Homeobox protein Nkx-2.5

Function

Transcription factor required for the development of the heart and the spleen. During heart development, acts as a transcriptional activator of NPPA/ANF in cooperation with GATA4 (By similarity). May cooperate with TBX2 to negatively modulate expression of NPPA/ANF in the atrioventricular canal (By similarity). Binds to the core DNA motif of NPPA promoter. Together with PBX1, required for spleen development through a mechanism that involves CDKN2B repression. Positively regulates transcription of genes such as COL3A1 and MMP2, resulting in increased pulmonary endothelial fibrosis in response to hypoxia.

Classification

Family (Pfam)

PF00046 Homeodomain

InterPro

HD, HD_metazoa, Homeobox_CS, Homeobox_NK-like, Homeodomain-like_sf

Functional cluster

Homeobox & Zinc-Finger Transcription Factors

Experimental structures · PDB · 4

• 3RKQ X-ray 1.70A
• 4S0H X-ray 2.82A
• 6WC2 X-ray 2.10A
• 6WC5 X-ray 2.90A

A predicted model is available from AlphaFold.

Gene Ontology · 63

• GO:0000785 chromatin
• GO:0005737 cytoplasm
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0032991 protein-containing complex
• GO:0032993 protein-DNA complex
• GO:0090575 RNA polymerase II transcription regulator complex
• GO:0005667 transcription regulator complex
• GO:0003682 chromatin binding
• GO:0003677 DNA binding
• GO:0001216 DNA-binding transcription activator activity
• GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
• GO:0003700 DNA-binding transcription factor activity
• GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
• GO:0042803 protein homodimerization activity
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
• GO:0043565 sequence-specific DNA binding
• GO:1990837 sequence-specific double-stranded DNA binding
• GO:0000976 transcription cis-regulatory region binding
• GO:0007512 adult heart development
• GO:0003180 aortic valve morphogenesis
• GO:0055014 atrial cardiac muscle cell development
• GO:0003228 atrial cardiac muscle tissue development
• GO:0060413 atrial septum morphogenesis
• GO:0003162 atrioventricular node development
• GO:0003166 bundle of His development
• GO:0003161 cardiac conduction system development
• GO:0055013 cardiac muscle cell development
• GO:0055008 cardiac muscle tissue morphogenesis
• GO:0030154 cell differentiation
• GO:0035050 embryonic heart tube development
• GO:0001947 heart looping
• GO:0003007 heart morphogenesis
• GO:0030097 hemopoiesis
• GO:0043066 negative regulation of apoptotic process
• GO:0090090 negative regulation of canonical Wnt signaling pathway
• GO:0010667 negative regulation of cardiac muscle cell apoptotic process
• GO:0045892 negative regulation of DNA-templated transcription
• GO:0010832 negative regulation of myotube differentiation
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0003148 outflow tract septum morphogenesis
• GO:0060037 pharyngeal system development
• GO:0051891 positive regulation of cardioblast differentiation
• GO:0008284 positive regulation of cell population proliferation
• GO:0045893 positive regulation of DNA-templated transcription
• GO:0010628 positive regulation of gene expression
• GO:0045823 positive regulation of heart contraction
• GO:0045666 positive regulation of neuron differentiation
• GO:0010765 positive regulation of sodium ion transport
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0060261 positive regulation of transcription initiation by RNA polymerase II
• GO:1903779 regulation of cardiac conduction
• GO:0055117 regulation of cardiac muscle contraction
• GO:0006355 regulation of DNA-templated transcription
• GO:0006357 regulation of transcription by RNA polymerase II
• GO:0003221 right ventricular cardiac muscle tissue morphogenesis
• GO:0003285 septum secundum development
• GO:0048536 spleen development
• GO:0030878 thyroid gland development
• GO:0001570 vasculogenesis
• GO:0055015 ventricular cardiac muscle cell development
• GO:0060412 ventricular septum morphogenesis

Disease associations

• atrial septal defect 7 MONDO:0007173
• tetralogy of fallot MONDO:0008542
• conotruncal heart malformations MONDO:0016581
• hypothyroidism, congenital, nongoitrous, 5 MONDO:0009154
• ventricular septal defect 3 MONDO:0013749
• hypoplastic left heart syndrome 2 MONDO:0013752

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Homeobox protein Nkx-2.5 0.99
• Homeobox protein Nkx-2.5 0.99
• Homeobox protein Hox-D1 0.89
• Homeobox protein Hox-A10 0.88
• Homeobox protein Hox-A9 0.88
• Iroquois-class homeodomain protein IRX-4 0.87
• Homeobox protein Hox-D1 0.87
• Homeobox protein Hox-D11 0.87
• Paired mesoderm homeobox protein 2A 0.87
• Homeobox protein MSX-1 0.86
• Homeobox protein MSX-1 0.85
• Homeobox protein CDX-1 0.85

Co-cited proteins · studied together in the literature

• Transcription factor GATA-4 2 shared papers
• T-box transcription factor TBX5 1 shared papers
• T-box transcription factor TBX1 1 shared papers
• Insulin gene enhancer protein ISL-1 1 shared papers
• Protein jagged-1 1 shared papers
• T-box transcription factor TBX2 1 shared papers
• Homeobox protein Nkx-2.5 1 shared papers
• Pre-B-cell leukemia transcription factor 1 1 shared papers
• Enhancer of filamentation 1 1 shared papers
• SMAD family member 3 1 shared papers

Literature · 20 cited papers

• NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci. Transl. Med. · 2018
• Intermolecular interactions of cardiac transcription factors NKX2.5 and TBX5. Biochemistry · 2016
• Crystal structure of the human NKX2.5 homeodomain in complex with DNA target. Biochemistry · 2012
• Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev. Cell · 2012
• Formation of the building plan of the human heart: morphogenesis, growth, and differentiation. Circulation · 2011
• A novel NKX2-5 mutation in familial ventricular septal defect. Int. J. Mol. Med. · 2011
• Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease. Genetica · 2010
• Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot. J. Med. Genet. · 2010
• The effect of p.Arg25Cys alteration in NKX2-5 on conotruncal heart anomalies: mutation or polymorphism? Pediatr. Cardiol. · 2008
• Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J. Clin. Endocrinol. Metab. · 2006
• Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. Am. J. Med. Genet. A · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• … and 8 more in the literature graph