SIX2_HUMAN
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 03-AUG-2022, entry version 163.
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_016932.4.
DR AlphaFoldDB; Q9NPC8; -.
DR SMR; Q9NPC8; -.
DR BioGRID; 115959; 31.
DR CORUM; Q9NPC8; -.
DR IntAct; Q9NPC8; 25.
DR MINT; Q9NPC8; -.
DR STRING; 9606.ENSP00000304502; -.
DR iPTMnet; Q9NPC8; -.
DR PhosphoSitePlus; Q9NPC8; -.
DR BioMuta; SIX2; -.
DR DMDM; 12230598; -.
DR EPD; Q9NPC8; -.
DR jPOST; Q9NPC8; -.
DR MassIVE; Q9NPC8; -.
DR MaxQB; Q9NPC8; -.
DR PaxDb; Q9NPC8; -.
DR PeptideAtlas; Q9NPC8; -.
DR PRIDE; Q9NPC8; -.
DR ProteomicsDB; 81972; -.
DR Antibodypedia; 29934; 184 antibodies from 31 providers.
DR DNASU; 10736; -.
DR Ensembl; ENST00000303077.7; ENSP00000304502.6; ENSG00000170577.8.
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 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 neXtProt; NX_Q9NPC8; -.
DR OpenTargets; ENSG00000170577; -.
DR Orphanet; 488437; SIX2-related frontonasal dysplasia.
DR PharmGKB; PA35788; -.
DR VEuPathDB; HostDB:ENSG00000170577; -.
DR eggNOG; KOG0775; Eukaryota.
DR GeneTree; ENSGT00940000158292; -.
DR HOGENOM; CLU_046914_2_0_1; -.
DR InParanoid; Q9NPC8; -.
DR OMA; SVHHDTI; -.
DR OrthoDB; 1061244at2759; -.
DR PhylomeDB; Q9NPC8; -.
DR TreeFam; TF315545; -.
DR PathwayCommons; Q9NPC8; -.
DR SignaLink; Q9NPC8; -.
DR BioGRID-ORCS; 10736; 17 hits in 1096 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 111 other tissues.
DR Genevisible; Q9NPC8; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
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:0002062; P:chondrocyte differentiation; IEA:Ensembl.
DR GO; GO:0072137; P:condensed mesenchymal cell proliferation; IEA:Ensembl.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Ensembl.
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:0042474; P:middle ear morphogenesis; IEA:Ensembl.
DR GO; GO:0030857; P:negative regulation of epithelial cell differentiation; IEA:Ensembl.
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:0006606; P:protein import into nucleus; IEA:Ensembl.
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 InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR031701; SIX1_SD.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF16878; SIX1_SD; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 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; 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 173..192
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 193..230
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 231..257
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
