P42582 (NKX25_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Homeobox protein Nkx-2.5

Alternative name(s):
Cardiac-specific homeobox
Homeobox protein CSX
Homeobox protein NK-2 homolog E

Gene names

Name:	Nkx2-5
Synonyms:	Csx, Nkx-2.5, Nkx2e

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	318 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Implicated in commitment to and/or differentiation of the myocardial lineage. Acts as a transcriptional activator of ANF in cooperation with GATA4. Ref.6
Subunit structure	Interacts with HIPK1 and HIPK2, but not HIPK3. Interacts with the C-terminal zinc finger of GATA4 through its homeobox domain. Also interacts with JARID2 which represses its ability to activate transcription of ANF. Interacts with FBLIM1. Ref.5 Ref.6 Ref.7 Ref.8
Subcellular location	Nucleus Probable.
Tissue specificity	Predominantly in the adult and embryonic heart, and to a lesser extent in lingual muscle, spleen and stomach.
Developmental stage	Expression preceeds the onset of myogenic differentiation, and continues in cardiomyocytes of embryonic, fetal and adult hearts. It is also expressed laterally in future pharyngeal endoderm which is believed to produce the heart inducer. After foregut closure expression in endoderm is limited to the pharyngeal floor, dorsal to the developing heart tube. The thyroid primordium a derivative of the pharyngeal floor continues to express the protein after its levels diminish in the rest of the pharynx.
Sequence similarities	Belongs to the NK-2 homeobox family. Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
Cellular component	Nucleus
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Developmental protein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	BMP signaling pathway Inferred from direct assay PubMed 17360443. Source: MGI Purkinje myocyte differentiation Inferred from mutant phenotype PubMed 17250822. Source: MGI adult heart development Inferred from mutant phenotype PubMed 7628699. Source: MGI apoptotic process involved in heart morphogenesis Inferred from mutant phenotype PubMed 16510504. Source: MGI atrial cardiac muscle cell development Traceable author statement PubMed 9621431. Source: BHF-UCL atrial septum morphogenesis Inferred from electronic annotation. Source: Compara atrioventricular node cell development Inferred from mutant phenotype PubMed 19546853. Source: MGI atrioventricular node cell fate commitment Inferred from mutant phenotype PubMed 15109497. Source: MGI bundle of His development Inferred from genetic interaction PubMed 17604724. Source: MGI canonical Wnt receptor signaling pathway Inferred from direct assay PubMed 17360443. Source: MGI cardiac muscle cell proliferation Inferred from genetic interaction PubMed 17350578. Source: MGI cardiac muscle contraction Inferred from mutant phenotype PubMed 19546853. Source: MGI cardiac ventricle formation Inferred from genetic interaction PubMed 19035347. Source: MGI embryonic heart tube left/right pattern formation Inferred from mutant phenotype PubMed 9192865. Source: MGI endoderm development Traceable author statement PubMed 9621431. Source: BHF-UCL heart looping Inferred from mutant phenotype PubMed 16510504PubMed 7628699PubMed 9192865. Source: MGI heart trabecula formation Inferred from mutant phenotype PubMed 16510504. Source: MGI hemopoiesis Inferred from mutant phenotype PubMed 10021345. Source: MGI negative regulation of canonical Wnt receptor signaling pathway Inferred from direct assay PubMed 19479054. Source: BHF-UCL negative regulation of cardiac muscle cell apoptotic process Inferred from mutant phenotype PubMed 11889119. Source: BHF-UCL negative regulation of myotube differentiation Inferred from electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 12023302. Source: MGI outflow tract morphogenesis Inferred from mutant phenotype PubMed 16510504. Source: MGI outflow tract septum morphogenesis Inferred from electronic annotation. Source: Compara pharyngeal system development Inferred from genetic interaction PubMed 11390666. Source: MGI positive regulation of cardioblast differentiation Inferred from mutant phenotype PubMed 11889119. Source: BHF-UCL positive regulation of cell proliferation Inferred from genetic interaction PubMed 11390666. Source: MGI positive regulation of heart contraction Inferred from mutant phenotype PubMed 18689573. Source: BHF-UCL positive regulation of neuron differentiation Inferred from electronic annotation. Source: Compara positive regulation of sodium ion transport Inferred from mutant phenotype PubMed 18689573. Source: BHF-UCL positive regulation of transcription initiation from RNA polymerase II promoter Inferred from direct assay PubMed 8887666. Source: BHF-UCL positive regulation of transcription via serum response element binding Inferred from direct assay PubMed 8887666. Source: BHF-UCL positive regulation of voltage-gated calcium channel activity Inferred from mutant phenotype PubMed 18689573. Source: BHF-UCL proepicardium development Inferred from mutant phenotype PubMed 18722343. Source: MGI pulmonary myocardium development Inferred from mutant phenotype PubMed 17823370. Source: MGI regulation of cardiac muscle cell proliferation Inferred from direct assay PubMed 20713518. Source: MGI regulation of cardiac muscle contraction Inferred from mutant phenotype PubMed 18689573. Source: BHF-UCL right ventricular cardiac muscle tissue morphogenesis Inferred from electronic annotation. Source: Compara sarcomere organization Inferred from genetic interaction PubMed 20457810. Source: MGI septum secundum development Inferred from electronic annotation. Source: Compara spleen development Traceable author statement PubMed 9621431. Source: BHF-UCL thyroid gland development Inferred from mutant phenotype PubMed 16418214. Source: BHF-UCL tongue development Traceable author statement PubMed 9621431. Source: BHF-UCL vasculogenesis Inferred from mutant phenotype PubMed 10021345. Source: MGI ventricular cardiac myofibril development Inferred from mutant phenotype PubMed 19546853. Source: MGI ventricular septum morphogenesis Inferred from electronic annotation. Source: Compara ventricular trabecula myocardium morphogenesis Inferred from mutant phenotype PubMed 15109497. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay PubMed 15653675. Source: BHF-UCL transcription factor complex Inferred from direct assay PubMed 12023302. Source: MGI
Molecular_function	RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Inferred from direct assay PubMed 21379568. Source: MGI RNA polymerase II transcription cofactor activity Inferred from mutant phenotype PubMed 15363409. Source: BHF-UCL RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription Inferred from mutant phenotype PubMed 15363409. Source: BHF-UCL chromatin binding Inferred from direct assay PubMed 19483677PubMed 21379568. Source: MGI protein homodimerization activity Inferred from direct assay PubMed 11042197. Source: UniProtKB sequence-specific DNA binding Inferred from electronic annotation. Source: Compara serum response element binding Inferred from direct assay PubMed 8887666. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CAMTA2	O94983	2	EBI-297021,EBI-936534	From a different organism.
Gata4	Q08369	4	EBI-297021,EBI-297008
Jarid2	Q62315	3	EBI-297021,EBI-493592

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 318	318	Homeobox protein Nkx-2.5		PRO_0000048938
Regions
	DNA binding	137 – 196	60	Homeobox
	Compositional bias	41 – 107	67	Ala/Pro-rich
	Compositional bias	206 – 280	75	Ala/Pro-rich
Experimental info
	Sequence conflict	62	1	A → R in L20300. Ref.4
	Sequence conflict	164 – 165	2	AP → PA Ref.1
	Sequence conflict	234	1	A → T Ref.3
	Sequence conflict	276 – 277	2	QP → HA Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P42582 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: 6A3E7859F46D4FA6	FASTA	318	34,163
	10 20 30 40 50 60 MFPSPALTPT PFSVKDILNL EQQQRSLASG DLSARLEATL APASCMLAAF KPEAYSGPEA 70 80 90 100 110 120 AASGLAELRA EMGPAPSPPK CSPAFPAAPT FYPGAYGDPD PAKDPRADKK ELCALQKAVE 130 140 150 160 170 180 LDKAETDGAE RPRARRRRKP RVLFSQAQVY ELERRFKQQR YLSAPERDQL ASVLKLTSTQ 190 200 210 220 230 240 VKIWFQNRRY KCKRQRQDQT LELLGPPPPP ARRIAVPVLV RDGKPCLGDP AAYAPAYGVG 250 260 270 280 290 300 LNAYGYNAYP YPSYGGAACS PGYSCAAYPA APPAAQPPAA SANSNFVNFG VGDLNTVQSP 310 GMPQGNSGVS TLHGIRAW

References

[1]	"Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants." Lints T.J., Parsons L.M., Hartley L., Lyons I., Harvey R.P. Development 119:419-431(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE. Tissue: Heart.
[2]	Erratum Lints T.J., Parsons L.M., Hartley L., Lyons I., Harvey R.P. Development 119:969-969(1993) [PubMed] [Europe PMC] [Abstract]
[3]	"A GATA-dependent nkx-2.5 regulatory element activates early cardiac gene expression in transgenic mice." Searcy R.D., Vincent E.B., Liberatore C.M., Yutzey K.E. Development 125:4461-4470(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: 129/J.
[4]	"Csx: a murine homeobox-containing gene specifically expressed in the developing heart." Komuro I., Izumo S. Proc. Natl. Acad. Sci. U.S.A. 90:8145-8149(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 17-318.
[5]	"Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors." Kim Y.H., Choi C.Y., Lee S.-J., Conti M.A., Kim Y. J. Biol. Chem. 273:25875-25879(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HIPK1 AND HIPK2. Strain: BALB/c.
[6]	"The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression." Lee Y., Shioi T., Kasahara H., Jobe S.M., Wiese R.J., Markham B.E., Izumo S. Mol. Cell. Biol. 18:3120-3129(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH GATA4.
[7]	"A novel LIM protein Cal promotes cardiac differentiation by association with CSX/NKX2-5." Akazawa H., Kudoh S., Mochizuki N., Takekoshi N., Takano H., Nagai T., Komuro I. J. Cell Biol. 164:395-405(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FBLIM1.
[8]	"Jumonji represses atrial natriuretic factor gene expression by inhibiting transcriptional activities of cardiac transcription factors." Kim T.-G., Chen J., Sadoshima J., Lee Y. Mol. Cell. Biol. 24:10151-10160(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH JARID2.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L20300 mRNA. No translation available. AF091351 Genomic DNA. Translation: AAC97934.1. X75415 mRNA. Translation: CAA53169.1.
IPI	IPI00117496.
RefSeq	NP_032726.1. NM_008700.2.
UniGene	Mm.41974.
3D structure databases
ProteinModelPortal	P42582.
SMR	P42582. Positions 137-191.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-33031N.
IntAct	P42582. 4 interactions.
PTM databases
PhosphoSite	P42582.
Proteomic databases
PRIDE	P42582.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000015723; ENSMUSP00000015723; ENSMUSG00000015579.
GeneID	18091.
KEGG	mmu:18091.
Organism-specific databases
CTD	1482.
MGI	MGI:97350. Nkx2-5.
Phylogenomic databases
eggNOG	NOG310976.
HOGENOM	HOG000231923.
HOVERGEN	HBG006689.
InParanoid	P42582.
KO	K09345.
OMA	YGGAACS.
OrthoDB	EOG4K0QP6.
Gene expression databases
ArrayExpress	P42582.
Bgee	P42582.
Genevestigator	P42582.
GermOnline	ENSMUSG00000015579. Mus musculus.
Family and domain databases
Gene3D	1.10.10.60. 1 hit.
InterPro	IPR017970. Homeobox_CS. IPR020479. Homeobox_metazoa. IPR001356. Homeodomain. IPR009057. Homeodomain-like. [Graphical view]
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
PRINTS	PR00024. HOMEOBOX.
SMART	SM00389. HOX. 1 hit. [Graphical view]
SUPFAM	SSF46689. Homeodomain_like. 1 hit.
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	NKX2-5. mouse.
NextBio	293235.
SOURCE	Search...

Entry information

Entry name

NKX25_MOUSE

Accession

Primary (citable) accession number: P42582
Secondary accession number(s): P97335

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	April 3, 2013
This is version 110 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program