Receptor tyrosine kinase signaling plays prominent roles in tumorigenesis, and activating oncogenic point mutations in the core pathway components Ras, Raf, or MEK are prevalent in many types of cancer. Intriguingly, however, analogous oncogenic mutations in the downstream effector kinase ERK have not been described or validated in vivo To determine if a point mutation could render ERK intrinsically active and oncogenic, we have assayed in Drosophila the effects of a mutation that confers constitutive activity upon a yeast ERK ortholog and has also been identified in a few human tumors. Our analyses indicate that a fly ERK ortholog harboring this mutation alone (Rolled^R80S), and more so in conjunction with the known sevenmaker mutation (Rolled^R80S+D334N), suppresses multiple phenotypes caused by loss of Ras-Raf-MEK pathway activity, consistent with an intrinsic activity that is independent of upstream signaling. Moreover, expression of Rolled^R80S and Rolled^R80S+D334N induces tissue overgrowth in an established Drosophila cancer model. Our findings thus demonstrate that activating mutations can bestow ERK with pro-proliferative, tumorigenic capabilities and suggest that Drosophila represents an effective experimental system for determining the oncogenicity of ERK mutants and their response to therapy.

中文翻译：

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ERK 的激活突变导致果蝇突变组织中出现增生性肿瘤。


受体酪氨酸激酶信号转导在肿瘤发生中发挥着重要作用，核心通路组件 Ras、Raf 或 MEK 中激活致癌点突变在许多类型的癌症中普遍存在。然而，有趣的是，下游效应激酶 ERK 中的类似致癌突变尚未在体内得到描述或验证。为了确定点突变是否可以使 ERK 具有内在活性和致癌性，我们在果蝇中检测了赋予其组成型活性的突变的影响。一种酵母 ERK 直向同源物，也在一些人类肿瘤中得到了鉴定。我们的分析表明，单独携带此突变（Rolled ^R80S ）的果蝇ERK直系同源物，尤其是与已知的sevenmaker突变（Rolled ^{R80S + D334N} ）结合，抑制了由Ras-Raf-MEK途径活性丧失引起的多种表型，一致具有独立于上游信号传导的内在活动。此外，Rolled ^R80S和 Rolled ^R80S+D334N的表达在已建立的果蝇癌症模型中诱导组织过度生长。因此，我们的研究结果表明，激活突变可以赋予 ERK 促增殖、致瘤能力，并表明果蝇代表了确定 ERK 突变体的致癌性及其对治疗反应的有效实验系统。