NKX2-2 (NK2 homeobox 2)

2008-01-01   Stephen L Lessnick , Leah A Owen 

Department of Oncological Sciences, University of Utah School of Medicine, Center for Children, Huntsman Cancer Institute,, Division of Pediatric Hematology\\\/Oncology, University of Utah School of Medicine, Salt Lake City, Utah, USA

Identity

HGNC
LOCATION
20p11.22
LOCUSID
ALIAS
NKX2.2,NKX2B
FUSION GENES

DNA/RNA

Description

Start- 21,439,648 base pairs from p arm terminus; End- 21,442,699 base pairs from p arm terminus; Size- 3,051 bases; Orientation- minus strand

Proteins

Atlas Image
Schematic of NKX2-2 functional domains. The positions of the transcriptional repressor domain (TN), the homeodomain (HD), the NK2-specific domain (SD), and the transcriptional activation domain (TAD) are shown.

Description

273 amino acids; 30133 Da. NKX2-2 is a member of the NK2 family of homeobox transcription factors. It has known roles in the development of the CNS as well as pancreatic beta cell differentiation. In the CNS NKX2-2 is known to be activated by SHH signaling which is important for its initial role in ventral patterning. NKX2-2 expression has additionally been shown to be critical for the differentiation of oligodendrocytes, and in fact necessary for this process to occur. In both instances, NKX2-2 mediated transcripitional repression is both necessary and sufficient for these processes to occur. Regulation of NKX2-2 expression in the pancreas is less well understood. NKX2-2 knock-out mice die soon after birth from diabetic complications as a result of a lack of fully differentiated pancreatic beta cells. While NKX2-2 mediated transcriptional repression has been demonstrated to be necessary and sufficient for its role in ß-cell differentiation, it remains unclear whether NKX2-2 mediated transcriptional activation is important for NKX2-2 function in adult ß-cells.

Expression

V3 neural progenitors; oligodendrocyte precursor cells; precursor and adult pancreatic beta cells.

Localisation

Nuclear

Function

NKX2-2 is a transcription factor

Homology

NKX2-2 shares homology with other members of the NK2 family of transcription factors most notably in the TN transcriptional repression, DNA binding homeodomain, and specific domain regions.

Implicated in

Entity name
Ewings sarcoma
Prognosis
Roughly 50% survival at 5 years for Ewings sarcoma.
Cytogenetics
Ewings sarcoma cells harbor the characteristic translocation t(11;22)(q24;q12) in roughly 90% of cases.
Hybrid gene
t(11;22)(q24;q12) fuses the 5 region of the EWSR1 gene on chromosome 22 with the 3 portion of the FLI-1 gene on chromosome 11.
Fusion protein
The translocation fusion product is termed EWS/FLI.
Atlas Image
Schematic diagram of wild-type EWS, wild-type FLI, and the EWS/FLI fusion transcripts.
Oncogenesis
NKX2-2 is up-regulated in Ewings sarcoma by the EWS/FLI translocation protein product. NKX2.2 expression is necessary for the oncogenic phenotype of Ewings sarcoma cells.

Bibliography

Pubmed IDLast YearTitleAuthors
102171451999Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling.Briscoe J et al
15229031992Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.Delattre O et al
172021862007Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet.Doyle MJ et al
85163241993Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation.May WA et al
112903242001Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube.Muhr J et al
169691122006Identification of target genes in their native cellular context: an analysis of EWS/FLI in Ewing's sarcoma.Owen LA et al
166979602006Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma.Smith R et al
95841211998Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells.Sussel L et al
109442152000Intramolecular control of transcriptional activity by the NK2-specific domain in NK-2 homeodomain proteins.Watada H et al
156955212005Stage-specific expression of myelin basic protein in oligodendrocytes involves Nkx2.2-mediated repression that is relieved by the Sp1 transcription factor.Wei Q et al

Other Information

Locus ID:

NCBI: 4821
MIM: 604612
HGNC: 7835
Ensembl: ENSG00000125820

Variants:

dbSNP: 4821
ClinVar: 4821
TCGA: ENSG00000125820
COSMIC: NKX2-2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000125820ENST00000377142O95096

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Maturity onset diabetes of the youngKEGGko04950
Maturity onset diabetes of the youngKEGGhsa04950
Developmental BiologyREACTOMER-HSA-1266738
Regulation of beta-cell developmentREACTOMER-HSA-186712
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cellsREACTOMER-HSA-210746
Regulation of gene expression in beta cellsREACTOMER-HSA-210745

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
166979602006Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma.137
214817902011Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia.124
190112422009Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin.62
184146622008EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing's sarcoma.61
244119432014Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.37
216248112011Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells.28
249821382014Transcription factor induction of human oligodendrocyte progenitor fate and differentiation.25
168737042006Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects.19
224469432012NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.15
268471752016Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma.15

Citation

Stephen L Lessnick ; Leah A Owen

NKX2-2 (NK2 homeobox 2)

Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

Online version: http://atlasgeneticsoncology.org/gene/44177/nkx2-2