title: A point mutation in the extracellular domain of KIT promotes tumorigenesis of mast cells via ligand-independent auto-dimerization.
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.
authors.affiliation: 1] Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan [2] Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Amagai
authors.affiliation: Laboratories of Veterinary Molecular Pathology and Therapeutics.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: 1] Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan [2] Eco-friendly Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeonbuk, Korea.
authors.forename: Kyungsook
authors.initials: K
authors.lastname: Jung
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Oida
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Hyosun
authors.initials: H
authors.lastname: Jang
authors.affiliation: Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Ishizaka
authors.affiliation: 1] Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan [2] Laboratories of Veterinary Molecular Pathology and Therapeutics.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: 1] Cooperative Major in Advanced Health Science, Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan [2] Comparative Animal Medicine, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000235:genetics; D017354:Point Mutation; D055503:Protein Multimerization / Q000235:genetics*; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit