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Protein

Homeobox protein SIX3

Gene

SIX3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 AND CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is AES and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 functions also in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway (By similarity). Plays a role in eye development by suppressing WNT1 expression and in dorsal-ventral patterning by repressing BMP signaling pathway.By similarity1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi206 – 265HomeoboxPROSITE-ProRule annotationAdd BLAST60

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Repressor

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

BioCyciZFISH:ENSG00000138083-MONOMER.
SIGNORiO95343.

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX3
Alternative name(s):
Sine oculis homeobox homolog 3
Gene namesi
Name:SIX3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:10889. SIX3.

Subcellular locationi

  • Nucleus PROSITE-ProRule annotationBy similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Holoprosencephaly 2 (HPE2)6 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability.
See also OMIM:157170
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07133537G → C in SCHZC AND HPE2. 2 PublicationsCorresponds to variant rs199823175dbSNPEnsembl.1
Natural variantiVAR_03841869G → D in HPE2. 1 PublicationCorresponds to variant rs121917881dbSNPEnsembl.1
Natural variantiVAR_07133679M → V in HPE2. 1 Publication1
Natural variantiVAR_02379792V → G in HPE2. 1 Publication1
Natural variantiVAR_07133793A → D in HPE2. 1 Publication1
Natural variantiVAR_023798105I → V in HPE2. 1 Publication1
Natural variantiVAR_071338113W → C in HPE2. 1 PublicationCorresponds to variant rs137853021dbSNPEnsembl.1
Natural variantiVAR_071339114S → L in HPE2. 1 Publication1
Natural variantiVAR_071340138V → D in HPE2. 1 Publication1
Natural variantiVAR_071341155Missing in HPE2. 1 Publication1
Natural variantiVAR_071342157F → I in HPE2. 1 Publication1
Natural variantiVAR_071344172A → V in HPE2. 1 Publication1
Natural variantiVAR_023799173H → P in HPE2. 1 Publication1
Natural variantiVAR_071345174Y → H in HPE2. 1 Publication1
Natural variantiVAR_023800202T → I in HPE2. 1 Publication1
Natural variantiVAR_071346213F → V in HPE2. 1 Publication1
Natural variantiVAR_071347218R → P in HPE2. 1 Publication1
Natural variantiVAR_071348218R → W in HPE2. 1 Publication1
Natural variantiVAR_003771226L → V in HPE2. 1 PublicationCorresponds to variant rs121917878dbSNPEnsembl.1
Natural variantiVAR_071349227Q → P in HPE2. 1 Publication1
Natural variantiVAR_023801231P → R in HPE2. 1 Publication1
Natural variantiVAR_071350244G → C in HPE2. 1 Publication1
Natural variantiVAR_003772250V → A in HPE2; Significantly decreased its ability to activate NR4A3. 2 PublicationsCorresponds to variant rs121917880dbSNPEnsembl.1
Natural variantiVAR_071351254F → L in HPE2. 1 Publication1
Natural variantiVAR_071352257R → G in HPE2. 1 Publication1
Natural variantiVAR_003773257R → P in HPE2; Significantly decreased interaction with NR4A3; Significantly decreased its ability to activate NR4A3. 2 PublicationsCorresponds to variant rs121917879dbSNPEnsembl.1
Natural variantiVAR_023802257R → W in HPE2. 1 Publication1
Natural variantiVAR_071353258R → L in HPE2. 1 Publication1
Natural variantiVAR_071354262R → H in HPE2. 1 Publication1
Natural variantiVAR_071355269R → M in HPE2. 1 Publication1
Natural variantiVAR_071356269R → S in HPE2. 1 Publication1
Natural variantiVAR_071357269R → T in HPE2. 1 Publication1
Natural variantiVAR_071358297P → L in HPE2. 1 PublicationCorresponds to variant rs780942050dbSNPEnsembl.1
Schizencephaly (SCHZC)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionExtremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. Large portions of the cerebral hemispheres may be absent and replaced by cerebro-spinal fluid.
See also OMIM:269160
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07133537G → C in SCHZC AND HPE2. 2 PublicationsCorresponds to variant rs199823175dbSNPEnsembl.1
Natural variantiVAR_071343167A → S in SCHZC. 1 PublicationCorresponds to variant rs387906868dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi87F → E: Decreased interaction with AES and loss ineteraction with TLE1. 1 Publication1
Mutagenesisi95V → P: Loss of interaction with TLE1 and AES; when associated with P-99. 1 Publication1
Mutagenesisi99L → P: Loss of interaction with TLE1 and AES; when associated with P-95. 1 Publication1

Keywords - Diseasei

Disease mutation, Holoprosencephaly

Organism-specific databases

DisGeNETi6496.
MalaCardsiSIX3.
MIMi157170. phenotype.
269160. phenotype.
OpenTargetsiENSG00000138083.
Orphaneti93925. Alobar holoprosencephaly.
93924. Lobar holoprosencephaly.
280200. Microform holoprosencephaly.
93926. Midline interhemispheric variant of holoprosencephaly.
799. Schizencephaly.
220386. Semilobar holoprosencephaly.
280195. Septopreoptic holoprosencephaly.
PharmGKBiPA35789.

Polymorphism and mutation databases

BioMutaiSIX3.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000492991 – 332Homeobox protein SIX3Add BLAST332

Proteomic databases

EPDiO95343.
MaxQBiO95343.
PaxDbiO95343.
PeptideAtlasiO95343.
PRIDEiO95343.

PTM databases

iPTMnetiO95343.
PhosphoSitePlusiO95343.

Expressioni

Developmental stagei

Expression is detected in Rathke's pouch and overlying ventral diencephalon at carnegie stage 17 and in the anterior and posterior lobes of the pituitary at carnegie stage 20. At fetal stage, expression is observed in the anterior pituitary, and the ventricular zones of the hypothalamus and telencephalic vesicles.1 Publication

Gene expression databases

BgeeiENSG00000138083.
CleanExiHS_SIX3.
GenevisibleiO95343. HS.

Interactioni

Subunit structurei

Interacts with EYA4; translocates EYA4 from the cytoplasm to the nucleus and promotes activation of their target genes (By similarity). Interacts with MTA1 and HDAC2; represses its own transcription (By similarity). Interacts with MTA1; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (By similarity). Interacts with EYA1; promotes EYA1 translocation to the nucleus (By similarity). Interacts with TLE1 and AES (via Q domain); can act in combination with either TLE1 and/or AES leading to transcriptional repression or activation, respectively. Interacts (via homeobox) with NR4A3; differentially regulates the transcriptional activities NR4A3. Interacts with GMNN. Interacts with TLE4.By similarity3 Publications

GO - Molecular functioni

  • transcription corepressor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi112387. 5 interactors.
STRINGi9606.ENSP00000260653.

Structurei

3D structure databases

ProteinModelPortaliO95343.
SMRiO95343.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni72 – 119Interaction with AESBy similarityAdd BLAST48
Regioni232 – 234Bind to RHO promoterBy similarity3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi33 – 69Gly-richPROSITE-ProRule annotationAdd BLAST37

Sequence similaritiesi

Belongs to the SIX/Sine oculis homeobox family.Curated
Contains 1 homeobox DNA-binding domain.PROSITE-ProRule annotation

Keywords - Domaini

Homeobox

Phylogenomic databases

eggNOGiKOG0775. Eukaryota.
ENOG410XRPB. LUCA.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261680.
HOVERGENiHBG003609.
InParanoidiO95343.
KOiK19473.
OMAiSSMTERV.
OrthoDBiEOG091G083I.
PhylomeDBiO95343.
TreeFamiTF315545.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
IPR031701. SIX1_SD.
IPR032949. SIX3.
[Graphical view]
PANTHERiPTHR10390:SF31. PTHR10390:SF31. 1 hit.
PfamiPF00046. Homeobox. 1 hit.
PF16878. SIX1_SD. 1 hit.
[Graphical view]
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS50071. HOMEOBOX_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O95343-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVFRSPLDLY SSHFLLPNFA DSHHRSILLA SSGGGNGAGG GGGAGGGSGG
60 70 80 90 100
GNGAGGGGAG GAGGGGGGGS RAPPEELSMF QLPTLNFSPE QVASVCETLE
110 120 130 140 150
ETGDIERLGR FLWSLPVAPG ACEAINKHES ILRARAVVAF HTGNFRDLYH
160 170 180 190 200
ILENHKFTKE SHGKLQAMWL EAHYQEAEKL RGRPLGPVDK YRVRKKFPLP
210 220 230 240 250
RTIWDGEQKT HCFKERTRSL LREWYLQDPY PNPSKKRELA QATGLTPTQV
260 270 280 290 300
GNWFKNRRQR DRAAAAKNRL QHQAIGPSGM RSLAEPGCPT HGSAESPSTA
310 320 330
ASPTTSVSSL TERADTGTSI LSVTSSDSEC DV
Length:332
Mass (Da):35,487
Last modified:May 1, 1999 - v1
Checksum:i21EA07F6A2DD978F
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07133537G → C in SCHZC AND HPE2. 2 PublicationsCorresponds to variant rs199823175dbSNPEnsembl.1
Natural variantiVAR_03841869G → D in HPE2. 1 PublicationCorresponds to variant rs121917881dbSNPEnsembl.1
Natural variantiVAR_07133679M → V in HPE2. 1 Publication1
Natural variantiVAR_02379792V → G in HPE2. 1 Publication1
Natural variantiVAR_07133793A → D in HPE2. 1 Publication1
Natural variantiVAR_023798105I → V in HPE2. 1 Publication1
Natural variantiVAR_071338113W → C in HPE2. 1 PublicationCorresponds to variant rs137853021dbSNPEnsembl.1
Natural variantiVAR_071339114S → L in HPE2. 1 Publication1
Natural variantiVAR_071340138V → D in HPE2. 1 Publication1
Natural variantiVAR_071341155Missing in HPE2. 1 Publication1
Natural variantiVAR_071342157F → I in HPE2. 1 Publication1
Natural variantiVAR_071343167A → S in SCHZC. 1 PublicationCorresponds to variant rs387906868dbSNPEnsembl.1
Natural variantiVAR_071344172A → V in HPE2. 1 Publication1
Natural variantiVAR_023799173H → P in HPE2. 1 Publication1
Natural variantiVAR_071345174Y → H in HPE2. 1 Publication1
Natural variantiVAR_023800202T → I in HPE2. 1 Publication1
Natural variantiVAR_071346213F → V in HPE2. 1 Publication1
Natural variantiVAR_071347218R → P in HPE2. 1 Publication1
Natural variantiVAR_071348218R → W in HPE2. 1 Publication1
Natural variantiVAR_003771226L → V in HPE2. 1 PublicationCorresponds to variant rs121917878dbSNPEnsembl.1
Natural variantiVAR_071349227Q → P in HPE2. 1 Publication1
Natural variantiVAR_023801231P → R in HPE2. 1 Publication1
Natural variantiVAR_071350244G → C in HPE2. 1 Publication1
Natural variantiVAR_003772250V → A in HPE2; Significantly decreased its ability to activate NR4A3. 2 PublicationsCorresponds to variant rs121917880dbSNPEnsembl.1
Natural variantiVAR_071351254F → L in HPE2. 1 Publication1
Natural variantiVAR_071352257R → G in HPE2. 1 Publication1
Natural variantiVAR_003773257R → P in HPE2; Significantly decreased interaction with NR4A3; Significantly decreased its ability to activate NR4A3. 2 PublicationsCorresponds to variant rs121917879dbSNPEnsembl.1
Natural variantiVAR_023802257R → W in HPE2. 1 Publication1
Natural variantiVAR_071353258R → L in HPE2. 1 Publication1
Natural variantiVAR_071354262R → H in HPE2. 1 Publication1
Natural variantiVAR_071355269R → M in HPE2. 1 Publication1
Natural variantiVAR_071356269R → S in HPE2. 1 Publication1
Natural variantiVAR_071357269R → T in HPE2. 1 Publication1
Natural variantiVAR_071358297P → L in HPE2. 1 PublicationCorresponds to variant rs780942050dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF092047 Genomic DNA. Translation: AAD11939.1.
AF049339 Genomic DNA. Translation: AAD15753.1.
AF083891 Genomic DNA. Translation: AAD51091.1.
AJ012611 mRNA. Translation: CAB42539.1.
AC012354 Genomic DNA. Translation: AAX93283.1.
CH471053 Genomic DNA. Translation: EAX00267.1.
CH471053 Genomic DNA. Translation: EAX00268.1.
CCDSiCCDS1821.1.
RefSeqiNP_005404.1. NM_005413.3.
UniGeneiHs.567336.

Genome annotation databases

EnsembliENST00000260653; ENSP00000260653; ENSG00000138083.
GeneIDi6496.
KEGGihsa:6496.
UCSCiuc002run.2. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF092047 Genomic DNA. Translation: AAD11939.1.
AF049339 Genomic DNA. Translation: AAD15753.1.
AF083891 Genomic DNA. Translation: AAD51091.1.
AJ012611 mRNA. Translation: CAB42539.1.
AC012354 Genomic DNA. Translation: AAX93283.1.
CH471053 Genomic DNA. Translation: EAX00267.1.
CH471053 Genomic DNA. Translation: EAX00268.1.
CCDSiCCDS1821.1.
RefSeqiNP_005404.1. NM_005413.3.
UniGeneiHs.567336.

3D structure databases

ProteinModelPortaliO95343.
SMRiO95343.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112387. 5 interactors.
STRINGi9606.ENSP00000260653.

PTM databases

iPTMnetiO95343.
PhosphoSitePlusiO95343.

Polymorphism and mutation databases

BioMutaiSIX3.

Proteomic databases

EPDiO95343.
MaxQBiO95343.
PaxDbiO95343.
PeptideAtlasiO95343.
PRIDEiO95343.

Protocols and materials databases

DNASUi6496.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000260653; ENSP00000260653; ENSG00000138083.
GeneIDi6496.
KEGGihsa:6496.
UCSCiuc002run.2. human.

Organism-specific databases

CTDi6496.
DisGeNETi6496.
GeneCardsiSIX3.
GeneReviewsiSIX3.
H-InvDBHIX0161628.
HGNCiHGNC:10889. SIX3.
MalaCardsiSIX3.
MIMi157170. phenotype.
269160. phenotype.
603714. gene.
neXtProtiNX_O95343.
OpenTargetsiENSG00000138083.
Orphaneti93925. Alobar holoprosencephaly.
93924. Lobar holoprosencephaly.
280200. Microform holoprosencephaly.
93926. Midline interhemispheric variant of holoprosencephaly.
799. Schizencephaly.
220386. Semilobar holoprosencephaly.
280195. Septopreoptic holoprosencephaly.
PharmGKBiPA35789.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0775. Eukaryota.
ENOG410XRPB. LUCA.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261680.
HOVERGENiHBG003609.
InParanoidiO95343.
KOiK19473.
OMAiSSMTERV.
OrthoDBiEOG091G083I.
PhylomeDBiO95343.
TreeFamiTF315545.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000138083-MONOMER.
SIGNORiO95343.

Miscellaneous databases

ChiTaRSiSIX3. human.
GeneWikiiSIX3.
GenomeRNAii6496.
PROiO95343.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000138083.
CleanExiHS_SIX3.
GenevisibleiO95343. HS.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
IPR031701. SIX1_SD.
IPR032949. SIX3.
[Graphical view]
PANTHERiPTHR10390:SF31. PTHR10390:SF31. 1 hit.
PfamiPF00046. Homeobox. 1 hit.
PF16878. SIX1_SD. 1 hit.
[Graphical view]
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSIX3_HUMAN
AccessioniPrimary (citable) accession number: O95343
Secondary accession number(s): D6W5A5, Q53T42
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: May 1, 1999
Last modified: November 2, 2016
This is version 143 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: 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. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.