Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth
Phosphorylation at Ser-181 of Oncogenic KRAS Is Required for Tumor Growth
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DOI：
10.1158/0008-5472.can-13-1750
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Agell, Neus
中科院分区：
文献类型：
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作者：
Barcelo, Carles;Paco, Noelia;Agell, Neus
最近有报道称，KRAS磷酸化可以在体外调节突变KRAS蛋白的活性。在这项研究中，我们将S181定义为体内突变KRAS致癌功能所需的特异性磷酸化位点。磷酸突变体S181A未能在小鼠中诱导肿瘤，而磷酸模拟突变体S181D与野生型KRAS蛋白相比表现出增强的肿瘤形成能力。由表达不可磷酸化的KRAS S181A突变体的细胞组成的肿瘤的生长减少与细胞凋亡增加相关。相反，由表达磷酸化KRAS S181D突变体的细胞组成的肿瘤的生长增加与KRAS的两个主要下游效应物AKT和ERK的活化增加相关。PKC抑制剂的药物治疗损害了与磷酸化KRAS水平降低和效应物活化降低相关的肿瘤生长。在一组表达各种KRAS亚型的人肿瘤细胞系中，我们发现KRAS磷酸化对生存和致瘤活性至关重要。此外，我们在一组原发性人胰腺肿瘤中鉴定了磷酸化KRAS。综上所述，我们的研究结果表明，KRAS需要S181磷酸化来表现其致癌特性，这意味着其抑制代表了攻击KRAS驱动的肿瘤的相关靶点。（C）2013年AACR。
KRAS phosphorylation has been reported recently to modulate the activity of mutant KRAS protein in vitro. In this study, we defined S181 as a specific phosphorylation site required to license the oncogenic function of mutant KRAS in vivo. The phosphomutant S181A failed to induce tumors in mice, whereas the phosphomimetic mutant S181D exhibited an enhanced tumor formation capacity, compared with the wild-type KRAS protein. Reduced growth of tumors composed of cells expressing the nonphosphorylatable KRAS S181A mutant was correlated with increased apoptosis. Conversely, increased growth of tumors composed of cells expressing the phosphomimetic KRAS S181D mutant was correlated with increased activation of AKT and ERK, two major downstream effectors of KRAS. Pharmacologic treatment with PKC inhibitors impaired tumor growth associated with reduced levels of phosphorylated KRAS and reduced effector activation. In a panel of human tumor cell lines expressing various KRAS isoforms, we showed that KRAS phosphorylation was essential for survival and tumorigenic activity. Furthermore, we identified phosphorylated KRAS in a panel of primary human pancreatic tumors. Taken together, our findings establish that KRAS requires S181 phosphorylation to manifest its oncogenic properties, implying that its inhibition represents a relevant target to attack KRAS-driven tumors. (C)2013 AACR.