Role of gain-of-function mutations of c-kit gene on tumor development in gastrointestinal stromal tumor.

c-kit原癌基因编码一种受体酪氨酸激酶（KIT），其配体是干细胞因子（SCF）。KIT由胞外结构域、跨膜结构域、近膜结构域和酪氨酸激酶结构域组成。c-kit基因的功能获得性突变已在啮齿类动物和人类的几种肿瘤肥大细胞系以及人类肥大细胞肿瘤中发现。KIT在这些细胞系和肿瘤中的组成性激活是c-kit基因酪氨酸激酶结构域点突变的结果。大部分间充质肿瘤不表现出平滑肌细胞或雪旺细胞的典型特征，目前被认为是胃肠道间质瘤（GIST）。我们发现大多数gist表达KIT。来自gist的c-kit互补DNA测序显示跨膜和酪氨酸激酶结构域之间的区域存在多种突变。gist中大部分突变位于近膜结构域的11个氨基酸（Lys-550 ~ Val-560）中。相应的突变体KIT蛋白在没有KIT配体的情况下被本构二聚化和激活。稳定转染突变的c-kit互补dna可诱导Ba/F3小鼠淋巴样细胞恶性转化。在短时间内发生的GIST中，c-kit突变占绝大多数，而c-kit突变有一半参与了GIST的肿瘤发展。

The c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT), the ligand of which is stem cell factor (SCF). KIT consists of an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine kinase domain. Gain-of-function mutations of the c-kit gene have been found in several tumor mast cell lines of rodents and humans and in mast cell tumors of humans. The constitutive activation of KIT in these cell lines and tumors was the result of a point mutation in the tyrosine kinase domain of the c-kit gene.A large proportion of mesenchymal tumors, which do not show typical features of smooth muscle cells or Schwann cells, are presently designated as gastrointestinal stromal tumor (GIST). We found that most of GISTs expressed KIT. Sequencing of c-kit complementary DNA from GISTs revealed a variety of mutations in the region between the transmembrane and tyrosine kinase domains. Most of mutations in GISTs were located with in the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain. The corresponding mutant KIT proteins were constitutively dimerized and activated without the KIT ligands. Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells. Most of all GISTs which developed during a short periods showed mutations of c-kit, while half of mutations of c-kit contribute to tumor development in GIST.