Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms
Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms
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DOI：
10.1046/j.1523-1747.1999.00488.x
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发表时间：
1999-02-01
影响因子：
6.5
通讯作者：
Caughey, GH
中科院分区：
文献类型：
--
作者：
Ma, YS;Longley, BJ;Caughey, GH
原癌基因c-KIT编码具有配体依赖性酪氨酸激酶活性的生长因子受体KIT，其由包括肥大细胞在内的几种细胞类型表达。引起KIT组成性激活的c-KIT跨膜编码区突变能够转化细胞系，并已在人肥大细胞系和人胃肠道间质瘤中原位鉴定，但尚未在任何种属的肿瘤性肥大细胞中原位证实。为了确定c-KIT巨噬细胞膜突变是否发生在肥大细胞肿瘤的发展中，我们检查了犬肥大细胞瘤，这是犬最常见的肿瘤之一，通常表现为恶性，不像人类孤立性肥大细胞瘤。对从七只狗身上取出的肿瘤组织中产生的c-KIT cDNA进行测序，发现其中三个肿瘤的细胞内近膜编码区总共含有四个突变，该编码区在脊椎动物中完全保守。此外，在来自另外两只狗的三个肥大细胞系中发现了两个突变。来自一条线的一个突变与在其中一个肿瘤中原位发现的突变相匹配。第二个是在不同时间来自一只狗的两个品系中发现的，表明突变存在于动物体内。所有五个突变引起KIT的高自发酪氨酸磷酸化。我们的研究提供了原位证据，激活c-KIT内膜突变存在于肥大细胞瘤形成的发病机制中，因此可能有助于肥大细胞瘤形成的发病机制。我们的数据还表明，在控制受体激酶活性的KIT质膜区域的抑制作用。
The proto-oncogene c-KIT encodes a growth factor receptor, KIT, with Ligand-dependent tyrosine kinase activity that is expressed by several cell types including mast cells. c-KIT juxtamembrane coding region mutations causing constitutive activation of KIT are capable of transforming cell lines and have been identified in a human mast cell line and in situ in human gastrointestinal stromal tumors, but have not been demonstrated in situ in neoplastic mast cells from any species. To determine whether c-KIT juxtamembrane mutations occur in the development of mast cell neoplasms, we examined canine mastocytomas, which are among the most common tumors of dogs and which often behave in a malignant fashion, unlike human solitary mastocytomas. Sequencing of c-KIT cDNA generated from tumor tissues removed from seven dogs revealed that three of the tumors contained a total of four mutations in an intracellular juxtamembrane coding region that is completely conserved among vertebrates. In addition, two mutations were found in three mast cell lines derived from two additional dogs. One mutation from one line matched that found in situ in one of the tumors. The second was found in two lines derived from one dog at different times, indicating that the mutation was present in situ in the animal. All five mutations cause high spontaneous tyrosine phosphorylation of KIT. Our study provides in situ evidence that activating c-KIT juxtamembrane mutations are present in, and may therefore contribute to, the pathogenesis of mast cell neoplasia. Our data also suggest an inhibitory role for the KIT juxtamembrane region in controlling the receptor kinase activity.