Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Homeobox protein SIX4

Gene

Six4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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 from a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 site of the muscle-specific genes enhancer (PubMed:14966291). Acts cooperatively with EYA proteins to transactivate their target genes through interaction and nuclear translocation of EYA protein (PubMed:10490620). 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 (PubMed:15788460). Controls myoblast determination by transactivating MYF5, MYOD1 and MYF6 (PubMed:15788460, PubMed:17592144). Controls somitic differentiation in myocyte through MYOG transactivation (PubMed:15788460). 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 (PubMed:19962975, PubMed:21884692). 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 (PubMed:21884692). During muscle regeneration, negatively regulates differentiation of muscle satellite cells through down-regulation of MYOG expression (PubMed:20696153). During kidney development regulates the early stages of metanephros development and ureteric bud formation through regulation of GDNF, SALL1, PAX8 and PAX2 expression (PubMed:17300925). 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 (PubMed:23987514). 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 (PubMed:19027001). Promotes survival of sensory neurons during early trigeminal gangliogenesis (PubMed:16938278). In the developing dorsal root ganglia, up-regulates SLC12A2 transcription (PubMed:15955062). Regulates early thymus/parathyroid organogenesis through regulation of GCM2 and FOXN1 expression (PubMed:16530750). Forms gustatory papillae during development of the tongue (PubMed:21978088). Also plays a role during embryonic cranial skeleton morphogenesis (PubMed:20515681).1 Publication15 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi216 – 275HomeoboxPROSITE-ProRule annotationAdd BLAST60

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, DNA-binding
Biological processTranscription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Homeobox protein SIX4
Alternative name(s):
Sine oculis homeobox homolog 4
Skeletal muscle-specific ARE-binding protein AREC3
Gene namesi
Name:Six4
Synonyms:Arec3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:106034 Six4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice are viable and fertile; no gross morphological or histological abnormalities, or defects in hearing ability are detected in homozygous mice (PubMed:11313460). Double homozygous SIX1 and SIX4 knockout mice die soon after birth and show developmental defects in various organs (PubMed:15955062). Double homozygous SIX1 and SIX4 knockout mice causes severe defects in the trigeminal ganglia (PubMed:16938278). Double homozygous SIX1 and SIX4 knockout mice exhibit more severe kidney phenotypes than the SIX1 knockout mice. Double homozygous SIX1 and SIX4 knockout embryos show distinct morphological changes: fusion of the lateral lingual swellings is delayed, and the tongue is poorly developed. The primordia of fungiform papillae appears earlier, and the papillae rapidly increases in size; thus fusion of each papilla is evident. The circumvallate papillae show severe defects: invagination of the trenches starts asymmetrically, which results in longer and shorter trenches (PubMed:21978088). Double homozygous SIX1 and SIX4 knockout neonatal mice have a male-to-female sex-reversal phenotype in XY mutant gonads (PubMed:23987514). Double homozygous SIX1 and SIX4 knockout neonatal mice are characterized by severe craniofacial and rib defects, and general muscle hypoplasia (PubMed:15788460).6 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000493042 – 775Homeobox protein SIX4Add BLAST774

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei634PhosphoserineBy similarity1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiQ61321
PRIDEiQ61321

PTM databases

PhosphoSitePlusiQ61321

Expressioni

Tissue specificityi

Mainly expressed in the skeletal muscle (isoform 1 and isoform 2 but not isoform 3), and weakly in the heart. Also found in the retina and the distal tube of kidney. Expressed in skeletal muscle, nasal epithelium, cochlea, parathyroid and salivary gland (PubMed:11313460). Expressed in muscle satellite cells of normal and regenerating muscles (PubMed:20696153).2 Publications

Developmental stagei

At E8.5 expressed at the surface ectoderm outside the neural folds, somites, presomitic mesoderm. At E9.5 expressed at the nasal and otic placodes, cranial ganglia, branchial arches, somites (dermamyotomes and sclerotomes). At E10.5-E11.5 expressed at the nasal pits, otic vesicles, cranial ganglia, dorsal root ganglia, branchial arches, somites, myotomes, limb mesenchyme, notochord, mesonephros. At E12.5-E13.5 expressed in skeletal muscles, mesenchyme in limbs and digits, nasal epithelium, inner ear (PubMed:11313460). Weakly expressed in the nephrogenic cord on E9.5 and in the metanephric mesenchyme on E10.5 (PubMed:17300925). At E11.5 expressed in the epithelium of the lateral lingual swellings, and in the tongue epithelium, mesenchyme, and muscles at E12.5. In the fungiform papillae, expressed in the epithelium at E14-E16.5. In the circumvallate and foliate papillae, expression is observed in the trench wall of these papillae at E15.5-P0 (PubMed:21978088). At E11.5 mainly found in limbs, and somites, where is expressed in the dorsal root ganglion, myotomes, and ventral and dorsal dermomyotomal lips (PubMed:15788460). Expressed in a wide domain of the ectoderm in the presumptive olfactory region and in the thickened olfactory placode. Expressed in the peripheral precursors of the pit. At E12.5-E14.5, expression become progressively restricted to the apical and basal progenitors.Also expressed strongly in the preplacodal region at E8.0 and in the presumptive olfactory ectoderm at E9.0 (PubMed:19027001). At E10.5 expressed in the progenitors of the dermomyotome and in the myocytes (PubMed:19962975).6 Publications

Gene expression databases

BgeeiENSMUSG00000034460 Expressed in 241 organ(s), highest expression level in muscle of arm
ExpressionAtlasiQ61321 baseline and differential
GenevisibleiQ61321 MM

Interactioni

Subunit structurei

Interacts with EYA3; acts cooperatively with EYA3 to transactivate target genes through interaction and nuclear translocation of EYA3 protein (PubMed:12215533, PubMed:10490620).1 Publication2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Kdm6aO705462EBI-986524,EBI-1573712

Protein-protein interaction databases

BioGridi203262, 1 interactor
IntActiQ61321, 2 interactors
MINTiQ61321
STRINGi10090.ENSMUSP00000036150

Structurei

3D structure databases

ProteinModelPortaliQ61321
SMRiQ61321
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni582 – 775Transactivation domainAdd BLAST194

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi2 – 5Poly-Ser4
Compositional biasi58 – 61Poly-Ala4
Compositional biasi70 – 76Poly-Ala7
Compositional biasi92 – 95Poly-Ala4

Sequence similaritiesi

Belongs to the SIX/Sine oculis homeobox family.Curated

Keywords - Domaini

Homeobox

Phylogenomic databases

eggNOGiKOG0775 Eukaryota
ENOG410XRPB LUCA
GeneTreeiENSGT00540000070251
HOGENOMiHOG000261651
HOVERGENiHBG017802
InParanoidiQ61321
KOiK15615
OMAiHDIADSQ
OrthoDBiEOG091G083I
PhylomeDBiQ61321
TreeFamiTF315545

Family and domain databases

CDDicd00086 homeodomain, 1 hit
InterProiView protein in InterPro
IPR009057 Homeobox-like_sf
IPR017970 Homeobox_CS
IPR001356 Homeobox_dom
IPR031701 SIX1_SD
PfamiView protein in Pfam
PF00046 Homeobox, 1 hit
PF16878 SIX1_SD, 1 hit
SMARTiView protein in SMART
SM00389 HOX, 1 hit
SUPFAMiSSF46689 SSF46689, 1 hit
PROSITEiView protein in PROSITE
PS00027 HOMEOBOX_1, 1 hit
PS50071 HOMEOBOX_2, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

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

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket
Note: Additional isoforms seem to exist.

This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 1 (identifier: Q61321-1) [UniParc]FASTAAdd to basket
Also known as: SM

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MSSSSPTGQI ASAADIKQEN GMESASEGQE AHREVAGGAA AGLSPPAPAP
60 70 80 90 100
FPLEPGDAAA ASRVSREEGA AAAGAADQVQ LHSELLGRHQ HAAAAQPPLA
110 120 130 140 150
FSPDHVACVC EALQQGGNLD RLARFLWSLP QSDLLRGNES LLKARALVAF
160 170 180 190 200
HQGIYPELYS ILESHSFESA NHPLLQQLWY KARYTEAERA RGRPLGAVDK
210 220 230 240 250
YRLRRKFPLP RTIWDGEETV YCFKEKSRNA LKELYKQNRY PSPAEKRHLA
260 270 280 290 300
KITGLSLTQV SNWFKNRRQR DRNPSETQSK SESDGNPSTE DESSKGHEDL
310 320 330 340 350
SPHPLSGASD GVTNLSLSSH VEPVYMQQIG NAKISLSSSG VLLNGSLVPA
360 370 380 390 400
STSPVFLNGN SFIQGHNGVI LNGLNVGNTQ TVSLNPPKMS SNIVGNGIAM
410 420 430 440 450
TDILGSTSQD VKEFKVLQSS AVNSAATTSY SPSAPVSFPG LIPCTEVKRE
460 470 480 490 500
GIQTVASQDG GSVVTFTTPV QINQYGIVQI PNSGANGQFL NGSIGFSPLQ
510 520 530 540 550
LPPVSVAASQ GNLSVTPSTS DGSTFTSEPA TVQHGKLFLS PLTPSAVVYT
560 570 580 590 600
VPNSGQTVGA VKQEGLERGL VFSQLMPVNH SAQVNASLSS ENLSGSGLHP
610 620 630 640 650
LTSSLVNVSA AHGFSLTPPT LLNPTELNPD LAESQPVSAP VASKCTVSSV
660 670 680 690 700
SNTNYATLQN CSLIPGQDLL SGPMTQAALG EIVPTAEEQV SHASTAVHQD
710 720 730 740 750
FVREQRLVLQ SVPNIKENFL QNSENKATNN LMMLDSKSKY VLDGMVEAGC
760 770
EDLGTDKKEL AKLQTVQLDE DMQDL
Length:775
Mass (Da):82,263
Last modified:November 1, 1996 - v1
Checksum:iB06EBB64E04E5061
GO
Isoform 2 (identifier: Q61321-2) [UniParc]FASTAAdd to basket
Also known as: M18

The sequence of this isoform differs from the canonical sequence as follows:
     1-9: MSSSSPTGQ → QKAAIRLHYFALAAILM
     37-100: Missing.

Note: Incomplete sequence.
Show »
Length:719
Mass (Da):77,203
Checksum:iC977A113A9400399
GO
Isoform 3 (identifier: Q61321-3) [UniParc]FASTAAdd to basket
Also known as: M8

The sequence of this isoform differs from the canonical sequence as follows:
     1-9: MSSSSPTGQ → QKAAIRLHYFALAAILM
     188-319: ERARGRPLGA...DGVTNLSLSS → AGNSPCPAPS...CNKLEMLRYH
     320-775: Missing.

Note: Incomplete sequence.
Show »
Length:327
Mass (Da):35,213
Checksum:i6DA3154D4C09125A
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H3BL91H3BL91_MOUSE
Homeobox protein SIX4
Six4
518Annotation score:

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0022931 – 9MSSSSPTGQ → QKAAIRLHYFALAAILM in isoform 2 and isoform 3. Curated9
Alternative sequenceiVSP_00229437 – 100Missing in isoform 2. CuratedAdd BLAST64
Alternative sequenceiVSP_002295188 – 319ERARG…LSLSS → AGNSPCPAPSGTARRRCIVS RRSRATRSRSSTSRIATPRR LRSGTWPRSPASPSPRSATG SRTGGSVTETPPRPSPKANR MATPVPRMNPARDMRICLLI HFQAHLMASPTSASLATWSQ YICNKLEMLRYH in isoform 3. CuratedAdd BLAST132
Alternative sequenceiVSP_002296320 – 775Missing in isoform 3. CuratedAdd BLAST456

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D50416 mRNA Translation: BAA08915.1
D50417 mRNA Translation: BAA08916.1
D50418 mRNA Translation: BAA08917.1
BC137931 mRNA Translation: AAI37932.1
BC137934 mRNA Translation: AAI37935.1
CCDSiCCDS25974.1 [Q61321-1]
PIRiS63626
S63628
S63629
RefSeqiNP_035512.1, NM_011382.2 [Q61321-1]
UniGeneiMm.249575
Mm.465027

Genome annotation databases

EnsembliENSMUST00000043208; ENSMUSP00000036150; ENSMUSG00000034460 [Q61321-1]
GeneIDi20474
KEGGimmu:20474
UCSCiuc007nwb.1 mouse [Q61321-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D50416 mRNA Translation: BAA08915.1
D50417 mRNA Translation: BAA08916.1
D50418 mRNA Translation: BAA08917.1
BC137931 mRNA Translation: AAI37932.1
BC137934 mRNA Translation: AAI37935.1
CCDSiCCDS25974.1 [Q61321-1]
PIRiS63626
S63628
S63629
RefSeqiNP_035512.1, NM_011382.2 [Q61321-1]
UniGeneiMm.249575
Mm.465027

3D structure databases

ProteinModelPortaliQ61321
SMRiQ61321
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi203262, 1 interactor
IntActiQ61321, 2 interactors
MINTiQ61321
STRINGi10090.ENSMUSP00000036150

PTM databases

PhosphoSitePlusiQ61321

Proteomic databases

PaxDbiQ61321
PRIDEiQ61321

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000043208; ENSMUSP00000036150; ENSMUSG00000034460 [Q61321-1]
GeneIDi20474
KEGGimmu:20474
UCSCiuc007nwb.1 mouse [Q61321-1]

Organism-specific databases

CTDi51804
MGIiMGI:106034 Six4

Phylogenomic databases

eggNOGiKOG0775 Eukaryota
ENOG410XRPB LUCA
GeneTreeiENSGT00540000070251
HOGENOMiHOG000261651
HOVERGENiHBG017802
InParanoidiQ61321
KOiK15615
OMAiHDIADSQ
OrthoDBiEOG091G083I
PhylomeDBiQ61321
TreeFamiTF315545

Miscellaneous databases

PROiPR:Q61321
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000034460 Expressed in 241 organ(s), highest expression level in muscle of arm
ExpressionAtlasiQ61321 baseline and differential
GenevisibleiQ61321 MM

Family and domain databases

CDDicd00086 homeodomain, 1 hit
InterProiView protein in InterPro
IPR009057 Homeobox-like_sf
IPR017970 Homeobox_CS
IPR001356 Homeobox_dom
IPR031701 SIX1_SD
PfamiView protein in Pfam
PF00046 Homeobox, 1 hit
PF16878 SIX1_SD, 1 hit
SMARTiView protein in SMART
SM00389 HOX, 1 hit
SUPFAMiSSF46689 SSF46689, 1 hit
PROSITEiView protein in PROSITE
PS00027 HOMEOBOX_1, 1 hit
PS50071 HOMEOBOX_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSIX4_MOUSE
AccessioniPrimary (citable) accession number: Q61321
Secondary accession number(s): B2RQH3, Q61322, Q61323
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: November 7, 2018
This is version 159 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again