A point mutation in the extracellular domain of KIT promotes tumorigenesis of mast cells via ligand-independent auto-dimerization.
A point mutation in the extracellular domain of KIT promotes tumorigenesis of mast cells via ligand-independent auto-dimerization.
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试剂盒细胞外结构域中的点突变可通过非配体无依赖性自动化促进肥大细胞的肿瘤发生。
DOI：
10.1038/srep09775
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发表时间：
2015-05-12
影响因子：
4.6
通讯作者：
Tanaka A
中科院分区：
文献类型：
--
作者：
Amagai Y;Matsuda A;Jung K;Oida K;Jang H;Ishizaka S;Matsuda H;Tanaka A
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-2N508I cells proliferated in a cytokine-independent manner and showed KIT auto-phosphorylation. Subcutaneous injection of IC-2N508I 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.
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