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Protein

Homeobox protein SIX4

Gene

SIX4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a DNA sequence on these target genes and is involved in processes like cell differentiation, cell migration and cell survival. Transactivates gene expression by binding a 5'-[CAT]A[CT][CT][CTG]GA[GAT]-3' motif present in the Trex site and a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 site of the muscle-specific genes enhancer. Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein. Acts synergistically with SIX1 to regulate target genes involved in formation of various organs, including muscle, kidney, gonad, ganglia, olfactory epithelium and cranial skeleton. Plays a role in several important steps of muscle development. Controls the genesis of hypaxial myogenic progenitors in the dermomyotome by transactivating PAX3 and the delamination and migration of the hypaxial precursors from the ventral lip to the limb buds through the transactivation of PAX3, MET and LBX1. Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6. Controls somitic differentiation in myocyte through MYOG transactivation. Plays a role in synaptogenesis and sarcomere organization by participating in myofiber specialization during embryogenesis by activating fast muscle program in the primary myotome resulting in an up-regulation of fast muscle genes, including ATP2A1, MYL1 and TNNT3. Simultaneously, is also able to activate inhibitors of slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting the activation of the slow muscle genes. During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression. During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression. Plays a role in gonad development by regulating both testis determination and size determination. In gonadal sex determination, transactivates ZFPM2 by binding a MEF3 consensus sequence, resulting in SRY up-regulation. In gonadal size determination, transactivates NR5A1 by binding a MEF3 consensus sequence resulting in gonadal precursor cell formation regulation. During olfactory development mediates the specification and patterning of olfactory placode through fibroblast growth factor and BMP4 signaling pathways and also regulates epithelial cell proliferation during placode formation. Promotes survival of sensory neurons during early trigeminal gangliogenesis. In the developing dorsal root ganglia, up-regulates SLC12A2 transcription. Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression. Forms gustatory papillae during development of the tongue. Also plays a role during embryonic cranial skeleton morphogenesis.By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi223 – 28260HomeoboxPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

SignaLinkiQ9UIU6.

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX4
Alternative name(s):
Sine oculis homeobox homolog 4
Gene namesi
Name:SIX4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:10890. SIX4.

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA35790.

Polymorphism and mutation databases

BioMutaiSIX4.
DMDMi254763333.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed1 Publication
Chaini2 – 781780Homeobox protein SIX4PRO_0000049303Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserine1 Publication
Modified residuei640 – 6401Phosphoserine1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ9UIU6.
PaxDbiQ9UIU6.
PRIDEiQ9UIU6.

PTM databases

PhosphoSiteiQ9UIU6.

Expressioni

Gene expression databases

BgeeiQ9UIU6.
CleanExiHS_SIX4.
ExpressionAtlasiQ9UIU6. baseline and differential.
GenevisibleiQ9UIU6. HS.

Organism-specific databases

HPAiHPA031794.

Interactioni

Subunit structurei

Interacts with EYA3; acts cooperatively with EYA3 to transactivate target genes through interaction and nuclear translocation of EYA3 protein.By similarity

Protein-protein interaction databases

BioGridi119730. 3 interactions.
IntActiQ9UIU6. 1 interaction.
MINTiMINT-7949397.
STRINGi9606.ENSP00000216513.

Structurei

3D structure databases

ProteinModelPortaliQ9UIU6.
SMRiQ9UIU6. Positions 106-279.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi36 – 10267Ala-richAdd
BLAST

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

eggNOGiNOG244874.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261651.
HOVERGENiHBG017802.
InParanoidiQ9UIU6.
KOiK15615.
OMAiQQGGNLD.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ9UIU6.
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.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9UIU6-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSSSPTGQI ASAADIKQEN GMESASEGQE AHREVAGGAA VGLSPPAPAP
60 70 80 90 100
FPLEPGDAAT AAARVSGEEG AVAAAAAGAA ADQVQLHSEL LGRHHHAAAA
110 120 130 140 150
AAQTPLAFSP DHVACVCEAL QQGGNLDRLA RFLWSLPQSD LLRGNESLLK
160 170 180 190 200
ARALVAFHQG IYPELYSILE SHSFESANHP LLQQLWYKAR YTEAERARGR
210 220 230 240 250
PLGAVDKYRL RRKFPLPRTI WDGEETVYCF KEKSRNALKE LYKQNRYPSP
260 270 280 290 300
AEKRHLAKIT GLSLTQVSNW FKNRRQRDRN PSETQSKSES DGNPSTEDES
310 320 330 340 350
SKGHEDLSPH PLSSSSDGIT NLSLSSHMEP VYMQQIGNAK ISLSSSGVLL
360 370 380 390 400
NGSLVPASTS PVFLNGNSFI QGPSGVILNG LNVGNTQAVA LNPPKMSSNI
410 420 430 440 450
VSNGISMTDI LGSTSQDVKE FKVLQSSANS ATTTSYSPSV PVSFPGLIPS
460 470 480 490 500
TEVKREGIQT VASQDGGSVV TFTTPVQINQ YGIVQIPNSG ANSQFLNGSI
510 520 530 540 550
GFSPLQLPPV SVAASQGNIS VSSSTSDGST FTSESTTVQQ GKVFLSSLAP
560 570 580 590 600
SAVVYTVPNT GQTIGSVKQE GLERSLVFSQ LMPVNQNAQV NANLSSENIS
610 620 630 640 650
GSGLHPLASS LVNVSPTHNF SLSPSTLLNP TELNRDIADS QPMSAPVASK
660 670 680 690 700
STVTSVSNTN YATLQNCSLI TGQDLLSVPM TQAALGEIVP TAEDQVGHPS
710 720 730 740 750
PAVHQDFVQE HRLVLQSVAN MKENFLSNSE SKATSSLMML DSKSKYVLDG
760 770 780
MVDTVCEDLE TDKKELAKLQ TVQLDEDMQD L
Length:781
Mass (Da):82,933
Last modified:July 28, 2009 - v2
Checksum:i0054080AFF7BFF7E
GO

Sequence cautioni

The sequence BAA86223.1 differs from that shown. Reason: Erroneous initiation. Curated
The sequence EAW80786.1 differs from that shown. Reason: Erroneous initiation. Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti23 – 231E → Q in a breast cancer sample; somatic mutation. 1 Publication
VAR_036441
Natural varianti446 – 4461G → D in a breast cancer sample; somatic mutation. 1 Publication
VAR_036442
Natural varianti605 – 6051H → P.2 Publications
Corresponds to variant rs3742636 [ dbSNP | Ensembl ].
VAR_058281
Natural varianti780 – 7801D → E in a breast cancer sample; somatic mutation. 1 Publication
VAR_036443

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB024687 Genomic DNA. Translation: BAA86223.1. Different initiation.
AL132777 Genomic DNA. No translation available.
CH471061 Genomic DNA. Translation: EAW80786.1. Different initiation.
BC098135 mRNA. Translation: AAH98135.1.
BC098282 mRNA. Translation: AAH98282.1.
BC099722 mRNA. Translation: AAH99722.1.
BC101934 mRNA. Translation: AAI01935.1.
CCDSiCCDS9749.2.
RefSeqiNP_059116.3. NM_017420.4.
UniGeneiHs.690393.
Hs.97849.

Genome annotation databases

EnsembliENST00000216513; ENSP00000216513; ENSG00000100625.
GeneIDi51804.
KEGGihsa:51804.
UCSCiuc001xfc.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB024687 Genomic DNA. Translation: BAA86223.1. Different initiation.
AL132777 Genomic DNA. No translation available.
CH471061 Genomic DNA. Translation: EAW80786.1. Different initiation.
BC098135 mRNA. Translation: AAH98135.1.
BC098282 mRNA. Translation: AAH98282.1.
BC099722 mRNA. Translation: AAH99722.1.
BC101934 mRNA. Translation: AAI01935.1.
CCDSiCCDS9749.2.
RefSeqiNP_059116.3. NM_017420.4.
UniGeneiHs.690393.
Hs.97849.

3D structure databases

ProteinModelPortaliQ9UIU6.
SMRiQ9UIU6. Positions 106-279.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119730. 3 interactions.
IntActiQ9UIU6. 1 interaction.
MINTiMINT-7949397.
STRINGi9606.ENSP00000216513.

PTM databases

PhosphoSiteiQ9UIU6.

Polymorphism and mutation databases

BioMutaiSIX4.
DMDMi254763333.

Proteomic databases

MaxQBiQ9UIU6.
PaxDbiQ9UIU6.
PRIDEiQ9UIU6.

Protocols and materials databases

DNASUi51804.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000216513; ENSP00000216513; ENSG00000100625.
GeneIDi51804.
KEGGihsa:51804.
UCSCiuc001xfc.3. human.

Organism-specific databases

CTDi51804.
GeneCardsiGC14M061176.
H-InvDBHIX0037650.
HGNCiHGNC:10890. SIX4.
HPAiHPA031794.
MIMi606342. gene.
neXtProtiNX_Q9UIU6.
PharmGKBiPA35790.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG244874.
GeneTreeiENSGT00540000070251.
HOGENOMiHOG000261651.
HOVERGENiHBG017802.
InParanoidiQ9UIU6.
KOiK15615.
OMAiQQGGNLD.
OrthoDBiEOG7C5M8Z.
PhylomeDBiQ9UIU6.
TreeFamiTF315545.

Enzyme and pathway databases

SignaLinkiQ9UIU6.

Miscellaneous databases

GeneWikiiSIX4.
GenomeRNAii51804.
NextBioi55920.
PROiQ9UIU6.
SOURCEiSearch...

Gene expression databases

BgeeiQ9UIU6.
CleanExiHS_SIX4.
ExpressionAtlasiQ9UIU6. baseline and differential.
GenevisibleiQ9UIU6. HS.

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. "Structure and chromosome mapping of the human SIX4 and murine Six4 genes."
    Ozaki H., Yamada K., Kobayashi M., Asakawa S., Minoshima S., Shimizu N., Kajitani M., Kawakami K.
    Cytogenet. Cell Genet. 87:108-112(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PRO-605.
  2. "The DNA sequence and analysis of human chromosome 14."
    Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H.
    , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J.
    Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "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] OF 22-781, VARIANT PRO-605.
  5. "Quantitative proteomic identification of six4 as the trex-binding factor in the muscle creatine kinase enhancer."
    Himeda C.L., Ranish J.A., Angello J.C., Maire P., Aebersold R., Hauschka S.D.
    Mol. Cell. Biol. 24:2132-2143(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY.
  6. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-640, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic kidney.
  7. "System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
    Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
    Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
  8. Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLN-23; ASP-446 AND GLU-780.

Entry informationi

Entry nameiSIX4_HUMAN
AccessioniPrimary (citable) accession number: Q9UIU6
Secondary accession number(s): Q4QQH5, Q4V764
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: July 28, 2009
Last modified: July 22, 2015
This is version 119 of the entry and version 2 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 14
    Human chromosome 14: 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

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.