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Protein

Homeobox protein SIX1

Gene

Six1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development. Plays an important role in the development of several organs, including kidney, muscle and inner ear. Depending on context, functions as transcriptional repressor or activator. Lacks an activation domain, and requires interaction with EYA family members for transcription activation. Mediates nuclear translocation of EYA1 and EYA2. Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter. Regulates the expression of numerous genes, including MYC, CCNA1, CCND1 and EZR. Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2.8 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi124 – 18360HomeoboxPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

  • anatomical structure development Source: MGI
  • aorta morphogenesis Source: MGI
  • apoptotic process Source: UniProtKB-KW
  • branching involved in ureteric bud morphogenesis Source: MGI
  • cochlea morphogenesis Source: MGI
  • embryonic cranial skeleton morphogenesis Source: MGI
  • embryonic skeletal system morphogenesis Source: MGI
  • epithelial cell differentiation Source: MGI
  • facial nerve morphogenesis Source: MGI
  • fungiform papilla morphogenesis Source: UniProtKB
  • generation of neurons Source: UniProtKB
  • inner ear development Source: UniProtKB
  • inner ear morphogenesis Source: MGI
  • kidney development Source: UniProtKB
  • mesonephric tubule formation Source: UniProtKB
  • metanephric mesenchyme development Source: UniProtKB
  • middle ear morphogenesis Source: MGI
  • myoblast migration Source: MGI
  • myotome development Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of branching involved in ureteric bud morphogenesis Source: MGI
  • negative regulation of neuron apoptotic process Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • neurogenesis Source: UniProtKB
  • neuron fate specification Source: MGI
  • olfactory placode formation Source: UniProtKB
  • organ induction Source: MGI
  • otic vesicle development Source: MGI
  • outflow tract morphogenesis Source: MGI
  • pattern specification process Source: MGI
  • pharyngeal system development Source: UniProtKB
  • positive regulation of branching involved in ureteric bud morphogenesis Source: UniProtKB
  • positive regulation of mesenchymal cell proliferation involved in ureter development Source: MGI
  • positive regulation of secondary heart field cardioblast proliferation Source: MGI
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • positive regulation of ureteric bud formation Source: UniProtKB
  • protein localization to nucleus Source: MGI
  • regulation of branch elongation involved in ureteric bud branching Source: UniProtKB
  • regulation of epithelial cell proliferation Source: UniProtKB
  • regulation of gene expression Source: MGI
  • regulation of neuron differentiation Source: MGI
  • regulation of protein localization Source: MGI
  • regulation of satellite cell proliferation Source: UniProtKB
  • regulation of skeletal muscle cell differentiation Source: UniProtKB
  • regulation of synaptic growth at neuromuscular junction Source: MGI
  • regulation of transcription, DNA-templated Source: MGI
  • renal system development Source: MGI
  • sensory perception of sound Source: MGI
  • skeletal muscle tissue development Source: UniProtKB
  • skeletal system morphogenesis Source: MGI
  • thymus development Source: MGI
  • thyroid gland development Source: MGI
  • tongue development Source: UniProtKB
  • transcription from RNA polymerase II promoter Source: GOC
  • trigeminal ganglion development Source: UniProtKB
  • ureteric bud development Source: MGI
  • ureter smooth muscle cell differentiation Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Activator, Developmental protein, Repressor

Keywords - Biological processi

Apoptosis, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX1
Alternative name(s):
Sine oculis homeobox homolog 1
Gene namesi
Name:Six1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:102780. Six1.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB-SubCell
  • nucleolus Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Perinatal lethality. Mice show failure in renal organogenesis, a severe reduction of most migratory hypaxial muscles including those of the forelimb, diaphragm and tongue, and severe rib-cage deformation. Besides, mice display craniofacial defects, including loss of inner ear structures. Pax2, Six2 and Sall1 expression is markedly reduced in the metanephric mesenchyme at E10.5 during kidney development. Mice lacking both Six1 and Eya1 show defects in kidney development, complete absence of hypaxial muscle, severe reduction in epaxial muscle and a 5-10-fold by volume smaller pituarity than the wild-type gland.5 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 284284Homeobox protein SIX1PRO_0000049296Add
BLAST

Post-translational modificationi

Phosphorylated during interphase; becomes hyperphosphorylated during mitosis. Hyperphosphorylation impairs binding to promoter elements (By similarity).By similarity
Ubiquitinated by the anaphase promoting complex (APC), leading to its proteasomal degradation.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiQ62231.

PTM databases

PhosphoSiteiQ62231.

Expressioni

Tissue specificityi

Expressed in phalangeal tendons and in skeletal muscle and in head and body mesenchyme.

Developmental stagei

First expressed at E8.2-8.5 of embryo development in the anterior head mesoderm and developing pharyngeal pouches. Expression in the developing limb begins at E11 and is more pronounced dorsally. It progresses into the developing phalanges at E13.5. In the developing inner ear detected in the otic placode and the surrounding surface ectoderm at E8.5. Expression became prominent at the invaginating otic pit and the nascent otic vesicle at E9.5. At E10.5, expression was limited to the ventral half of the otic vesicle. Subsequently, the expression became gradually restricted to the cochlear region at E11.5 and E12.5. At later stages detected exclusively in the cochlea at E14.5, and the expression in the cochlear duct persisted in the neonate. In the developing kidney, is expressed in the uninduced metanephric mesenchyme at E10.5 and in the induced mesenchyme around the ureteric bud at E11.5. At E17.5 to P0, expression becomes restricted to a subpopulation of collecting tubule epithelial cells.2 Publications

Gene expression databases

BgeeiQ62231.
ExpressionAtlasiQ62231. baseline and differential.
GenevisibleiQ62231. MM.

Interactioni

Subunit structurei

Interacts with EYA1. Interacts with CDC20 (By similarity). Interacts with DACH1, EYA2 and EYA3.By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Eya1P977673EBI-1368483,EBI-1368503

Protein-protein interaction databases

BioGridi203259. 10 interactions.
IntActiQ62231. 1 interaction.
STRINGi10090.ENSMUSP00000059026.

Structurei

3D structure databases

ProteinModelPortaliQ62231.
SMRiQ62231. Positions 1-185.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

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

eggNOGiNOG289502.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261680.
HOVERGENiHBG003609.
InParanoidiQ62231.
KOiK15614.
OMAiGHSLQAH.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ62231.
TreeFamiTF315545.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
[Graphical view]
PfamiPF00046. Homeobox. 1 hit.
[Graphical view]
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q62231-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSMLPSFGFT QEQVACVCEV LQQGGNLERL GRFLWSLPAC DHLHKNESVL
60 70 80 90 100
KAKAVVAFHR GNFRELYKIL ESHQFSPHNH PKLQQLWLKA HYVEAEKLRG
110 120 130 140 150
RPLGAVGKYR VRRKFPLPRT IWDGEETSYC FKEKSRGVLR EWYAHNPYPS
160 170 180 190 200
PREKRELAEA TGLTTTQVSN WFKNRRQRDR AAEAKERENT ENNNSSSNKQ
210 220 230 240 250
NQLSPLEGGK PLMSSSEEEF SPPQSPDQNS VLLLQSNMGH ARSSNYSLPG
260 270 280
LTASQPSHGL QAHQHQLQDS LLGPLTSSLV DLGS
Length:284
Mass (Da):32,210
Last modified:April 13, 2004 - v2
Checksum:i4A6F88000FB9F8EB
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti12 – 143EQV → GQG in CAA56585 (PubMed:7720577).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X80339 mRNA. Translation: CAA56585.1.
BC023304 mRNA. Translation: AAH23304.1.
CCDSiCCDS25973.1.
PIRiS60751.
RefSeqiNP_033215.2. NM_009189.3.
UniGeneiMm.4645.

Genome annotation databases

EnsembliENSMUST00000050029; ENSMUSP00000059026; ENSMUSG00000051367.
GeneIDi20471.
KEGGimmu:20471.
UCSCiuc007nwa.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X80339 mRNA. Translation: CAA56585.1.
BC023304 mRNA. Translation: AAH23304.1.
CCDSiCCDS25973.1.
PIRiS60751.
RefSeqiNP_033215.2. NM_009189.3.
UniGeneiMm.4645.

3D structure databases

ProteinModelPortaliQ62231.
SMRiQ62231. Positions 1-185.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi203259. 10 interactions.
IntActiQ62231. 1 interaction.
STRINGi10090.ENSMUSP00000059026.

PTM databases

PhosphoSiteiQ62231.

Proteomic databases

PRIDEiQ62231.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000050029; ENSMUSP00000059026; ENSMUSG00000051367.
GeneIDi20471.
KEGGimmu:20471.
UCSCiuc007nwa.2. mouse.

Organism-specific databases

CTDi6495.
MGIiMGI:102780. Six1.

Phylogenomic databases

eggNOGiNOG289502.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261680.
HOVERGENiHBG003609.
InParanoidiQ62231.
KOiK15614.
OMAiGHSLQAH.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ62231.
TreeFamiTF315545.

Miscellaneous databases

NextBioi298579.
PROiQ62231.
SOURCEiSearch...

Gene expression databases

BgeeiQ62231.
ExpressionAtlasiQ62231. baseline and differential.
GenevisibleiQ62231. MM.

Family and domain databases

Gene3Di1.10.10.60. 1 hit.
InterProiIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
[Graphical view]
PfamiPF00046. Homeobox. 1 hit.
[Graphical view]
SMARTiSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMiSSF46689. SSF46689. 1 hit.
PROSITEiPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Homeobox genes and connective tissue patterning."
    Oliver G., Wehr R., Jenkins N.A., Copeland N.G., Cheyette B.N.R., Hartenstein V., Zipursky S.L., Gruss P.
    Development 121:693-705(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 12-284.
    Strain: C57BL/6J.
    Tissue: Embryo.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
    Tissue: Salivary gland.
  3. "Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1."
    Sato S., Nakamura M., Cho D.H., Tapscott S.J., Ozaki H., Kawakami K.
    Hum. Mol. Genet. 11:1045-1058(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH EYA2.
  4. "Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site."
    Spitz F., Demignon J., Porteu A., Kahn A., Concordet J.P., Daegelen D., Maire P.
    Proc. Natl. Acad. Sci. U.S.A. 95:14220-14225(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: DNA-BINDING.
  5. "Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein."
    Ikeda K., Watanabe Y., Ohto H., Kawakami K.
    Mol. Cell. Biol. 22:6759-6766(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH EYA3.
  6. Cited for: DISRUPTION PHENOTYPE, FUNCTION.
  7. "Six1 is required for the early organogenesis of mammalian kidney."
    Xu P.X., Zheng W., Huang L., Maire P., Laclef C., Silvius D.
    Development 130:3085-3094(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE.
  8. "Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice."
    Laclef C., Souil E., Demignon J., Maire P.
    Mech. Dev. 120:669-679(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION.
  9. "Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis."
    Li X., Oghi K.A., Zhang J., Krones A., Bush K.T., Glass C.K., Nigam S.K., Aggarwal A.K., Maas R., Rose D.W., Rosenfeld M.G.
    Nature 426:247-254(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE, INTERACTION WITH DACH1 AND EYA3.
  10. Cited for: FUNCTION, DEVELOPMENTAL STAGE.
  11. "The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis."
    Yu Y., Davicioni E., Triche T.J., Merlino G.
    Cancer Res. 66:1982-1989(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  12. "Genesis of muscle fiber-type diversity during mouse embryogenesis relies on Six1 and Six4 gene expression."
    Richard A.F., Demignon J., Sakakibara I., Pujol J., Favier M., Strochlic L., Le Grand F., Sgarioto N., Guernec A., Schmitt A., Cagnard N., Huang R., Legay C., Guillet-Deniau I., Maire P.
    Dev. Biol. 359:303-320(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiSIX1_MOUSE
AccessioniPrimary (citable) accession number: Q62231
Secondary accession number(s): Q8CIL7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: April 13, 2004
Last modified: July 22, 2015
This is version 133 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.