| RRC ID |
35155
|
| 著者 |
Amagai Y, Matsuda A, Jung K, Oida K, Jang H, Ishizaka S, Matsuda H, Tanaka A.
|
| タイトル |
A point mutation in the extracellular domain of KIT promotes tumorigenesis of mast cells via ligand-independent auto-dimerization.
|
| ジャーナル |
Sci Rep
|
| Abstract |
Mutations in the juxtamembrane and tyrosine kinase domains of the KIT receptor have been implicated in several cancers and are known to promote tumorigenesis. However, the pathophysiological manifestations of mutations in the extracellular domain remain unknown. In this study, we examined the impact of a mutation in the extracellular domain of KIT on mast cell tumorigenesis. A KIT mutant with an Asn508Ile variation (N508I) in the extracellular domain derived from a canine mast cell tumor was introduced into IC-2 cells. The IC-2(N508I) cells proliferated in a cytokine-independent manner and showed KIT auto-phosphorylation. Subcutaneous injection of IC-2(N508I) cells into the dorsal area of immunodeficient BALB/c-nu/nu mice resulted in the formation of solid tumors, but tumor progression was abrogated by treatment with a tyrosine kinase inhibitor (STI571). In addition, the N508I mutant KIT protein dimerized in the absence of the natural ligand, stem cell factor. Structure modeling indicates that the increased hydrophobicity of the mutant led to the stabilization of KIT dimers. These results suggest that this extracellular domain mutation confers a ligand-independent tumorigenic phenotype to mast cells by KIT auto-dimerization that is STI571-sensitive. This is the first report demonstrating the tumorigenic potential of a mutation in the extracellular domain of KIT.
|
| 巻・号 |
5
|
| ページ |
9775
|
| 公開日 |
2015-5-12
|
| DOI |
10.1038/srep09775
|
| PII |
srep09775
|
| PMID |
25965812
|
| PMC |
PMC4428273
|
| MeSH |
Amino Acid Substitution
Animals
Cell Line
Cell Transformation, Neoplastic* / genetics
Cell Transformation, Neoplastic* / metabolism
Cell Transformation, Neoplastic* / pathology
Dogs
Mast Cells* / metabolism
Mast Cells* / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Phosphorylation / genetics
Point Mutation*
Protein Multimerization / genetics*
Protein Structure, Tertiary
Proto-Oncogene Proteins c-kit* / genetics
Proto-Oncogene Proteins c-kit* / metabolism
Stem Cell Factor / genetics
Stem Cell Factor / metabolism*
|
| IF |
3.998
|
| 引用数 |
5
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| 遺伝子材料 |
pMXs-KITWT-IRES-GFP (RDB13470)
pMXs-KITN508I-IRES-GFP (RDB13471). |
