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Protein

Homeobox protein SIX3

Gene

SIX3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

Keywordsi

Molecular functionDevelopmental protein, DNA-binding, Repressor
Biological processTranscription, Transcription regulation

Enzyme and pathway databases

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

EuPathDBiHostDB:ENSG00000138083.4
HGNCiHGNC:10889 SIX3
MIMi603714 gene
neXtProtiNX_O95343

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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 dbSNP:rs199823175EnsemblClinVar.1
Natural variantiVAR_03841869G → D in HPE2. 1 PublicationCorresponds to variant dbSNP:rs121917881EnsemblClinVar.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 dbSNP:rs137853021EnsemblClinVar.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 dbSNP:rs121917878EnsemblClinVar.1
Natural variantiVAR_071349227Q → P in HPE2. 1 Publication1
Natural variantiVAR_023801231P → R in HPE2. 1 Publication1
Natural variantiVAR_071350244G → C in HPE2. 1 PublicationCorresponds to variant dbSNP:rs989286015Ensembl.1
Natural variantiVAR_003772250V → A in HPE2; Significantly decreased its ability to activate NR4A3. 2 PublicationsCorresponds to variant dbSNP:rs121917880EnsemblClinVar.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 dbSNP:rs121917879EnsemblClinVar.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 dbSNP:rs780942050Ensembl.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 dbSNP:rs199823175EnsemblClinVar.1
Natural variantiVAR_071343167A → S in SCHZC. 1 PublicationCorresponds to variant dbSNP:rs387906868EnsemblClinVar.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
GeneReviewsiSIX3
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
ProteomicsDBi50811

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

Organism-specific databases

HPAiHPA067988

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

Binary interactionsi

WithEntry#Exp.IntActNotes
NR4A3Q925703EBI-13644574,EBI-13644623

GO - Molecular functioni

Protein-protein interaction databases

BioGridi112387, 5 interactors
IntActiO95343, 1 interactor
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

Keywords - Domaini

Homeobox

Phylogenomic databases

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

Family and domain databases

CDDicd00086 homeodomain, 1 hit
InterProiView protein in InterPro
IPR009057 Homeobox-like_sf
IPR001356 Homeobox_dom
IPR031701 SIX1_SD
IPR032949 SIX3
PANTHERiPTHR10390:SF31 PTHR10390:SF31, 1 hit
PfamiView protein in Pfam
PF00046 Homeobox, 1 hit
PF16878 SIX1_SD, 1 hit
SMARTiView protein in SMART
SM00389 HOX, 1 hit
SUPFAMiSSF46689 SSF46689, 1 hit
PROSITEiView protein in PROSITE
PS50071 HOMEOBOX_2, 1 hit

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 dbSNP:rs199823175EnsemblClinVar.1
Natural variantiVAR_03841869G → D in HPE2. 1 PublicationCorresponds to variant dbSNP:rs121917881EnsemblClinVar.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 dbSNP:rs137853021EnsemblClinVar.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 dbSNP:rs387906868EnsemblClinVar.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 dbSNP:rs121917878EnsemblClinVar.1
Natural variantiVAR_071349227Q → P in HPE2. 1 Publication1
Natural variantiVAR_023801231P → R in HPE2. 1 Publication1
Natural variantiVAR_071350244G → C in HPE2. 1 PublicationCorresponds to variant dbSNP:rs989286015Ensembl.1
Natural variantiVAR_003772250V → A in HPE2; Significantly decreased its ability to activate NR4A3. 2 PublicationsCorresponds to variant dbSNP:rs121917880EnsemblClinVar.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 dbSNP:rs121917879EnsemblClinVar.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 dbSNP:rs780942050Ensembl.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

Similar proteinsi

Entry informationi

Entry nameiSIX3_HUMAN
AccessioniPrimary (citable) accession number: O95343
Secondary accession number(s): D6W5A5, Q53T42
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: May 1, 1999
Last modified: June 20, 2018
This is version 155 of the entry and version 1 of the sequence. See 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

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