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Q9NPC8

- SIX2_HUMAN

UniProt

Q9NPC8 - SIX2_HUMAN

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Protein

Homeobox protein SIX2

Gene

SIX2

Organism
Homo sapiens (Human)
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. During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1. During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway. Also may be involved in limb tendon and ligament development (By similarity). Plays a role in cell proliferation and migration.By similarity1 Publication

Regions

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

GO - Molecular functioni

  1. sequence-specific DNA binding Source: Ensembl
  2. sequence-specific DNA binding transcription factor activity Source: ProtInc

GO - Biological processi

  1. anatomical structure morphogenesis Source: ProtInc
  2. anterior/posterior axis specification Source: UniProtKB
  3. cell migration Source: UniProtKB
  4. cell proliferation Source: UniProtKB
  5. chondrocyte differentiation Source: Ensembl
  6. embryonic cranial skeleton morphogenesis Source: Ensembl
  7. embryonic digestive tract morphogenesis Source: UniProtKB
  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. middle ear morphogenesis Source: Ensembl
  15. nephron development Source: UniProtKB
  16. nephron morphogenesis Source: UniProtKB
  17. positive regulation of chondrocyte proliferation Source: UniProtKB
  18. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
  19. protein import into nucleus Source: Ensembl
  20. regulation of branching involved in ureteric bud morphogenesis 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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:10888. SIX2.

Subcellular locationi

Nucleus By similarity

GO - Cellular componenti

  1. nucleus Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA35788.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 291291Homeobox protein SIX2PRO_0000049297Add
BLAST

Proteomic databases

MaxQBiQ9NPC8.
PaxDbiQ9NPC8.
PRIDEiQ9NPC8.

Expressioni

Tissue specificityi

Strongly expressed in skeletal muscle. Expressed in Wilms' tumor and in the cap mesenchyme of fetal kidney (at protein level).1 Publication

Developmental stagei

Found at 48 dpc in the anterior cranial base with detection concentrated in the sphenoid precursor. Expression is also detected in the pituitary gland.1 Publication

Gene expression databases

BgeeiQ9NPC8.
CleanExiHS_SIX2.
GenevestigatoriQ9NPC8.

Organism-specific databases

HPAiHPA052782.

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.By similarity

Protein-protein interaction databases

BioGridi115959. 1 interaction.
STRINGi9606.ENSP00000304502.

Structurei

3D structure databases

ProteinModelPortaliQ9NPC8.
SMRiQ9NPC8. 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.
InParanoidiQ9NPC8.
OMAiANSNSHN.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ9NPC8.
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.

Q9NPC8-1 [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 AAEAKERENN ENSNSNSHNP
210 220 230 240 250
LNGSGKSVLG SSEDEKTPSG TPDHSSSSPA LLLSPPPPGL PSLHSLGHPP
260 270 280 290
GPSAVPVPVP GGGGADPLQH HHGLQDSILN PMSANLVDLG S
Length:291
Mass (Da):32,286
Last modified:October 1, 2000 - v1
Checksum:i8388C3C331575BDD
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti43 – 431L → F in a renal hypodysplasia patient. 1 Publication
VAR_071207
Natural varianti241 – 2411P → L in a renal hypodysplasia patient. 1 Publication
VAR_071208
Natural varianti276 – 2761D → N in a renal hypodysplasia patient. 1 Publication
VAR_071209

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF136939 Genomic DNA. Translation: AAF69031.1.
AF136940 mRNA. Translation: AAF69032.1.
AF332196 mRNA. Translation: AAK16581.1.
AF332197 mRNA. Translation: AAK16582.1.
AF332198 Genomic DNA. Translation: AAK16583.1.
AF323498 Genomic DNA. Translation: AAK06773.1.
BT020100 mRNA. Translation: AAV38903.1.
CCDSiCCDS1822.1.
RefSeqiNP_058628.3. NM_016932.4.
UniGeneiHs.101937.

Genome annotation databases

EnsembliENST00000303077; ENSP00000304502; ENSG00000170577.
GeneIDi10736.
KEGGihsa:10736.
UCSCiuc002ruo.3. human.

Polymorphism databases

DMDMi12230598.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF136939 Genomic DNA. Translation: AAF69031.1 .
AF136940 mRNA. Translation: AAF69032.1 .
AF332196 mRNA. Translation: AAK16581.1 .
AF332197 mRNA. Translation: AAK16582.1 .
AF332198 Genomic DNA. Translation: AAK16583.1 .
AF323498 Genomic DNA. Translation: AAK06773.1 .
BT020100 mRNA. Translation: AAV38903.1 .
CCDSi CCDS1822.1.
RefSeqi NP_058628.3. NM_016932.4.
UniGenei Hs.101937.

3D structure databases

ProteinModelPortali Q9NPC8.
SMRi Q9NPC8. Positions 1-185.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 115959. 1 interaction.
STRINGi 9606.ENSP00000304502.

Polymorphism databases

DMDMi 12230598.

Proteomic databases

MaxQBi Q9NPC8.
PaxDbi Q9NPC8.
PRIDEi Q9NPC8.

Protocols and materials databases

DNASUi 10736.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000303077 ; ENSP00000304502 ; ENSG00000170577 .
GeneIDi 10736.
KEGGi hsa:10736.
UCSCi uc002ruo.3. human.

Organism-specific databases

CTDi 10736.
GeneCardsi GC02M045232.
HGNCi HGNC:10888. SIX2.
HPAi HPA052782.
MIMi 604994. gene.
neXtProti NX_Q9NPC8.
PharmGKBi PA35788.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG289502.
GeneTreei ENSGT00540000070251.
HOGENOMi HOG000261680.
HOVERGENi HBG003609.
InParanoidi Q9NPC8.
OMAi ANSNSHN.
OrthoDBi EOG7C5M8Z.
PhylomeDBi Q9NPC8.
TreeFami TF315545.

Miscellaneous databases

GeneWikii SIX2.
GenomeRNAii 10736.
NextBioi 40762.
PROi Q9NPC8.
SOURCEi Search...

Gene expression databases

Bgeei Q9NPC8.
CleanExi HS_SIX2.
Genevestigatori Q9NPC8.

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. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
  2. "Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2."
    Boucher C.A., Winchester C.L., Hamilton G.M., Winter A.D., Johnson K.J., Bailey M.E.S.
    Gene 247:145-151(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
  3. "Molecular characterization of the human SIX2 gene: alternative polyadenylation and localization within the HPE2 critical region 2p21."
    Hedrich K., Hehr A.J., Hansmann I., Hehr U.
    Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
    Tissue: Salivary gland.
  4. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
    Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
    Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
  5. "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: DEVELOPMENTAL STAGE.
  6. "SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain active in primitive elements of Wilms' tumor."
    Murphy A.J., Pierce J., de Caestecker C., Taylor C., Anderson J.R., Perantoni A.O., de Caestecker M.P., Lovvorn H.N. III
    J. Pediatr. Surg. 47:1239-1249(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  7. "The pluripotent renal stem cell regulator SIX2 is activated in renal neoplasms and influences cellular proliferation and migration."
    Senanayake U., Koller K., Pichler M., Leuschner I., Strohmaier H., Hadler U., Das S., Hoefler G., Guertl B.
    Hum. Pathol. 44:336-345(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CELL MIGRATION AND CELL PROLIFERATION.
  8. Cited for: VARIANTS PHE-43; LEU-241 AND ASN-276.

Entry informationi

Entry nameiSIX2_HUMAN
AccessioniPrimary (citable) accession number: Q9NPC8
Secondary accession number(s): Q9BXH7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: October 1, 2000
Last modified: October 29, 2014
This is version 111 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

External Data

Dasty 3