Nature2014-06-16 4:11 PM

SMYD3 是一个抗癌目标 SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer

论文摘要 

SMYD3在很大程度上是一种胞质赖氨酸甲基转移酶,在几种人类肿瘤中过度表达。这篇论文报告说,SMYD3在小鼠模型中是由Ras诱导的肿瘤形成所需的。这种酶将MAP3K2甲基化,后者抑制一种磷酸酶的结合并增强Ras/Raf 信号传导通道的效能。这些结果显示了赖氨酸甲基化在一个激酶信号传导通道中所起的一种出乎意料的作用,同时也将SMYD3确立为一个潜在治疗目标。

Abstract 

Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics1. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours2, 3, 4. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signaling.

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