SIX4_HUMAN
ID SIX4_HUMAN Reviewed; 781 AA.
AC Q9UIU6; Q4QQH5; Q4V764;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 28-JUL-2009, sequence version 2.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Homeobox protein SIX4;
DE AltName: Full=Sine oculis homeobox homolog 4;
GN Name=SIX4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PRO-605.
RX PubMed=10640827; DOI=10.1159/000015407;
RA Ozaki H., Yamada K., Kobayashi M., Asakawa S., Minoshima S., Shimizu N.,
RA Kajitani M., Kawakami K.;
RT "Structure and chromosome mapping of the human SIX4 and murine Six4
RT genes.";
RL Cytogenet. Cell Genet. 87:108-112(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 22-781, AND VARIANT PRO-605.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=14966291; DOI=10.1128/mcb.24.5.2132-2143.2004;
RA Himeda C.L., Ranish J.A., Angello J.C., Maire P., Aebersold R.,
RA Hauschka S.D.;
RT "Quantitative proteomic identification of six4 as the trex-binding factor
RT in the muscle creatine kinase enhancer.";
RL Mol. Cell. Biol. 24:2132-2143(2004).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-640, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [8]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-23; ASP-446 AND GLU-780.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Transcriptional regulator which can act as both a
CC transcriptional repressor and activator by binding a DNA sequence on
CC these target genes and is involved in processes like cell
CC differentiation, cell migration and cell survival. Transactivates gene
CC expression by binding a 5'-[CAT]A[CT][CT][CTG]GA[GAT]-3' motif present
CC in the Trex site and a 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3
CC site of the muscle-specific genes enhancer. Acts cooperatively with EYA
CC proteins to transactivate their target genes through interaction and
CC nuclear translocation of EYA protein. Acts synergistically with SIX1 to
CC regulate target genes involved in formation of various organs,
CC including muscle, kidney, gonad, ganglia, olfactory epithelium and
CC cranial skeleton. Plays a role in several important steps of muscle
CC development. Controls the genesis of hypaxial myogenic progenitors in
CC the dermomyotome by transactivating PAX3 and the delamination and
CC migration of the hypaxial precursors from the ventral lip to the limb
CC buds through the transactivation of PAX3, MET and LBX1. Controls
CC myoblast determination by transactivating MYF5, MYOD1 and MYF6.
CC Controls somitic differentiation in myocyte through MYOG
CC transactivation. Plays a role in synaptogenesis and sarcomere
CC organization by participating in myofiber specialization during
CC embryogenesis by activating fast muscle program in the primary myotome
CC resulting in an up-regulation of fast muscle genes, including ATP2A1,
CC MYL1 and TNNT3. Simultaneously, is also able to activate inhibitors of
CC slow muscle genes, such as SOX6, HRASLS, and HDAC4, thereby restricting
CC the activation of the slow muscle genes. During muscle regeneration,
CC negatively regulates differentiation of muscle satellite cells through
CC down-regulation of MYOG expression. During kidney development regulates
CC the early stages of metanephros development and ureteric bud formation
CC through regulation of GDNF, SALL1, PAX8 and PAX2 expression. Plays a
CC role in gonad development by regulating both testis determination and
CC size determination. In gonadal sex determination, transactivates ZFPM2
CC by binding a MEF3 consensus sequence, resulting in SRY up-regulation.
CC In gonadal size determination, transactivates NR5A1 by binding a MEF3
CC consensus sequence resulting in gonadal precursor cell formation
CC regulation. During olfactory development mediates the specification and
CC patterning of olfactory placode through fibroblast growth factor and
CC BMP4 signaling pathways and also regulates epithelial cell
CC proliferation during placode formation. Promotes survival of sensory
CC neurons during early trigeminal gangliogenesis. In the developing
CC dorsal root ganglia, up-regulates SLC12A2 transcription. Regulates
CC early thymus/parathyroid organogenesis through regulation of GCM2 and
CC FOXN1 expression. Forms gustatory papillae during development of the
CC tongue. Also plays a role during embryonic cranial skeleton
CC morphogenesis. {ECO:0000250|UniProtKB:Q61321}.
CC -!- SUBUNIT: Interacts with EYA3; acts cooperatively with EYA3 to
CC transactivate target genes through interaction and nuclear
CC translocation of EYA3 protein. {ECO:0000250|UniProtKB:Q61321}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q61321}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q61321}.
CC -!- SIMILARITY: Belongs to the SIX/Sine oculis homeobox family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA86223.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=EAW80786.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AB024687; BAA86223.1; ALT_INIT; Genomic_DNA.
DR EMBL; AL132777; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW80786.1; ALT_INIT; Genomic_DNA.
DR EMBL; BC098135; AAH98135.1; -; mRNA.
DR EMBL; BC098282; AAH98282.1; -; mRNA.
DR EMBL; BC099722; AAH99722.1; -; mRNA.
DR EMBL; BC101934; AAI01935.1; -; mRNA.
DR CCDS; CCDS9749.2; -.
DR RefSeq; NP_059116.3; NM_017420.4.
DR AlphaFoldDB; Q9UIU6; -.
DR SMR; Q9UIU6; -.
DR BioGRID; 119730; 40.
DR IntAct; Q9UIU6; 26.
DR MINT; Q9UIU6; -.
DR STRING; 9606.ENSP00000216513; -.
DR GlyGen; Q9UIU6; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9UIU6; -.
DR PhosphoSitePlus; Q9UIU6; -.
DR BioMuta; SIX4; -.
DR DMDM; 254763333; -.
DR EPD; Q9UIU6; -.
DR jPOST; Q9UIU6; -.
DR MassIVE; Q9UIU6; -.
DR MaxQB; Q9UIU6; -.
DR PaxDb; Q9UIU6; -.
DR PeptideAtlas; Q9UIU6; -.
DR PRIDE; Q9UIU6; -.
DR ProteomicsDB; 84568; -.
DR Antibodypedia; 24389; 181 antibodies from 27 providers.
DR DNASU; 51804; -.
DR Ensembl; ENST00000216513.5; ENSP00000216513.4; ENSG00000100625.9.
DR GeneID; 51804; -.
DR KEGG; hsa:51804; -.
DR MANE-Select; ENST00000216513.5; ENSP00000216513.4; NM_017420.5; NP_059116.3.
DR UCSC; uc001xfc.4; human.
DR CTD; 51804; -.
DR DisGeNET; 51804; -.
DR GeneCards; SIX4; -.
DR HGNC; HGNC:10890; SIX4.
DR HPA; ENSG00000100625; Group enriched (choroid plexus, parathyroid gland, salivary gland, skeletal muscle, tongue).
DR MIM; 606342; gene.
DR neXtProt; NX_Q9UIU6; -.
DR OpenTargets; ENSG00000100625; -.
DR PharmGKB; PA35790; -.
DR VEuPathDB; HostDB:ENSG00000100625; -.
DR eggNOG; KOG0775; Eukaryota.
DR GeneTree; ENSGT00940000160820; -.
DR HOGENOM; CLU_020633_2_0_1; -.
DR InParanoid; Q9UIU6; -.
DR OMA; MCGEMEA; -.
DR OrthoDB; 1061244at2759; -.
DR PhylomeDB; Q9UIU6; -.
DR TreeFam; TF315545; -.
DR PathwayCommons; Q9UIU6; -.
DR SignaLink; Q9UIU6; -.
DR SIGNOR; Q9UIU6; -.
DR BioGRID-ORCS; 51804; 15 hits in 1105 CRISPR screens.
DR ChiTaRS; SIX4; human.
DR GeneWiki; SIX4; -.
DR GenomeRNAi; 51804; -.
DR Pharos; Q9UIU6; Tbio.
DR PRO; PR:Q9UIU6; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q9UIU6; protein.
DR Bgee; ENSG00000100625; Expressed in bronchial epithelial cell and 159 other tissues.
DR ExpressionAtlas; Q9UIU6; baseline and differential.
DR Genevisible; Q9UIU6; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; IBA:GO_Central.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Ensembl.
DR GO; GO:0061197; P:fungiform papilla morphogenesis; ISS:UniProtKB.
DR GO; GO:0048699; P:generation of neurons; ISS:UniProtKB.
DR GO; GO:0042472; P:inner ear morphogenesis; IEA:Ensembl.
DR GO; GO:0008584; P:male gonad development; ISS:UniProtKB.
DR GO; GO:0030238; P:male sex determination; ISS:UniProtKB.
DR GO; GO:0046661; P:male sex differentiation; ISS:UniProtKB.
DR GO; GO:0072075; P:metanephric mesenchyme development; ISS:UniProtKB.
DR GO; GO:0051451; P:myoblast migration; IEA:Ensembl.
DR GO; GO:0061055; P:myotome development; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:1902725; P:negative regulation of satellite cell differentiation; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0030910; P:olfactory placode formation; ISS:UniProtKB.
DR GO; GO:0060037; P:pharyngeal system development; ISS:UniProtKB.
DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0072107; P:positive regulation of ureteric bud formation; ISS:UniProtKB.
DR GO; GO:0034504; P:protein localization to nucleus; ISS:UniProtKB.
DR GO; GO:0072095; P:regulation of branch elongation involved in ureteric bud branching; ISS:UniProtKB.
DR GO; GO:0050678; P:regulation of epithelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0032880; P:regulation of protein localization; IEA:Ensembl.
DR GO; GO:0008582; P:regulation of synaptic assembly at neuromuscular junction; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0045214; P:sarcomere organization; ISS:UniProtKB.
DR GO; GO:0098528; P:skeletal muscle fiber differentiation; ISS:UniProtKB.
DR GO; GO:0007519; P:skeletal muscle tissue development; ISS:UniProtKB.
DR GO; GO:0048538; P:thymus development; IEA:Ensembl.
DR GO; GO:0043586; P:tongue development; ISS:UniProtKB.
DR GO; GO:0061551; P:trigeminal ganglion development; ISS:UniProtKB.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR031701; SIX1_SD.
DR Pfam; PF00046; Homeodomain; 1.
DR Pfam; PF16878; SIX1_SD; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Developmental protein; DNA-binding; Homeobox;
KW Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:21406692"
FT CHAIN 2..781
FT /note="Homeobox protein SIX4"
FT /id="PRO_0000049303"
FT DNA_BIND 223..282
FT /note="Homeobox"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT REGION 1..55
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 270..321
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 292..306
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 307..321
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 640
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17525332"
FT VARIANT 23
FT /note="E -> Q (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036441"
FT VARIANT 446
FT /note="G -> D (in a breast cancer sample; somatic mutation;
FT dbSNP:rs750515774)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036442"
FT VARIANT 605
FT /note="H -> P (in dbSNP:rs3742636)"
FT /evidence="ECO:0000269|PubMed:10640827,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_058281"
FT VARIANT 780
FT /note="D -> E (in a breast cancer sample; somatic mutation;
FT dbSNP:rs1264571513)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036443"
SQ SEQUENCE 781 AA; 82933 MW; 0054080AFF7BFF7E CRC64;
MSSSSPTGQI ASAADIKQEN GMESASEGQE AHREVAGGAA VGLSPPAPAP FPLEPGDAAT
AAARVSGEEG AVAAAAAGAA ADQVQLHSEL LGRHHHAAAA AAQTPLAFSP DHVACVCEAL
QQGGNLDRLA RFLWSLPQSD LLRGNESLLK ARALVAFHQG IYPELYSILE SHSFESANHP
LLQQLWYKAR YTEAERARGR PLGAVDKYRL RRKFPLPRTI WDGEETVYCF KEKSRNALKE
LYKQNRYPSP AEKRHLAKIT GLSLTQVSNW FKNRRQRDRN PSETQSKSES DGNPSTEDES
SKGHEDLSPH PLSSSSDGIT NLSLSSHMEP VYMQQIGNAK ISLSSSGVLL NGSLVPASTS
PVFLNGNSFI QGPSGVILNG LNVGNTQAVA LNPPKMSSNI VSNGISMTDI LGSTSQDVKE
FKVLQSSANS ATTTSYSPSV PVSFPGLIPS TEVKREGIQT VASQDGGSVV TFTTPVQINQ
YGIVQIPNSG ANSQFLNGSI GFSPLQLPPV SVAASQGNIS VSSSTSDGST FTSESTTVQQ
GKVFLSSLAP SAVVYTVPNT GQTIGSVKQE GLERSLVFSQ LMPVNQNAQV NANLSSENIS
GSGLHPLASS LVNVSPTHNF SLSPSTLLNP TELNRDIADS QPMSAPVASK STVTSVSNTN
YATLQNCSLI TGQDLLSVPM TQAALGEIVP TAEDQVGHPS PAVHQDFVQE HRLVLQSVAN
MKENFLSNSE SKATSSLMML DSKSKYVLDG MVDTVCEDLE TDKKELAKLQ TVQLDEDMQD
L
