NKX25_MOUSE
ID NKX25_MOUSE Reviewed; 318 AA.
AC P42582; P97335;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Homeobox protein Nkx-2.5;
DE AltName: Full=Cardiac-specific homeobox;
DE AltName: Full=Homeobox protein CSX;
DE AltName: Full=Homeobox protein NK-2 homolog E;
GN Name=Nkx2-5; Synonyms=Csx, Nkx-2.5, Nkx2e;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE.
RC TISSUE=Heart;
RX PubMed=7904557; DOI=10.1242/dev.119.2.419;
RA Lints T.J., Parsons L.M., Hartley L., Lyons I., Harvey R.P.;
RT "Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor
RT cells and their myogenic descendants.";
RL Development 119:419-431(1993).
RN [2]
RP ERRATUM OF PUBMED:7904557.
RX PubMed=7910553; DOI=10.1242/dev.119.3.969;
RA Lints T.J., Parsons L.M., Hartley L., Lyons I., Harvey R.P.;
RL Development 119:969-969(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/J;
RX PubMed=9778505; DOI=10.1242/dev.125.22.4461;
RA Searcy R.D., Vincent E.B., Liberatore C.M., Yutzey K.E.;
RT "A GATA-dependent nkx-2.5 regulatory element activates early cardiac gene
RT expression in transgenic mice.";
RL Development 125:4461-4470(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 17-318.
RX PubMed=7690144; DOI=10.1073/pnas.90.17.8145;
RA Komuro I., Izumo S.;
RT "Csx: a murine homeobox-containing gene specifically expressed in the
RT developing heart.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:8145-8149(1993).
RN [5]
RP INTERACTION WITH HIPK1 AND HIPK2.
RC STRAIN=BALB/cJ;
RX PubMed=9748262; DOI=10.1074/jbc.273.40.25875;
RA Kim Y.H., Choi C.Y., Lee S.-J., Conti M.A., Kim Y.;
RT "Homeodomain-interacting protein kinases, a novel family of co-repressors
RT for homeodomain transcription factors.";
RL J. Biol. Chem. 273:25875-25879(1998).
RN [6]
RP FUNCTION, AND INTERACTION WITH GATA4.
RX PubMed=9584153; DOI=10.1128/mcb.18.6.3120;
RA Lee Y., Shioi T., Kasahara H., Jobe S.M., Wiese R.J., Markham B.E.,
RA Izumo S.;
RT "The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically
RT associates with the zinc finger protein GATA4 and cooperatively activates
RT atrial natriuretic factor gene expression.";
RL Mol. Cell. Biol. 18:3120-3129(1998).
RN [7]
RP FUNCTION.
RX PubMed=12023302; DOI=10.1101/gad.222902;
RA Habets P.E., Moorman A.F., Clout D.E., van Roon M.A., Lingbeek M.,
RA van Lohuizen M., Campione M., Christoffels V.M.;
RT "Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the
RT atrioventricular canal: implications for cardiac chamber formation.";
RL Genes Dev. 16:1234-1246(2002).
RN [8]
RP INTERACTION WITH FBLIM1.
RX PubMed=14757752; DOI=10.1083/jcb.200309159;
RA Akazawa H., Kudoh S., Mochizuki N., Takekoshi N., Takano H., Nagai T.,
RA Komuro I.;
RT "A novel LIM protein Cal promotes cardiac differentiation by association
RT with CSX/NKX2-5.";
RL J. Cell Biol. 164:395-405(2004).
RN [9]
RP INTERACTION WITH JARID2.
RX PubMed=15542826; DOI=10.1128/mcb.24.23.10151-10160.2004;
RA Kim T.-G., Chen J., Sadoshima J., Lee Y.;
RT "Jumonji represses atrial natriuretic factor gene expression by inhibiting
RT transcriptional activities of cardiac transcription factors.";
RL Mol. Cell. Biol. 24:10151-10160(2004).
RN [10]
RP INTERACTION WITH TBX18.
RX PubMed=17584735; DOI=10.1074/jbc.m703724200;
RA Farin H.F., Bussen M., Schmidt M.K., Singh M.K., Schuster-Gossler K.,
RA Kispert A.;
RT "Transcriptional repression by the T-box proteins Tbx18 and Tbx15 depends
RT on Groucho corepressors.";
RL J. Biol. Chem. 282:25748-25759(2007).
RN [11]
RP FUNCTION, INTERACTION WITH NSD2, AND SUBCELLULAR LOCATION.
RX PubMed=19483677; DOI=10.1038/nature08086;
RA Nimura K., Ura K., Shiratori H., Ikawa M., Okabe M., Schwartz R.J.,
RA Kaneda Y.;
RT "A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-
RT Hirschhorn syndrome.";
RL Nature 460:287-291(2009).
RN [12]
RP FUNCTION.
RX PubMed=22560297; DOI=10.1016/j.devcel.2012.02.009;
RA Koss M., Bolze A., Brendolan A., Saggese M., Capellini T.D., Bojilova E.,
RA Boisson B., Prall O.W., Elliott D.A., Solloway M., Lenti E., Hidaka C.,
RA Chang C.P., Mahlaoui N., Harvey R.P., Casanova J.L., Selleri L.;
RT "Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15
RT module.";
RL Dev. Cell 22:913-926(2012).
CC -!- FUNCTION: Transcription factor required for the development of the
CC heart and the spleen (PubMed:9584153, PubMed:19483677,
CC PubMed:22560297). During heart development, acts as a transcriptional
CC activator of NPPA/ANF in cooperation with GATA4 (PubMed:9584153). May
CC cooperate with TBX2 to negatively modulate expression of NPPA/ANF in
CC the atrioventricular canal (PubMed:12023302). Binds to the core DNA
CC motif of NPPA promoter (PubMed:19483677). Together with PBX1, required
CC for spleen development through a mechanism that involves CDKN2B
CC repression (PubMed:22560297). {ECO:0000269|PubMed:12023302,
CC ECO:0000269|PubMed:19483677, ECO:0000269|PubMed:22560297,
CC ECO:0000269|PubMed:9584153}.
CC -!- SUBUNIT: Homodimer (via the homeobox); binds DNA as homodimer.
CC Interacts (via the homeobox) with TBX5 (via the T-box); this complex
CC binds DNA (By similarity). Interacts with HIPK1 and HIPK2, but not
CC HIPK3 (PubMed:9748262). Interacts with the C-terminal zinc finger of
CC GATA4 through its homeobox domain (PubMed:9584153). Also interacts with
CC JARID2 which represses its ability to activate transcription of ANF
CC (PubMed:15542826). Interacts with FBLIM1 (PubMed:14757752). Interacts
CC with TBX18 (PubMed:17584735). Interacts with histone methyltransferase
CC NSD2 (via HMG box) (PubMed:19483677). {ECO:0000250|UniProtKB:P52952,
CC ECO:0000269|PubMed:14757752, ECO:0000269|PubMed:15542826,
CC ECO:0000269|PubMed:17584735, ECO:0000269|PubMed:19483677,
CC ECO:0000269|PubMed:9584153, ECO:0000269|PubMed:9748262}.
CC -!- INTERACTION:
CC P42582; Q08369: Gata4; NbExp=4; IntAct=EBI-297021, EBI-297008;
CC P42582; Q62315: Jarid2; NbExp=3; IntAct=EBI-297021, EBI-493592;
CC P42582; Q8BVE8-2: Nsd2; NbExp=2; IntAct=EBI-297021, EBI-11518042;
CC P42582; O94983: CAMTA2; Xeno; NbExp=2; IntAct=EBI-297021, EBI-936534;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19483677}.
CC -!- TISSUE SPECIFICITY: Predominantly in the adult and embryonic heart, and
CC to a lesser extent in lingual muscle, spleen and stomach.
CC -!- DEVELOPMENTAL STAGE: Expression preceeds the onset of myogenic
CC differentiation, and continues in cardiomyocytes of embryonic, fetal
CC and adult hearts. It is also expressed laterally in future pharyngeal
CC endoderm which is believed to produce the heart inducer. After foregut
CC closure expression in endoderm is limited to the pharyngeal floor,
CC dorsal to the developing heart tube. The thyroid primordium a
CC derivative of the pharyngeal floor continues to express the protein
CC after its levels diminish in the rest of the pharynx.
CC -!- DOMAIN: The homeobox domain binds to double-stranded DNA.
CC {ECO:0000250|UniProtKB:P52952}.
CC -!- SIMILARITY: Belongs to the NK-2 homeobox family. {ECO:0000305}.
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DR EMBL; L20300; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AF091351; AAC97934.1; -; Genomic_DNA.
DR EMBL; X75415; CAA53169.1; -; mRNA.
DR CCDS; CCDS28556.1; -.
DR RefSeq; NP_032726.1; NM_008700.2.
DR RefSeq; XP_006523860.1; XM_006523797.3.
DR PDB; 5FLV; X-ray; 3.00 A; A/E/I/M=134-197.
DR PDBsum; 5FLV; -.
DR AlphaFoldDB; P42582; -.
DR SMR; P42582; -.
DR BioGRID; 201778; 12.
DR ComplexPortal; CPX-72; NKX2-5 homodimer complex.
DR CORUM; P42582; -.
DR DIP; DIP-33031N; -.
DR IntAct; P42582; 5.
DR STRING; 10090.ENSMUSP00000015723; -.
DR BindingDB; P42582; -.
DR ChEMBL; CHEMBL4105872; -.
DR iPTMnet; P42582; -.
DR PhosphoSitePlus; P42582; -.
DR PaxDb; P42582; -.
DR PRIDE; P42582; -.
DR ProteomicsDB; 293854; -.
DR Antibodypedia; 28950; 520 antibodies from 41 providers.
DR DNASU; 18091; -.
DR Ensembl; ENSMUST00000015723; ENSMUSP00000015723; ENSMUSG00000015579.
DR GeneID; 18091; -.
DR KEGG; mmu:18091; -.
DR UCSC; uc008beo.1; mouse.
DR CTD; 1482; -.
DR MGI; MGI:97350; Nkx2-5.
DR VEuPathDB; HostDB:ENSMUSG00000015579; -.
DR eggNOG; KOG0842; Eukaryota.
DR GeneTree; ENSGT00940000158996; -.
DR HOGENOM; CLU_049543_0_0_1; -.
DR InParanoid; P42582; -.
DR OMA; EQHQSGL; -.
DR OrthoDB; 1191455at2759; -.
DR PhylomeDB; P42582; -.
DR TreeFam; TF351204; -.
DR BioGRID-ORCS; 18091; 2 hits in 75 CRISPR screens.
DR ChiTaRS; Nkx2-5; mouse.
DR PRO; PR:P42582; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; P42582; protein.
DR Bgee; ENSMUSG00000015579; Expressed in cardiac atrium and 87 other tissues.
DR ExpressionAtlas; P42582; baseline and differential.
DR Genevisible; P42582; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0032993; C:protein-DNA complex; ISS:UniProtKB.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:MGI.
DR GO; GO:0005667; C:transcription regulator complex; IDA:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0001216; F:DNA-binding transcription activator activity; ISO:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:MGI.
DR GO; GO:0042826; F:histone deacetylase binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISO:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR GO; GO:0007512; P:adult heart development; IMP:MGI.
DR GO; GO:0006915; P:apoptotic process; IGI:MGI.
DR GO; GO:0003278; P:apoptotic process involved in heart morphogenesis; IMP:MGI.
DR GO; GO:0055014; P:atrial cardiac muscle cell development; TAS:BHF-UCL.
DR GO; GO:0003228; P:atrial cardiac muscle tissue development; IMP:BHF-UCL.
DR GO; GO:0060413; P:atrial septum morphogenesis; ISO:MGI.
DR GO; GO:0060928; P:atrioventricular node cell development; IMP:MGI.
DR GO; GO:0060929; P:atrioventricular node cell fate commitment; IMP:MGI.
DR GO; GO:0003162; P:atrioventricular node development; IMP:BHF-UCL.
DR GO; GO:0003166; P:bundle of His development; IGI:MGI.
DR GO; GO:0003161; P:cardiac conduction system development; IGI:MGI.
DR GO; GO:0055013; P:cardiac muscle cell development; IMP:BHF-UCL.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; IDA:UniProtKB.
DR GO; GO:0060038; P:cardiac muscle cell proliferation; IGI:MGI.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:MGI.
DR GO; GO:0048738; P:cardiac muscle tissue development; IMP:MGI.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR GO; GO:0003211; P:cardiac ventricle formation; IGI:MGI.
DR GO; GO:0003208; P:cardiac ventricle morphogenesis; IMP:MGI.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0008283; P:cell population proliferation; IGI:MGI.
DR GO; GO:0035050; P:embryonic heart tube development; IGI:MGI.
DR GO; GO:0060971; P:embryonic heart tube left/right pattern formation; IMP:MGI.
DR GO; GO:0007492; P:endoderm development; TAS:BHF-UCL.
DR GO; GO:1904019; P:epithelial cell apoptotic process; IGI:MGI.
DR GO; GO:0030855; P:epithelial cell differentiation; IGI:MGI.
DR GO; GO:0050673; P:epithelial cell proliferation; IGI:MGI.
DR GO; GO:0060047; P:heart contraction; IGI:MGI.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:0001947; P:heart looping; IMP:MGI.
DR GO; GO:0003007; P:heart morphogenesis; IMP:BHF-UCL.
DR GO; GO:0060347; P:heart trabecula formation; IMP:MGI.
DR GO; GO:0030097; P:hemopoiesis; IMP:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IMP:BHF-UCL.
DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; IGI:MGI.
DR GO; GO:0010832; P:negative regulation of myotube differentiation; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0003151; P:outflow tract morphogenesis; IMP:MGI.
DR GO; GO:0003148; P:outflow tract septum morphogenesis; ISO:MGI.
DR GO; GO:0060037; P:pharyngeal system development; IGI:MGI.
DR GO; GO:0051891; P:positive regulation of cardioblast differentiation; IMP:BHF-UCL.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IGI:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0045823; P:positive regulation of heart contraction; IMP:BHF-UCL.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISO:MGI.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0060261; P:positive regulation of transcription initiation from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0010735; P:positive regulation of transcription via serum response element binding; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0003342; P:proepicardium development; IMP:MGI.
DR GO; GO:0003350; P:pulmonary myocardium development; IMP:MGI.
DR GO; GO:0003168; P:Purkinje myocyte differentiation; IMP:MGI.
DR GO; GO:1903779; P:regulation of cardiac conduction; IMP:BHF-UCL.
DR GO; GO:0060043; P:regulation of cardiac muscle cell proliferation; IDA:MGI.
DR GO; GO:0055117; P:regulation of cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0003221; P:right ventricular cardiac muscle tissue morphogenesis; ISO:MGI.
DR GO; GO:0003285; P:septum secundum development; ISO:MGI.
DR GO; GO:0048536; P:spleen development; IGI:MGI.
DR GO; GO:0030878; P:thyroid gland development; IMP:BHF-UCL.
DR GO; GO:0043586; P:tongue development; TAS:BHF-UCL.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0001570; P:vasculogenesis; IMP:MGI.
DR GO; GO:0055015; P:ventricular cardiac muscle cell development; TAS:BHF-UCL.
DR GO; GO:0055005; P:ventricular cardiac myofibril assembly; IMP:MGI.
DR GO; GO:0060412; P:ventricular septum morphogenesis; ISO:MGI.
DR GO; GO:0003222; P:ventricular trabecula myocardium morphogenesis; IMP:MGI.
DR CDD; cd00086; homeodomain; 1.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR020479; Homeobox_metazoa.
DR InterPro; IPR033629; NKX-2.5.
DR PANTHER; PTHR24340:SF28; PTHR24340:SF28; 1.
DR Pfam; PF00046; Homeodomain; 1.
DR PRINTS; PR00024; HOMEOBOX.
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 3D-structure; Developmental protein; DNA-binding; Homeobox; Nucleus;
KW Reference proteome.
FT CHAIN 1..318
FT /note="Homeobox protein Nkx-2.5"
FT /id="PRO_0000048938"
FT DNA_BIND 137..196
FT /note="Homeobox"
FT /evidence="ECO:0000250|UniProtKB:P52952,
FT ECO:0000255|PROSITE-ProRule:PRU00108"
FT CONFLICT 62
FT /note="A -> R (in Ref. 4; L20300)"
FT /evidence="ECO:0000305"
FT CONFLICT 164..165
FT /note="AP -> PA (in Ref. 1)"
FT /evidence="ECO:0000305"
FT CONFLICT 234
FT /note="A -> T (in Ref. 3)"
FT /evidence="ECO:0000305"
FT CONFLICT 276..277
FT /note="QP -> HA (in Ref. 1)"
FT /evidence="ECO:0000305"
FT HELIX 146..156
FT /evidence="ECO:0007829|PDB:5FLV"
FT HELIX 164..173
FT /evidence="ECO:0007829|PDB:5FLV"
FT HELIX 178..188
FT /evidence="ECO:0007829|PDB:5FLV"
FT HELIX 192..196
FT /evidence="ECO:0007829|PDB:5FLV"
SQ SEQUENCE 318 AA; 34163 MW; 6A3E7859F46D4FA6 CRC64;
MFPSPALTPT PFSVKDILNL EQQQRSLASG DLSARLEATL APASCMLAAF KPEAYSGPEA
AASGLAELRA EMGPAPSPPK CSPAFPAAPT FYPGAYGDPD PAKDPRADKK ELCALQKAVE
LDKAETDGAE RPRARRRRKP RVLFSQAQVY ELERRFKQQR YLSAPERDQL ASVLKLTSTQ
VKIWFQNRRY KCKRQRQDQT LELLGPPPPP ARRIAVPVLV RDGKPCLGDP AAYAPAYGVG
LNAYGYNAYP YPSYGGAACS PGYSCAAYPA APPAAQPPAA SANSNFVNFG VGDLNTVQSP
GMPQGNSGVS TLHGIRAW
