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Title 

A point mutation in the extracellular domain of KIT promotes tumorigenesis of mast cells via ligand-independent auto-dimerization

Authors 

Y AmagaiA MatsudaKyungsook JungK OidaH JangS IshizakaH MatsudaA Tanaka

Publisher 

Nature Publishing Group

Issue Date 

2015

Citation 

Scientific Reports, vol. 5, no. 0, pp. 9775-9775

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-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.

ISSN 

2045-2322

Link 

http://dx.doi.org/10.1038/srep09775

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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