ID   PITX3_HUMAN             Reviewed;         302 AA.
AC   O75364; Q5VZL2;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1998, sequence version 1.
DT   02-OCT-2024, entry version 199.
DE   RecName: Full=Pituitary homeobox 3;
DE   AltName: Full=Homeobox protein PITX3;
DE   AltName: Full=Paired-like homeodomain transcription factor 3;
GN   Name=PITX3; Synonyms=PTX3;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], VARIANT CTRCT11 ASN-13, AND INVOLVEMENT IN
RP   ASGD1.
RC   TISSUE=Craniofacial;
RX   PubMed=9620774; DOI=10.1038/527;
RA   Semina E.V., Ferrell R.E., Mintz-Hittner H.A., Bitoun P., Alward W.L.M.,
RA   Reiter R.S., Funkhauser C., Daack-Hirsch S., Murray J.C.;
RT   "A novel homeobox gene PITX3 is mutated in families with autosomal-dominant
RT   cataracts and ASMD.";
RL   Nat. Genet. 19:167-170(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15164054; DOI=10.1038/nature02462;
RA   Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA   Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA   Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA   Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA   Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA   Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA   Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA   Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA   Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA   Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA   Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA   Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA   McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA   Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA   Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA   Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA   Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA   Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA   Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA   Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA   Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 10.";
RL   Nature 429:375-381(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Muscle;
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   [4]
RP   INVOLVEMENT IN CTRCT11.
RX   PubMed=15286169; DOI=10.1136/jmg.2004.020289;
RA   Berry V., Yang Z., Addison P.K., Francis P.J., Ionides A., Karan G.,
RA   Jiang L., Lin W., Hu J., Yang R., Moore A., Zhang K., Bhattacharya S.S.;
RT   "Recurrent 17 bp duplication in PITX3 is primarily associated with
RT   posterior polar cataract (CPP4).";
RL   J. Med. Genet. 41:E109-E109(2004).
RN   [5]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
CC   -!- FUNCTION: Transcriptional regulator which is important for the
CC       differentiation and maintenance of meso-diencephalic dopaminergic
CC       (mdDA) neurons during development. In addition to its importance during
CC       development, it also has roles in the long-term survival and
CC       maintenance of the mdDA neurons. Activates NR4A2/NURR1-mediated
CC       transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are
CC       essential for development of mdDA neurons. Acts by decreasing the
CC       interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts
CC       through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1
CC       target genes in a repressed deacetylated state. Essential for the
CC       normal lens development and differentiation. Plays a critical role in
CC       the maintenance of mitotic activity of lens epithelial cells, fiber
CC       cell differentiation and in the control of the temporal and spatial
CC       activation of fiber cell-specific crystallins. Positively regulates
CC       FOXE3 expression and negatively regulates PROX1 in the anterior lens
CC       epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2
CC       and thus maintains lens epithelial cells in cell cycle (By similarity).
CC       {ECO:0000250}.
CC   -!- SUBUNIT: Interacts with SFPQ. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108,
CC       ECO:0000255|PROSITE-ProRule:PRU00138}.
CC   -!- TISSUE SPECIFICITY: Highly expressed in developing eye lens.
CC   -!- DISEASE: Anterior segment dysgenesis 1 (ASGD1) [MIM:107250]: A form of
CC       anterior segment dysgenesis, a group of defects affecting anterior
CC       structures of the eye including cornea, iris, lens, trabecular
CC       meshwork, and Schlemm canal. Anterior segment dysgeneses result from
CC       abnormal migration or differentiation of the neural crest derived
CC       mesenchymal cells that give rise to components of the anterior chamber
CC       during eye development. Different anterior segment anomalies may exist
CC       alone or in combination, including iris hypoplasia, enlarged or reduced
CC       corneal diameter, corneal vascularization and opacity, posterior
CC       embryotoxon, corectopia, polycoria, abnormal iridocorneal angle,
CC       ectopia lentis, and anterior synechiae between the iris and posterior
CC       corneal surface. Clinical conditions falling within the phenotypic
CC       spectrum of anterior segment dysgeneses include aniridia, Axenfeld
CC       anomaly, Reiger anomaly/syndrome, Peters anomaly, and
CC       iridogoniodysgenesis. {ECO:0000269|PubMed:9620774}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry.
CC   -!- DISEASE: Cataract 11, multiple types (CTRCT11) [MIM:610623]: An
CC       opacification of the crystalline lens of the eye that frequently
CC       results in visual impairment or blindness. Opacities vary in
CC       morphology, are often confined to a portion of the lens, and may be
CC       static or progressive. CTRCT11 includes posterior polar cataract, among
CC       others. Posterior polar cataract is a subcapsular opacity, usually
CC       disk-shaped, located at the back of the lens. Some CTRCT11 patients can
CC       present a severe phenotype including microphthalmia and neurological
CC       dysfunction. {ECO:0000269|PubMed:15286169, ECO:0000269|PubMed:9620774}.
CC       Note=The disease is caused by variants affecting the gene represented
CC       in this entry.
CC   -!- SIMILARITY: Belongs to the paired homeobox family. Bicoid subfamily.
CC       {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AF041339; AAC24502.1; -; mRNA.
DR   EMBL; AL160011; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC011642; AAH11642.1; -; mRNA.
DR   CCDS; CCDS7532.1; -.
DR   RefSeq; NP_005020.1; NM_005029.3.
DR   AlphaFoldDB; O75364; -.
DR   BMRB; O75364; -.
DR   SMR; O75364; -.
DR   BioGRID; 111326; 6.
DR   STRING; 9606.ENSP00000359019; -.
DR   iPTMnet; O75364; -.
DR   PhosphoSitePlus; O75364; -.
DR   BioMuta; PITX3; -.
DR   jPOST; O75364; -.
DR   MassIVE; O75364; -.
DR   PaxDb; 9606-ENSP00000359019; -.
DR   PeptideAtlas; O75364; -.
DR   ProteomicsDB; 49928; -.
DR   Antibodypedia; 18010; 265 antibodies from 35 providers.
DR   DNASU; 5309; -.
DR   Ensembl; ENST00000370002.8; ENSP00000359019.3; ENSG00000107859.11.
DR   GeneID; 5309; -.
DR   KEGG; hsa:5309; -.
DR   MANE-Select; ENST00000370002.8; ENSP00000359019.3; NM_005029.4; NP_005020.1.
DR   UCSC; uc001kuu.2; human.
DR   AGR; HGNC:9006; -.
DR   CTD; 5309; -.
DR   DisGeNET; 5309; -.
DR   GeneCards; PITX3; -.
DR   HGNC; HGNC:9006; PITX3.
DR   HPA; ENSG00000107859; Tissue enhanced (brain, skeletal muscle, tongue).
DR   MalaCards; PITX3; -.
DR   MIM; 107250; phenotype.
DR   MIM; 602669; gene.
DR   MIM; 610623; phenotype.
DR   neXtProt; NX_O75364; -.
DR   OpenTargets; ENSG00000107859; -.
DR   Orphanet; 162; Congenital cataract-anterior segment dysgenesis syndrome.
DR   Orphanet; 98993; Early-onset posterior polar cataract.
DR   PharmGKB; PA33340; -.
DR   VEuPathDB; HostDB:ENSG00000107859; -.
DR   eggNOG; KOG0486; Eukaryota.
DR   GeneTree; ENSGT00940000161801; -.
DR   HOGENOM; CLU_030301_0_0_1; -.
DR   InParanoid; O75364; -.
DR   OMA; NHTLSAC; -.
DR   OrthoDB; 5395268at2759; -.
DR   PhylomeDB; O75364; -.
DR   TreeFam; TF351940; -.
DR   PathwayCommons; O75364; -.
DR   SignaLink; O75364; -.
DR   SIGNOR; O75364; -.
DR   BioGRID-ORCS; 5309; 13 hits in 1170 CRISPR screens.
DR   GeneWiki; PITX3; -.
DR   GenomeRNAi; 5309; -.
DR   Pharos; O75364; Tbio.
DR   PRO; PR:O75364; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; O75364; protein.
DR   Bgee; ENSG00000107859; Expressed in hindlimb stylopod muscle and 63 other cell types or tissues.
DR   GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR   GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR   GO; GO:0009887; P:animal organ morphogenesis; TAS:ProtInc.
DR   GO; GO:1990792; P:cellular response to glial cell derived neurotrophic factor; IEA:Ensembl.
DR   GO; GO:0071542; P:dopaminergic neuron differentiation; ISS:UniProtKB.
DR   GO; GO:0002088; P:lens development in camera-type eye; ISS:UniProtKB.
DR   GO; GO:0002089; P:lens morphogenesis in camera-type eye; ISS:UniProtKB.
DR   GO; GO:0030901; P:midbrain development; ISS:UniProtKB.
DR   GO; GO:0014014; P:negative regulation of gliogenesis; IEA:Ensembl.
DR   GO; GO:1904935; P:positive regulation of cell proliferation in midbrain; IEA:Ensembl.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; ISS:UniProtKB.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0042220; P:response to cocaine; IEA:Ensembl.
DR   GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR   GO; GO:1904313; P:response to methamphetamine hydrochloride; IEA:Ensembl.
DR   CDD; cd00086; homeodomain; 1.
DR   Gene3D; 1.10.10.60; Homeodomain-like; 1.
DR   InterPro; IPR001356; HD.
DR   InterPro; IPR017970; Homeobox_CS.
DR   InterPro; IPR016233; Homeobox_Pitx/unc30.
DR   InterPro; IPR009057; Homeodomain-like_sf.
DR   InterPro; IPR003654; OAR_dom.
DR   PANTHER; PTHR45882:SF2; PITUITARY HOMEOBOX 3; 1.
DR   PANTHER; PTHR45882; PITUITARY HOMEOBOX HOMOLOG PTX1; 1.
DR   Pfam; PF00046; Homeodomain; 1.
DR   Pfam; PF03826; OAR; 1.
DR   PIRSF; PIRSF000563; Homeobox_protein_Pitx/Unc30; 1.
DR   SMART; SM00389; HOX; 1.
DR   SUPFAM; SSF46689; Homeodomain-like; 1.
DR   PROSITE; PS00027; HOMEOBOX_1; 1.
DR   PROSITE; PS50071; HOMEOBOX_2; 1.
DR   PROSITE; PS50803; OAR; 1.
PE   1: Evidence at protein level;
KW   Activator; Cataract; Developmental protein; Disease variant; DNA-binding;
KW   Homeobox; Nucleus; Phosphoprotein; Proteomics identification;
KW   Reference proteome; Transcription; Transcription regulation.
FT   CHAIN           1..302
FT                   /note="Pituitary homeobox 3"
FT                   /id="PRO_0000049229"
FT   DNA_BIND        62..121
FT                   /note="Homeobox"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT   REGION          1..71
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           262..275
FT                   /note="OAR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00138"
FT   MOTIF           268..272
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         52
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P81062"
FT   MOD_RES         57
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P81062"
FT   VARIANT         13
FT                   /note="S -> N (in CTRCT11; dbSNP:rs104894175)"
FT                   /evidence="ECO:0000269|PubMed:9620774"
FT                   /id="VAR_003767"
SQ   SEQUENCE   302 AA;  31832 MW;  1E5259206ABC2E87 CRC64;
     MEFGLLSEAE ARSPALSLSD AGTPHPQLPE HGCKGQEHSD SEKASASLPG GSPEDGSLKK
     KQRRQRTHFT SQQLQELEAT FQRNRYPDMS TREEIAVWTN LTEARVRVWF KNRRAKWRKR
     ERSQQAELCK GSFAAPLGGL VPPYEEVYPG YSYGNWPPKA LAPPLAAKTF PFAFNSVNVG
     PLASQPVFSP PSSIAASMVP SAAAAPGTVP GPGALQGLGG GPPGLAPAAV SSGAVSCPYA
     SAAAAAAAAA SSPYVYRDPC NSSLASLRLK AKQHASFSYP AVHGPPPAAN LSPCQYAVER
     PV
//