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Q62231 (SIX1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 124. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Homeobox protein SIX1
Alternative name(s):
Sine oculis homeobox homolog 1
Gene names
Name:Six1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length284 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.3 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12

Subunit structure

Interacts with EYA1. Interacts with CDC20 By similarity. Interacts with DACH1, EYA2 and EYA3. Ref.3 Ref.5 Ref.9

Subcellular location

Nucleus. Cytoplasm By similarity.

Tissue specificity

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

Developmental stage

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. Ref.7 Ref.11

Post-translational modification

Phosphorylated during interphase; becomes hyperphosphorylated during mitosis. Hyperphosphorylation impairs binding to promoter elements By similarity.

Ubiquitinated by the anaphase promoting complex (APC), leading to its proteasomal degradation By similarity.

Disruption phenotype

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. Ref.6 Ref.7 Ref.8 Ref.9 Ref.13

Sequence similarities

Belongs to the SIX/Sine oculis homeobox family.

Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
   Biological processApoptosis
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   DomainHomeobox
   LigandDNA-binding
   Molecular functionActivator
Developmental protein
Repressor
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processanatomical structure development

Inferred from genetic interaction PubMed 16530750. Source: MGI

aorta morphogenesis

Inferred from genetic interaction PubMed 21364285. Source: MGI

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

branching involved in ureteric bud morphogenesis

Inferred from genetic interaction Ref.7. Source: MGI

cochlea morphogenesis

Inferred from mutant phenotype PubMed 12874121. Source: MGI

embryonic cranial skeleton morphogenesis

Inferred from genetic interaction PubMed 20515681. Source: MGI

embryonic skeletal system morphogenesis

Inferred from genetic interaction PubMed 15788460. Source: MGI

epithelial cell differentiation

Inferred from mutant phenotype PubMed 16530750. Source: MGI

facial nerve morphogenesis

Inferred from mutant phenotype PubMed 12874121. Source: MGI

generation of neurons

Inferred from mutant phenotype PubMed 16938278. Source: UniProtKB

inner ear development

Inferred from mutant phenotype PubMed 19389353. Source: UniProtKB

inner ear morphogenesis

Inferred from genetic interaction PubMed 15788460. Source: MGI

kidney development

Inferred from mutant phenotype PubMed 16934795. Source: UniProtKB

mesonephric tubule formation

Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB

metanephric mesenchyme development

Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB

middle ear morphogenesis

Inferred from mutant phenotype PubMed 12874121. Source: MGI

myoblast migration

Inferred from genetic interaction PubMed 15788460. Source: MGI

negative regulation of branching involved in ureteric bud morphogenesis

Inferred from mutant phenotype PubMed 21281623. Source: MGI

negative regulation of neuron apoptotic process

Inferred from mutant phenotype PubMed 16938278. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 21281623. Source: MGI

neuron fate specification

Inferred from genetic interaction PubMed 22513373. Source: MGI

organ induction

Inferred from mutant phenotype Ref.7. Source: MGI

otic vesicle development

Inferred from mutant phenotype PubMed 16916509. Source: MGI

outflow tract morphogenesis

Inferred from genetic interaction PubMed 21364285. Source: MGI

pattern specification process

Inferred from mutant phenotype PubMed 16916509. Source: MGI

pharyngeal system development

Inferred from genetic interaction PubMed 21364285. Source: MGI

positive regulation of branching involved in ureteric bud morphogenesis

Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB

positive regulation of mesenchymal cell proliferation involved in ureter development

Inferred from genetic interaction PubMed 20110314. Source: MGI

positive regulation of secondary heart field cardioblast proliferation

Inferred from genetic interaction PubMed 21364285. Source: MGI

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 15955062. Source: MGI

positive regulation of transcription, DNA-templated

Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB

positive regulation of ureteric bud formation

Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB

protein localization to nucleus

Inferred from electronic annotation. Source: Ensembl

regulation of branch elongation involved in ureteric bud branching

Inferred from mutant phenotype PubMed 17300925. Source: UniProtKB

regulation of gene expression

Inferred from genetic interaction Ref.13. Source: MGI

regulation of neuron differentiation

Inferred from mutant phenotype PubMed 15496442. Source: MGI

regulation of protein localization

Inferred from genetic interaction Ref.13. Source: MGI

regulation of synaptic growth at neuromuscular junction

Inferred from genetic interaction Ref.13. Source: MGI

regulation of transcription, DNA-templated

Inferred from direct assay Ref.9. Source: MGI

renal system development

Inferred from genetic interaction PubMed 21281623. Source: MGI

sensory perception of sound

Inferred from mutant phenotype PubMed 12874121. Source: MGI

skeletal muscle tissue development

Inferred from genetic interaction PubMed 15788460. Source: MGI

skeletal system morphogenesis

Inferred from mutant phenotype PubMed 12874121. Source: MGI

thymus development

Inferred from mutant phenotype PubMed 16530750. Source: MGI

thyroid gland development

Inferred from mutant phenotype PubMed 16530750. Source: MGI

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

ureter smooth muscle cell differentiation

Inferred from mutant phenotype PubMed 20110314. Source: MGI

ureteric bud development

Inferred from mutant phenotype Ref.7. Source: MGI

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleolus

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay Ref.9Ref.4. Source: MGI

transcription factor complex

Inferred from direct assay Ref.9. Source: MGI

   Molecular_functionchromatin binding

Inferred from genetic interaction PubMed 19008232. Source: MGI

sequence-specific DNA binding

Inferred from direct assay PubMed 17098221Ref.4. Source: MGI

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 15955062. Source: MGI

transcription regulatory region DNA binding

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Eya1P977673EBI-1368483,EBI-1368503

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 284284Homeobox protein SIX1
PRO_0000049296

Regions

DNA binding124 – 18360Homeobox Ref.4

Experimental info

Sequence conflict12 – 143EQV → GQG in CAA56585. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q62231 [UniParc].

Last modified April 13, 2004. Version 2.
Checksum: 4A6F88000FB9F8EB

FASTA28432,210
        10         20         30         40         50         60 
MSMLPSFGFT QEQVACVCEV LQQGGNLERL GRFLWSLPAC DHLHKNESVL KAKAVVAFHR 

        70         80         90        100        110        120 
GNFRELYKIL ESHQFSPHNH PKLQQLWLKA HYVEAEKLRG RPLGAVGKYR VRRKFPLPRT 

       130        140        150        160        170        180 
IWDGEETSYC FKEKSRGVLR EWYAHNPYPS PREKRELAEA TGLTTTQVSN WFKNRRQRDR 

       190        200        210        220        230        240 
AAEAKERENT ENNNSSSNKQ NQLSPLEGGK PLMSSSEEEF SPPQSPDQNS VLLLQSNMGH 

       250        260        270        280 
ARSSNYSLPG LTASQPSHGL QAHQHQLQDS LLGPLTSSLV DLGS 

« Hide

References

« Hide 'large scale' references
[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]"Altered myogenesis in Six1-deficient mice."
Laclef C., Hamard G., Demignon J., Souil E., Houbron C., Maire P.
Development 130:2239-2252(2003) [PubMed] [Europe PMC] [Abstract]
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]Erratum
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 427:265-265(2004)
[11]"Six1 controls patterning of the mouse otic vesicle."
Ozaki H., Nakamura K., Funahashi J., Ikeda K., Yamada G., Tokano H., Okamura H.O., Kitamura K., Muto S., Kotaki H., Sudo K., Horai R., Iwakura Y., Kawakami K.
Development 131:551-562(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DEVELOPMENTAL STAGE.
[12]"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.
[13]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X80339 mRNA. Translation: CAA56585.1.
BC023304 mRNA. Translation: AAH23304.1.
PIRS60751.
RefSeqNP_033215.2. NM_009189.3.
UniGeneMm.4645.

3D structure databases

ProteinModelPortalQ62231.
SMRQ62231. Positions 1-185.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid203259. 10 interactions.
IntActQ62231. 1 interaction.

PTM databases

PhosphoSiteQ62231.

Proteomic databases

PRIDEQ62231.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000050029; ENSMUSP00000059026; ENSMUSG00000051367.
GeneID20471.
KEGGmmu:20471.
UCSCuc007nwa.2. mouse.

Organism-specific databases

CTD6495.
MGIMGI:102780. Six1.

Phylogenomic databases

eggNOGNOG289502.
GeneTreeENSGT00540000070251.
HOGENOMHOG000261680.
HOVERGENHBG003609.
InParanoidQ62231.
KOK15614.
OMAPRQAPAM.
OrthoDBEOG7C5M8Z.
PhylomeDBQ62231.
TreeFamTF315545.

Gene expression databases

ArrayExpressQ62231.
BgeeQ62231.
GenevestigatorQ62231.

Family and domain databases

Gene3D1.10.10.60. 1 hit.
InterProIPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
[Graphical view]
PfamPF00046. Homeobox. 1 hit.
[Graphical view]
SMARTSM00389. HOX. 1 hit.
[Graphical view]
SUPFAMSSF46689. SSF46689. 1 hit.
PROSITEPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio298579.
PROQ62231.
SOURCESearch...

Entry information

Entry nameSIX1_MOUSE
AccessionPrimary (citable) accession number: Q62231
Secondary accession number(s): Q8CIL7
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: April 13, 2004
Last modified: April 16, 2014
This is version 124 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot