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Q62232

- SIX2_MOUSE

UniProt

Q62232 - SIX2_MOUSE

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Protein

Homeobox protein SIX2

Gene

Six2

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

Functioni

Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach. During kidney development, maintains cap mesenchyme multipotent nephron progenitor cells in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud and cooperates with WNT9B to promote renewing progenitor cells proliferation. Acts through its interaction with TCF7L2 and OSR1 in a canonical Wnt signaling independent manner preventing transcription of differentiation genes in cap mesenchyme such as WNT4. Also acts independently of OSR1 to activate expression of many cap mesenchyme genes, including itself, GDNF and OSR1. During craniofacial development plays a role in growth and elongation of the cranial base through regulation of chondrocyte differentiation (PubMed:20515681). During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1 (PubMed:19660448). During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway (PubMed:18321982). Also may be involved in limb tendon and ligament development (PubMed:7720577). Plays a role in cell proliferation and migration (By similarity).By similarity9 Publications

Regions

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

GO - Molecular functioni

  1. protein complex binding Source: UniProtKB
  2. sequence-specific DNA binding Source: MGI
  3. sequence-specific DNA binding transcription factor activity Source: MGI
  4. transcription factor binding Source: UniProtKB

GO - Biological processi

  1. anterior/posterior axis specification Source: UniProtKB
  2. cell migration Source: UniProtKB
  3. cell proliferation Source: UniProtKB
  4. chondrocyte differentiation Source: MGI
  5. embryonic cranial skeleton morphogenesis Source: MGI
  6. embryonic digestive tract morphogenesis Source: UniProtKB
  7. embryonic skeletal system morphogenesis Source: MGI
  8. kidney development Source: UniProtKB
  9. mesenchymal cell differentiation involved in kidney development Source: UniProtKB
  10. mesenchymal stem cell maintenance involved in nephron morphogenesis Source: UniProtKB
  11. mesenchymal stem cell proliferation Source: UniProtKB
  12. mesenchymal to epithelial transition involved in metanephros morphogenesis Source: UniProtKB
  13. mesodermal cell fate specification Source: UniProtKB
  14. metanephros development Source: MGI
  15. middle ear morphogenesis Source: MGI
  16. negative regulation of cell differentiation Source: MGI
  17. nephron development Source: UniProtKB
  18. nephron morphogenesis Source: UniProtKB
  19. positive regulation of chondrocyte proliferation Source: UniProtKB
  20. positive regulation of transcription from RNA polymerase II promoter Source: MGI
  21. protein import into nucleus Source: MGI
  22. regulation of branching involved in ureteric bud morphogenesis Source: UniProtKB
  23. regulation of chondrocyte differentiation Source: UniProtKB
  24. regulation of ossification Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Ligandi

DNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX2
Alternative name(s):
Sine oculis homeobox homolog 2
Gene namesi
Name:Six2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 17

Organism-specific databases

MGIiMGI:102778. Six2.

Subcellular locationi

Nucleus 1 Publication

GO - Cellular componenti

  1. nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Six2 knockout heterozygous mice not exhibit any obvious abnormalities. However, Six2 knockout nullizygous mice die soon after birth.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 296296Homeobox protein SIX2PRO_0000049298Add
BLAST

Proteomic databases

PRIDEiQ62232.

PTM databases

PhosphoSiteiQ62232.

Expressioni

Tissue specificityi

Expressed in phalangeal tendons, in smooth muscle and in head and body mesenchyme.

Developmental stagei

First expressed at E8.5 of embryo development in a restricted mesodermal subpopulation at the anterior hindbrain level. Expression of SIX2 in the developing limb begins at E11 and is more pronounced ventrally. It progresses into the developing phalanges at E12.5. At E10.5 expressed in the metanephric blastema, which signals the ureteric bud to evaginate from the Wolffian duct. At E11.5 expressed at high levels in the dorsal anephric mesenchyme and is down-regulated where pretubular aggregates will form on the ventral side of the ureteric bud. At E14.5, expression persists in the peripheral mesenchyme of the renal cortex. At E9.5, expressed in the splanchnic mesoderm of the stomach anlage. By E10.5, expressed in the mesoderm of the posterior stomach. Expression is seen in the presumptive glandular stomach primordium at E11.5. At E12.5, becomes restricted to the mesenchyme of the antral region of the posterior stomach. At E14.5, expression remains in the antrum, just anterior to the pyloric sphincter.2 Publications

Inductioni

Down-regulated by CTNNB1 upon differentiarion. Activated by TLX1 in the kidney and repressed by HOXA2 in the branchial arch and facial mesenchyme.3 Publications

Gene expression databases

BgeeiQ62232.
GenevestigatoriQ62232.

Interactioni

Subunit structurei

Interacts with TCF7L2; in a canonical Wnt signaling independent manner; prevents transcription of differentiation genes in cap mesenchyme. Interacts with OSR1; form a strong repressor complex with TCF7L2, TLE2 and TLE3 to prevent the activation of Wnt/beta-catenin target genes in the cap mesenchyme. Interacts with HOXA11, EYA1 and EYA3.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Eya1P977673EBI-1368736,EBI-1368503

Protein-protein interaction databases

BioGridi203260. 1 interaction.
IntActiQ62232. 1 interaction.

Structurei

3D structure databases

ProteinModelPortaliQ62232.
SMRiQ62232. 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.
InParanoidiQ62232.
OMAiANSNSHN.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ62232.
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.

Q62232-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MSMLPTFGFT QEQVACVCEV LQQGGNIERL GRFLWSLPAC EHLHKNESVL
60 70 80 90 100
KAKAVVAFHR GNFRELYKIL ESHQFSPHNH AKLQQLWLKA HYIEAEKLRG
110 120 130 140 150
RPLGAVGKYR VRRKFPLPRS IWDGEETSYC FKEKSRSVLR EWYAHNPYPS
160 170 180 190 200
PREKRELAEA TGLTTTQVSN WFKNRRQRDR AAEAKERENS ENSNSSSHNP
210 220 230 240 250
LASSLNGSGK SVLGSSEDEK TPSGTPDHSS SSPALLLSPP PPPGLPSLHS
260 270 280 290
LGHPPGPSAV PVPVPGGGGA DPLQHHHSLQ DSILNPMSAN LVDLGS
Length:296
Mass (Da):32,718
Last modified:July 15, 1998 - v2
Checksum:i0FFAB002014D8E60
GO

Sequence cautioni

The sequence CAA56584.1 differs from that shown. Reason: Erroneous initiation. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti1 – 66MSMLPT → HVHARH in CAA56584. (PubMed:7720577)Curated
Sequence conflicti105 – 1051A → R in CAA56584. (PubMed:7720577)Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X80338 mRNA. Translation: CAA56584.1. Different initiation.
D83147 mRNA. Translation: BAA11825.1.
BC068021 mRNA. Translation: AAH68021.1.
CCDSiCCDS29007.1.
PIRiS74253.
RefSeqiNP_035510.1. NM_011380.2.
UniGeneiMm.5039.

Genome annotation databases

EnsembliENSMUST00000024947; ENSMUSP00000024947; ENSMUSG00000024134.
ENSMUST00000163568; ENSMUSP00000125871; ENSMUSG00000024134.
GeneIDi20472.
KEGGimmu:20472.
UCSCiuc008duc.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X80338 mRNA. Translation: CAA56584.1 . Different initiation.
D83147 mRNA. Translation: BAA11825.1 .
BC068021 mRNA. Translation: AAH68021.1 .
CCDSi CCDS29007.1.
PIRi S74253.
RefSeqi NP_035510.1. NM_011380.2.
UniGenei Mm.5039.

3D structure databases

ProteinModelPortali Q62232.
SMRi Q62232. Positions 1-185.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 203260. 1 interaction.
IntActi Q62232. 1 interaction.

PTM databases

PhosphoSitei Q62232.

Proteomic databases

PRIDEi Q62232.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000024947 ; ENSMUSP00000024947 ; ENSMUSG00000024134 .
ENSMUST00000163568 ; ENSMUSP00000125871 ; ENSMUSG00000024134 .
GeneIDi 20472.
KEGGi mmu:20472.
UCSCi uc008duc.2. mouse.

Organism-specific databases

CTDi 10736.
MGIi MGI:102778. Six2.

Phylogenomic databases

eggNOGi NOG289502.
GeneTreei ENSGT00540000070251.
HOGENOMi HOG000261680.
HOVERGENi HBG003609.
InParanoidi Q62232.
OMAi ANSNSHN.
OrthoDBi EOG7C5M8Z.
PhylomeDBi Q62232.
TreeFami TF315545.

Miscellaneous databases

NextBioi 298583.
PROi Q62232.
SOURCEi Search...

Gene expression databases

Bgeei Q62232.
Genevestigatori Q62232.

Family and domain databases

Gene3Di 1.10.10.60. 1 hit.
InterProi IPR017970. Homeobox_CS.
IPR001356. Homeobox_dom.
IPR009057. Homeodomain-like.
[Graphical view ]
Pfami PF00046. Homeobox. 1 hit.
[Graphical view ]
SMARTi SM00389. HOX. 1 hit.
[Graphical view ]
SUPFAMi SSF46689. SSF46689. 1 hit.
PROSITEi PS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

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], FUNCTION.
    Strain: C57BL/6J.
    Tissue: Embryo.
  2. "Identification and expression of Six family genes in mouse retina."
    Kawakami K., Ohto H., Takizawa T., Saito T.
    FEBS Lett. 393:259-263(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION.
    Strain: BALB/c.
  3. "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].
    Tissue: Embryo.
  4. "Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome."
    Buller C., Xu X., Marquis V., Schwanke R., Xu P.X.
    Hum. Mol. Genet. 10:2775-2781(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH EYA1.
  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: INTERACTION WITH EYA3.
  6. "Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney."
    Self M., Lagutin O.V., Bowling B., Hendrix J., Cai Y., Dressler G.R., Oliver G.
    EMBO J. 25:5214-5228(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN KIDNEY DEVELOPMENT, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE.
  7. "Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development."
    Kobayashi A., Valerius M.T., Mugford J.W., Carroll T.J., Self M., Oliver G., McMahon A.P.
    Cell Stem Cell 3:169-181(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN NEPHRON DEVELOPMENT.
  8. "Six2 functions redundantly immediately downstream of Hoxa2."
    Kutejova E., Engist B., Self M., Oliver G., Kirilenko P., Bobola N.
    Development 135:1463-1470(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN BRANCHIAL ARCH DEVELOPMENT, INDUCTION.
  9. "Six2 activity is required for the formation of the mammalian pyloric sphincter."
    Self M., Geng X., Oliver G.
    Dev. Biol. 334:409-417(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN STOMACH MORPHOGENESIS, DEVELOPMENTAL STAGE.
  10. "Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo."
    Yallowitz A.R., Gong K.Q., Swinehart I.T., Nelson L.T., Wellik D.M.
    Dev. Biol. 335:156-165(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  11. "Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base."
    He G., Tavella S., Hanley K.P., Self M., Oliver G., Grifone R., Hanley N., Ward C., Bobola N.
    Dev. Biol. 344:720-730(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CRANIOFACIAL DEVELOPMENT.
  12. "Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development."
    Karner C.M., Das A., Ma Z., Self M., Chen C., Lum L., Oliver G., Carroll T.J.
    Development 138:1247-1257(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PROGENITOR CELL PROLIFERATION.
  13. "Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks."
    Park J.S., Ma W., O'Brien L.L., Chung E., Guo J.J., Cheng J.G., Valerius M.T., McMahon J.A., Wong W.H., McMahon A.P.
    Dev. Cell 23:637-651(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN REGULATION OF NEPHRON PROGENITOR RENEWAL, INTERACTION WITH TCF7L2 AND HOXA11, INDUCTION.
  14. "Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis."
    Xu J., Liu H., Park J.S., Lan Y., Jiang R.
    Development 141:1442-1452(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN REGULATION OF NEPHRON PROGENITOR RENEWAL, INTERACTION WITH OSR1.

Entry informationi

Entry nameiSIX2_MOUSE
AccessioniPrimary (citable) accession number: Q62232
Secondary accession number(s): P70179
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: July 15, 1998
Last modified: October 29, 2014
This is version 115 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