/threonine
CC       protein phosphatase activity. {ECO:0000305}.
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DR   EMBL; U81604; AAB42068.1; -; mRNA.
DR   EMBL; U61112; AAB48019.1; -; mRNA.
DR   EMBL; AL627130; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH466552; EDL30095.1; -; Genomic_DNA.
DR   EMBL; AJ007996; CAA07819.1; -; mRNA.
DR   CCDS; CCDS18730.1; -. [P97480-1]
DR   CCDS; CCDS18731.1; -. [P97480-2]
DR   RefSeq; NP_034296.2; NM_010166.4. [P97480-1]
DR   RefSeq; NP_997596.1; NM_211357.3. [P97480-2]
DR   AlphaFoldDB; P97480; -.
DR   SMR; P97480; -.
DR   BioGRID; 199561; 4.
DR   CORUM; P97480; -.
DR   FunCoup; P97480; 2945.
DR   IntAct; P97480; 4.
DR   MINT; P97480; -.
DR   STRING; 10090.ENSMUSP00000080425; -.
DR   BindingDB; P97480; -.
DR   ChEMBL; CHEMBL4296244; -.
DR   DrugCentral; P97480; -.
DR   iPTMnet; P97480; -.
DR   PhosphoSitePlus; P97480; -.
DR   PaxDb; 10090-ENSMUSP00000080425; -.
DR   PeptideAtlas; P97480; -.
DR   ProteomicsDB; 275707; -. [P97480-1]
DR   ProteomicsDB; 275708; -. [P97480-2]
DR   Pumba; P97480; -.
DR   Antibodypedia; 16480; 164 antibodies from 28 providers.
DR   DNASU; 14050; -.
DR   Ensembl; ENSMUST00000020197.14; ENSMUSP00000020197.8; ENSMUSG00000028886.16. [P97480-2]
DR   Ensembl; ENSMUST00000079157.11; ENSMUSP00000078157.5; ENSMUSG00000028886.16. [P97480-1]
DR   Ensembl; ENSMUST00000180250.8; ENSMUSP00000136812.2; ENSMUSG00000028886.16. [P97480-2]
DR   GeneID; 14050; -.
DR   KEGG; mmu:14050; -.
DR   UCSC; uc008vbo.2; mouse. [P97480-1]
DR   UCSC; uc008vbq.2; mouse. [P97480-2]
DR   AGR; MGI:109339; -.
DR   CTD; 2140; -.
DR   MGI; MGI:109339; Eya3.
DR   VEuPathDB; HostDB:ENSMUSG00000028886; -.
DR   eggNOG; KOG3107; Eukaryota.
DR   GeneTree; ENSGT00950000182978; -.
DR   HOGENOM; CLU_021184_2_0_1; -.
DR   InParanoid; P97480; -.
DR   OrthoDB; 167668at2759; -.
DR   Reactome; R-MMU-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR   SABIO-RK; P97480; -.
DR   BioGRID-ORCS; 14050; 2 hits in 116 CRISPR screens.
DR   PRO; PR:P97480; -.
DR   Proteomes; UP000000589; Chromosome 4.
DR   RNAct; P97480; protein.
DR   Bgee; ENSMUSG00000028886; Expressed in undifferentiated genital tubercle and 267 other cell types or tissues.
DR   ExpressionAtlas; P97480; baseline and differential.
DR   GO; GO:0005813; C:centrosome; ISO:GO_Central.
DR   GO; GO:0005737; C:cytoplasm; EXP:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; ISO:GO_Central.
DR   GO; GO:0005634; C:nucleus; IDA:MGI.
DR   GO; GO:0005667; C:transcription regulator complex; IPI:MGI.
DR   GO; GO:0003682; F:chromatin binding; IGI:MGI.
DR   GO; GO:0140793; F:histone H2AXY142 phosphatase activity; ISS:UniProtKB.
DR   GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:MGI.
DR   GO; GO:0008138; F:protein tyrosine/serine/threonine phosphatase activity; IDA:MGI.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR   GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IBA:GO_Central.
DR   GO; GO:0045739; P:positive regulation of DNA repair; ISS:UniProtKB.
DR   GO; GO:0006470; P:protein dephosphorylation; IDA:MGI.
DR   GO; GO:0010212; P:response to ionizing radiation; ISS:UniProtKB.
DR   CDD; cd02601; HAD_Eya; 1.
DR   FunFam; 3.40.50.12350:FF:000002; Eyes absent homolog; 1.
DR   Gene3D; 3.40.50.12350; -; 1.
DR   InterPro; IPR028472; EYA.
DR   InterPro; IPR006545; EYA_dom.
DR   InterPro; IPR042577; EYA_dom_metazoan.
DR   InterPro; IPR038102; EYA_dom_sf.
DR   NCBIfam; TIGR01658; EYA-cons_domain; 1.
DR   PANTHER; PTHR10190; EYES ABSENT; 1.
DR   PANTHER; PTHR10190:SF5; EYES ABSENT HOMOLOG 3; 1.
DR   Pfam; PF00702; Hydrolase; 1.
DR   SFLD; SFLDG01129; C1.5:_HAD__Beta-PGM__Phosphata; 1.
DR   SFLD; SFLDS00003; Haloacid_Dehalogenase; 1.
PE   1: Evidence at protein level;
KW   Activator; Alternative splicing; Chromatin regulator; Cytoplasm;
KW   Developmental protein; DNA damage; DNA repair; Hydrolase; Magnesium;
KW   Metal-binding; Nucleus; Phosphoprotein; Protein phosphatase;
KW   Reference proteome; Transcription; Transcription regulation.
FT   CHAIN           1..510
FT                   /note="Protein phosphatase EYA3"
FT                   /id="PRO_0000218649"
FT   REGION          1..32
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          175..233
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        7..16
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        192..203
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        246
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000250|UniProtKB:O00167"
FT   ACT_SITE        248
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:O00167"
FT   BINDING         246
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:O00167"
FT   BINDING         248
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:O00167"
FT   BINDING         474
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:O00167"
FT   MOD_RES         199
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q99504"
FT   MOD_RES         203
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q99504"
FT   MOD_RES         375
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q99504"
FT   MOD_RES         409
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q99504"
FT   VAR_SEQ         1..105
FT                   /note="MQEPREQTLSQVNNPDASDEKPETSSLASNLSMSEEIMTCTDYIPRSSNDYT
FT                   SQMYSAKPYAHILSVPVSETTYPGQTQYQTLQQSQPYAVYPQATQTYGLPPFA -> MI
FT                   IPHKCILQT (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:9006082"
FT                   /id="VSP_001494"
FT   MUTAGEN         246
FT                   /note="D->A: Abolishes phosphatase activity and abolishes
FT                   coactivation of the SIX1-DACH1 complex."
FT                   /evidence="ECO:0000269|PubMed:14628042,
FT                   ECO:0000269|PubMed:14628052, ECO:0000269|PubMed:14628053"
FT   MUTAGEN         246
FT                   /note="D->N: Abolishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628042,
FT                   ECO:0000269|PubMed:14628052, ECO:0000269|PubMed:14628053"
FT   MUTAGEN         248
FT                   /note="D->N: Abolishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628052"
FT   MUTAGEN         250
FT                   /note="T->A: Abolishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628052"
FT   MUTAGEN         419
FT                   /note="T->A: Diminishes phosphatase activity by 24-fold."
FT                   /evidence="ECO:0000269|PubMed:14628052"
FT   MUTAGEN         420
FT                   /note="T->A: Diminishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628053"
FT   MUTAGEN         449
FT                   /note="K->Q: Abolishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628053"
FT   MUTAGEN         473
FT                   /note="G->A: Abolishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628052"
FT   MUTAGEN         474
FT                   /note="D->N: Diminishes phosphatase activity by 70%."
FT                   /evidence="ECO:0000269|PubMed:14628052,
FT                   ECO:0000269|PubMed:14628053"
FT   MUTAGEN         478
FT                   /note="E->Q: Abolishes phosphatase activity."
FT                   /evidence="ECO:0000269|PubMed:14628052,
FT                   ECO:0000269|PubMed:14628053"
FT   CONFLICT        200
FT                   /note="P -> L (in Ref. 2; AAB48019)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        272
FT                   /note="V -> A (in Ref. 1; AAB42068)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   510 AA;  55973 MW;  E82CC71DD1FD05F5 CRC64;
     MQEPREQTLS QVNNPDASDE KPETSSLASN LSMSEEIMTC TDYIPRSSND YTSQMYSAKP
     YAHILSVPVS ETTYPGQTQY QTLQQSQPYA VYPQATQTYG LPPFASSTNA SLIPTSSAIA
     NIPAAAVASI SNQDYPTYTI LGQNQYQACY PSSSFGVTGQ TNSDAETTTL AATTYQTEKP
     SAMVPAPATQ RLPSDSSASP PLSQTTPNKD ADDQARKNMT VKNRGKRKAD ASSSQDSELE
     RVFLWDLDET IIIFHSLLTG SYAQKYGKDP TVVIGSGLTM EEMIFEVADT HLFFNDLEEC
     DQVHVEDVAS DDNGQDLSNY SFSTDGFSGS GGSGSHGSSV GVQGGVDWMR KLAFRYRKVR
     EIYDKHKSNV GGLLSPQRKE ALQRLRAEIE VLTDSWLGTA LKSLLLIQSR KNCANVLITT
     TQLVPALAKV LLYGLGEIFP IENIYSATKI GKESCFERIV SRFGKKVTYV VIGDGRDEEI
     AAKQHNMPFW RITNHGDLVS LHQALELDFL
//