Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors
Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors
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DOI：
10.1038/sj.onc.1211019
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发表时间：
2008-06-05
期刊：
影响因子：
8
通讯作者：
Hatakeyama, M.
中科院分区：
文献类型：
--
作者：
Miyamoto, D.;Miyamoto, M.;Hatakeyama, M.
SHP-2蛋白酪氨酸磷酸酶在RAS依赖信号的激活中起重要作用。编码SHP-2的PTPN 11基因的功能获得性突变已在白血病易感性发育障碍努南综合征以及散发性儿童白血病中发现，表明SHP-2是一种良性疾病。去人癌蛋白。然而，SHP-2突变在非血液恶性肿瘤中的作用仍然不清楚。在此，我们筛选了原发性实体瘤中的PTPN 11突变，并在肝细胞癌病例中鉴定了导致SHP-2磷酸酶结构域中苏氨酸-507变为赖氨酸（T507 K）的1520 C> A突变。T507 K SHP-2表现出改变的底物特异性，略微升高的基础磷酸酶活性。在NIH 3 T3细胞中表达后，T507 K SHP-2诱导转化灶，这在野生型、努南特异性或白血病特异性SHP-2中未观察到。T507 K SHP-2转化的NIH 3 T3细胞具有非贴壁生长特性，并在裸鼠体内形成肿瘤。这些结果表明，磷酸酶活性的定量和/或定性改变决定了转化潜力以及单个SHP-2突变体作为癌蛋白的靶细胞/组织谱。尽管在实体瘤中很少见，但已鉴定的T507 K SHP-2代表了一类具有致癌RAS样转化活性的不同SHP-2突变体，这可能有助于实体瘤的发展。
SHP-2 protein tyrosine phosphatase plays an important role in activation of the RAS-dependent signaling. Gain-of-function mutations in the PTPN11 gene, which encodes SHP-2, have been found in the leukemia-prone developmental disorder Noonan syndrome as well as sporadic childhood leukemias, indicating that SHP-2 is a bona. de human oncoprotein. However, the role of SHP-2 mutations in non-hematological malignancies remains obscure. Here, we screened for PTPN11 mutations in primary solid tumors and identified a 1520C > A mutation that causes threonine-507 to lysine (T507K) substitution in the phosphatase domain of SHP-2 in a case of hepatocellular carcinoma. T507K SHP-2 exhibited altered substrate specificity with slightly elevated basal phosphatase activity. Upon expression in NIH3T3 cells, T507K SHP-2 induced transformed foci, which was not observed with wild type, Noonan-specific or leukemia-specific SHP-2. Furthermore, NIH3T3 cells transformed by T507K SHP-2 showed anchorage-independent growth and developed tumors in nude mice. These results indicate that quantitative and/or qualitative alteration in phosphatase activity determines the transforming potential as well as target cell/tissue spectrum of individual SHP-2 mutants as oncoproteins. Although rare in solid tumors, the identified T507K SHP-2 represents a distinct class of SHP-2 mutants with oncogenic RAS-like transforming activity, which could contribute to the development of solid tumors.