ID   SIX2_HUMAN              Reviewed;         291 AA.
AC   Q9NPC8; Q9BXH7;
DT   11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2000, sequence version 1.
DT   02-SEP-2026, entry version 182.
DE   RecName: Full=Homeobox protein SIX2;
DE   AltName: Full=Sine oculis homeobox homolog 2;
GN   Name=SIX2;
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 [GENOMIC DNA].
RX   PubMed=10677303; DOI=10.1086/302779;
RA   Celli J., Van Beusekom E., Hennekam R.C.M., Gallardo M.E., Smeets D.F.C.M.,
RA   Rodriguez de Cordoba S., Innis J.W., Frydman M., Konig R., Kingston H.,
RA   Tolmie J., Lutgarde L.C.P., van Bokhoven H., Brunner H.G.;
RT   "Familial syndromic esophageal atresia maps to 2p23-p24.";
RL   Am. J. Hum. Genet. 66:436-444(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX   PubMed=10773454; DOI=10.1016/s0378-1119(00)00105-0;
RA   Boucher C.A., Winchester C.L., Hamilton G.M., Winter A.D., Johnson K.J.,
RA   Bailey M.E.S.;
RT   "Structure, mapping and expression of the human gene encoding the
RT   homeodomain protein, SIX2.";
RL   Gene 247:145-151(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC   TISSUE=Salivary gland;
RA   Hedrich K., Hehr A.J., Hansmann I., Hehr U.;
RT   "Molecular characterization of the human SIX2 gene: alternative
RT   polyadenylation and localization within the HPE2 critical region 2p21.";
RL   Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA   Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA   Phelan M., Farmer A.;
RT   "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL   Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   DEVELOPMENTAL STAGE.
RX   PubMed=20515681; DOI=10.1016/j.ydbio.2010.05.509;
RA   He G., Tavella S., Hanley K.P., Self M., Oliver G., Grifone R., Hanley N.,
RA   Ward C., Bobola N.;
RT   "Inactivation of Six2 in mouse identifies a novel genetic mechanism
RT   controlling development and growth of the cranial base.";
RL   Dev. Biol. 344:720-730(2010).
RN   [6]
RP   TISSUE SPECIFICITY.
RX   PubMed=22703800; DOI=10.1016/j.jpedsurg.2012.03.034;
RA   Murphy A.J., Pierce J., de Caestecker C., Taylor C., Anderson J.R.,
RA   Perantoni A.O., de Caestecker M.P., Lovvorn H.N. III;
RT   "SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain
RT   active in primitive elements of Wilms' tumor.";
RL   J. Pediatr. Surg. 47:1239-1249(2012).
RN   [7]
RP   FUNCTION IN CELL MIGRATION AND CELL PROLIFERATION.
RX   PubMed=22995329; DOI=10.1016/j.humpath.2012.05.021;
RA   Senanayake U., Koller K., Pichler M., Leuschner I., Strohmaier H.,
RA   Hadler U., Das S., Hoefler G., Guertl B.;
RT   "The pluripotent renal stem cell regulator SIX2 is activated in renal
RT   neoplasms and influences cellular proliferation and migration.";
RL   Hum. Pathol. 44:336-345(2013).
RN   [8]
RP   VARIANTS PHE-43; LEU-241 AND ASN-276.
RX   PubMed=18305125; DOI=10.1681/asn.2006111282;
RA   Weber S., Taylor J.C., Winyard P., Baker K.F., Sullivan-Brown J.,
RA   Schild R., Knueppel T., Zurowska A.M., Caldas-Alfonso A., Litwin M.,
RA   Emre S., Ghiggeri G.M., Bakkaloglu A., Mehls O., Antignac C., Schaefer F.,
RA   Burdine R.D.;
RT   "SIX2 and BMP4 mutations associate with anomalous kidney development.";
RL   J. Am. Soc. Nephrol. 19:891-903(2008).
CC   -!- FUNCTION: Transcription factor that plays an important role in the
CC       development of several organs, including kidney, skull and stomach.
CC       During kidney development, maintains cap mesenchyme multipotent nephron
CC       progenitor cells in an undifferentiated state by opposing the inductive
CC       signals emanating from the ureteric bud and cooperates with WNT9B to
CC       promote renewing progenitor cells proliferation. Acts through its
CC       interaction with TCF7L2 and OSR1 in a canonical Wnt signaling
CC       independent manner preventing transcription of differentiation genes in
CC       cap mesenchyme such as WNT4. Also acts independently of OSR1 to
CC       activate expression of many cap mesenchyme genes, including itself,
CC       GDNF and OSR1. During craniofacial development plays a role in growth
CC       and elongation of the cranial base through regulation of chondrocyte
CC       differentiation. During stomach organogenesis, controls pyloric
CC       sphincter formation and mucosal growth through regulation of a gene
CC       network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1. During
CC       branchial arch development, acts to mediate HOXA2 control over the
CC       insulin-like growth factor pathway. May also be involved in limb tendon
CC       and ligament development (By similarity). Plays a role in cell
CC       proliferation and migration. {ECO:0000250|UniProtKB:Q62232,
CC       ECO:0000269|PubMed:22995329}.
CC   -!- SUBUNIT: Interacts with TCF7L2; in a canonical Wnt signaling
CC       independent manner; prevents transcription of differentiation genes in
CC       cap mesenchyme. Interacts with OSR1; form a strong repressor complex
CC       with TCF7L2, TLE2 and TLE3 to prevent the activation of Wnt/beta-
CC       catenin target genes in the cap mesenchyme. Interacts with HOXA11, EYA1
CC       and EYA3. {ECO:0000250|UniProtKB:Q62232}.
CC   -!- INTERACTION:
CC       Q9NPC8; Q8N3C7: CLIP4; NbExp=3; IntAct=EBI-12695166, EBI-5655540;
CC       Q9NPC8; Q04206-1: RELA; NbExp=2; IntAct=EBI-12695166, EBI-10826776;
CC       Q9NPC8; Q04726-4: TLE3; NbExp=3; IntAct=EBI-12695166, EBI-12014388;
CC       Q9NPC8; Q08117-2: TLE5; NbExp=3; IntAct=EBI-12695166, EBI-11741437;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q62232}.
CC   -!- TISSUE SPECIFICITY: Strongly expressed in skeletal muscle. Expressed in
CC       Wilms' tumor and in the cap mesenchyme of fetal kidney (at protein
CC       level). {ECO:0000269|PubMed:22703800}.
CC   -!- DEVELOPMENTAL STAGE: Found at 48 dpc in the anterior cranial base with
CC       detection concentrated in the sphenoid precursor. Expression is also
CC       detected in the pituitary gland. {ECO:0000269|PubMed:20515681}.
CC   -!- SIMILARITY: Belongs to the SIX/Sine oculis homeobox family.
CC       {ECO:0000305}.
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DR   EMBL; AF136939; AAF69031.1; -; Genomic_DNA.
DR   EMBL; AF136940; AAF69032.1; -; mRNA.
DR   EMBL; AF332196; AAK16581.1; -; mRNA.
DR   EMBL; AF332197; AAK16582.1; -; mRNA.
DR   EMBL; AF332198; AAK16583.1; -; Genomic_DNA.
DR   EMBL; AF323498; AAK06773.1; -; Genomic_DNA.
DR   EMBL; BT020100; AAV38903.1; -; mRNA.
DR   CCDS; CCDS1822.1; -.
DR   RefSeq; NP_058628.3; NM_016932.5.
DR   AlphaFoldDB; Q9NPC8; -.
DR   SMR; Q9NPC8; -.
DR   BioGRID; 115959; 32.
DR   CORUM; Q9NPC8; -.
DR   FunCoup; Q9NPC8; 667.
DR   IntAct; Q9NPC8; 27.
DR   MINT; Q9NPC8; -.
DR   NDEx; IQUERY-CP-SIX2; 4 NDEx IQuery Curated Pathways.
DR   STRING; 9606.ENSP00000304502; -.
DR   GlyGen; Q9NPC8; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q9NPC8; -.
DR   PhosphoSitePlus; Q9NPC8; -.
DR   BioMuta; SIX2; -.
DR   DMDM; 12230598; -.
DR   jPOST; Q9NPC8; -.
DR   MassIVE; Q9NPC8; -.
DR   PaxDb; 9606-ENSP00000304502; -.
DR   PeptideAtlas; Q9NPC8; -.
DR   ProteomicsDB; 81972; -.
DR   Pumba; Q9NPC8; -.
DR   Antibodypedia; 29934; 196 antibodies from 33 providers.
DR   DNASU; 10736; -.
DR   Ensembl; ENST00000303077.7; ENSP00000304502.6; ENSG00000170577.9.
DR   GeneID; 10736; -.
DR   KEGG; hsa:10736; -.
DR   MANE-Select; ENST00000303077.7; ENSP00000304502.6; NM_016932.5; NP_058628.3.
DR   UCSC; uc002ruo.4; human.
DR   AGR; HGNC:10888; -.
DR   ClinPGx; PA35788; -.
DR   CTD; 10736; -.
DR   DisGeNET; 10736; -.
DR   GeneCards; SIX2; -.
DR   HGNC; HGNC:10888; SIX2.
DR   HPA; ENSG00000170577; Tissue enhanced (salivary gland, skeletal muscle).
DR   MalaCards; SIX2; -.
DR   MIM; 604994; gene.
DR   OpenTargets; ENSG00000170577; -.
DR   Orphanet; 488437; SIX2-related frontonasal dysplasia.
DR   VEuPathDB; HostDB:ENSG00000170577; -.
DR   eggNOG; KOG0775; Eukaryota.
DR   GeneTree; ENSGT00940000158292; -.
DR   HOGENOM; CLU_046914_2_0_1; -.
DR   InParanoid; Q9NPC8; -.
DR   OMA; IHHHALQ; -.
DR   OrthoDB; 3501850at2759; -.
DR   PAN-GO; Q9NPC8; 6 GO annotations based on evolutionary models.
DR   PhylomeDB; Q9NPC8; -.
DR   PathwayCommons; Q9NPC8; -.
DR   Reactome; R-HSA-9830674; Formation of the ureteric bud.
DR   SignaLink; Q9NPC8; -.
DR   Agora; ENSG00000170577; -.
DR   BioGRID-ORCS; 10736; 19 hits in 1174 CRISPR screens.
DR   ChiTaRS; SIX2; human.
DR   GeneWiki; SIX2; -.
DR   GenomeRNAi; 10736; -.
DR   Pharos; Q9NPC8; Tbio.
DR   PRO; PR:Q9NPC8; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q9NPC8; protein.
DR   Bgee; ENSG00000170577; Expressed in olfactory segment of nasal mucosa and 112 other cell types or tissues.
DR   GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR   GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; NAS:ProtInc.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR   GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
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; TAS:ProtInc.
DR   GO; GO:0009948; P:anterior/posterior axis specification; ISS:UniProtKB.
DR   GO; GO:0016477; P:cell migration; IDA:UniProtKB.
DR   GO; GO:0008283; P:cell population proliferation; IDA:UniProtKB.
DR   GO; GO:0048557; P:embryonic digestive tract morphogenesis; ISS:UniProtKB.
DR   GO; GO:0001822; P:kidney development; IMP:UniProtKB.
DR   GO; GO:0072161; P:mesenchymal cell differentiation involved in kidney development; ISS:UniProtKB.
DR   GO; GO:0072038; P:mesenchymal stem cell maintenance involved in nephron morphogenesis; ISS:UniProtKB.
DR   GO; GO:0097168; P:mesenchymal stem cell proliferation; ISS:UniProtKB.
DR   GO; GO:0003337; P:mesenchymal to epithelial transition involved in metanephros morphogenesis; ISS:UniProtKB.
DR   GO; GO:0007501; P:mesodermal cell fate specification; ISS:UniProtKB.
DR   GO; GO:0072006; P:nephron development; ISS:UniProtKB.
DR   GO; GO:0072028; P:nephron morphogenesis; ISS:UniProtKB.
DR   GO; GO:1902732; P:positive regulation of chondrocyte proliferation; ISS:UniProtKB.
DR   GO; GO:0090189; P:regulation of branching involved in ureteric bud morphogenesis; ISS:UniProtKB.
DR   GO; GO:0032330; P:regulation of chondrocyte differentiation; IEA:Ensembl.
DR   GO; GO:0030278; P:regulation of ossification; IEA:Ensembl.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   CDD; cd00086; homeodomain; 1.
DR   FunFam; 1.10.10.60:FF:000063; SIX homeobox 2; 1.
DR   Gene3D; 1.10.10.60; Homeodomain-like; 1.
DR   InterPro; IPR001356; HD.
DR   InterPro; IPR017970; Homeobox_CS.
DR   InterPro; IPR009057; Homeodomain-like_sf.
DR   InterPro; IPR031701; SIX1_SD.
DR   PANTHER; PTHR10390; HOMEOBOX PROTEIN SIX; 1.
DR   PANTHER; PTHR10390:SF61; HOMEOBOX PROTEIN SIX2; 1.
DR   Pfam; PF00046; Homeodomain; 1.
DR   Pfam; PF16878; SIX1_SD; 1.
DR   SMART; SM00389; HOX; 1.
DR   SUPFAM; SSF46689; Homeodomain-like; 1.
DR   PROSITE; PS00027; HOMEOBOX_1; 1.
DR   PROSITE; PS50071; HOMEOBOX_2; 1.
PE   1: Evidence at protein level;
KW   Developmental protein; DNA-binding; Homeobox; Nucleus;
KW   Proteomics identification; Reference proteome.
FT   CHAIN           1..291
FT                   /note="Homeobox protein SIX2"
FT                   /id="PRO_0000049297"
FT   DNA_BIND        124..183
FT                   /note="Homeobox"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT   REGION          168..279
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        179..190
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        224..233
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        249..259
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VARIANT         43
FT                   /note="L -> F (in a renal hypodysplasia patient;
FT                   dbSNP:rs142188105)"
FT                   /evidence="ECO:0000269|PubMed:18305125"
FT                   /id="VAR_071207"
FT   VARIANT         241
FT                   /note="P -> L (in a renal hypodysplasia patient;
FT                   dbSNP:rs147806994)"
FT                   /evidence="ECO:0000269|PubMed:18305125"
FT                   /id="VAR_071208"
FT   VARIANT         276
FT                   /note="D -> N (in a renal hypodysplasia patient;
FT                   dbSNP:rs201675842)"
FT                   /evidence="ECO:0000269|PubMed:18305125"
FT                   /id="VAR_071209"
SQ   SEQUENCE   291 AA;  32286 MW;  8388C3C331575BDD CRC64;
     MSMLPTFGFT QEQVACVCEV LQQGGNIERL GRFLWSLPAC EHLHKNESVL KAKAVVAFHR
     GNFRELYKIL ESHQFSPHNH AKLQQLWLKA HYIEAEKLRG RPLGAVGKYR VRRKFPLPRS
     IWDGEETSYC FKEKSRSVLR EWYAHNPYPS PREKRELAEA TGLTTTQVSN WFKNRRQRDR
     AAEAKERENN ENSNSNSHNP LNGSGKSVLG SSEDEKTPSG TPDHSSSSPA LLLSPPPPGL
     PSLHSLGHPP GPSAVPVPVP GGGGADPLQH HHGLQDSILN PMSANLVDLG S
//