title: A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors.
abstract: OBJECTIVE
  The c-kit gene encodes a receptor tyrosine kinase (KIT). Recently, we found gain-of-function mutations of the c-kit gene in gastrointestinal stromal tumors (GISTs). All mutations were confined within the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain, but one GIST showed a novel deletion-type mutation at codon 579 (Asp) in the juxtamembrane domain. The aim of this study was to clarify whether the mutation is activating.
  
  
  METHODS
  Mutant c-kit cDNA was transfected into an interleukin 3 (IL-3)-dependent Ba/F3 murine lymphoid cell line, and the magnitude of autophosphorylation of the mutant KIT was examined with or without stem cell factor (SCF), a ligand of KIT. An in vitro kinase assay was also performed. The biological behavior of the transfectant was estimated by both an in vitro proliferation assay and in vivo transplantation to nude mice.
  
  
  RESULTS
  The mutant KIT exhibited constitutive phosphorylation and strong kinase activity without SCF. The transfectant grew autonomously without IL-3 and SCF, and it formed tumors in nude mice.
  
  
  CONCLUSIONS
  Deletion at codon 579 (Asp) in the juxtamembrane domain of the c-kit gene is a novel gain-of-function mutation other than the region between Lys-550 and Val-560.
authors.affiliation: Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakahara
authors.forename: K
authors.initials: K
authors.lastname: Isozaki
authors.forename: S
authors.initials: S
authors.lastname: Hirota
authors.forename: J
authors.initials: J
authors.lastname: Miyagawa
authors.forename: N
authors.initials: N
authors.lastname: Hase-Sawada
authors.forename: M
authors.initials: M
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Nishida
authors.forename: S
authors.initials: S
authors.lastname: Kanayama
authors.forename: Y
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Y
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D006801:Humans; D008637:Mesenchymoma / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D019009:Proto-Oncogene Proteins c-kit