SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer.
SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer.
复制标题
DOI：
10.1038/nature13320
复制
发表时间：
2014-06-12
期刊：
影响因子：
64.8
通讯作者：
Gozani, Or
中科院分区：
文献类型：
--
作者：
Mazur, Pawel K.;Reynoird, Nicolas;Khatri, Purvesh;Jansen, Pascal W. T. C.;Wilkinson, Alex W.;Liu, Shichong;Barbash, Olena;Van Aller, Glenn S.;Huddleston, Michael;Dhanak, Dashyant;Tummino, Peter J.;Kruger, Ryan G.;Garcia, Benjamin A.;Butte, Atul J.;Vermeulen, Michiel;Sage, Julien;Gozani, Or
赖氨酸甲基化信号的失调已经成为癌症发病机制中的常见病因因素，几种组蛋白赖氨酸甲基转移酶（KMT）的抑制剂被开发为化学治疗剂。主要是细胞质的KMT SMYD 3（SET和MYND结构域包含蛋白3）在许多人类肿瘤中过表达。然而，SMYD 3调节癌症途径的分子机制及其与体内肿瘤发生的关系在很大程度上是未知的。在这里，我们表明，通过SMYD 3甲基化MAP 3 K2增加MAP激酶信号传导，并促进Ras驱动的癌的形成。使用胰腺导管腺癌（PDAC）和肺腺癌（LAC）的小鼠模型，我们发现消除SMYD 3催化活性抑制了响应致癌Ras的肿瘤发展。我们采用蛋白质阵列技术鉴定了作为SMYD 3靶点的MAP 3 K2激酶。在癌细胞系中，SMYD 3介导的MAP 3 K2在赖氨酸260处的甲基化增强Ras/Raf/MEK/ERK信号传导模块的激活。最后，PP 2A磷酸酶复合物（MAP激酶途径的关键负调节剂）与MAP 3 K2结合，这种相互作用被甲基化阻断。总之，我们的研究结果阐明了赖氨酸甲基化在整合细胞质激酶信号级联中的新作用，并建立了SMYD 3在致癌Ras信号调节中的关键作用。
Deregulation in lysine methylation signaling has emerged as a common etiologic factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumors. 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 signaling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LAC), we found that abrogating SMYD3 catalytic activity inhibits tumor development in response to oncogenic Ras. We employed 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 signaling module. 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-signaling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signaling.
登录
查看更多内容
DOI：
10.1084/jem.20122709
发表时间：
2013-10-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Khatri P;Roedder S;Kimura N;De Vusser K;Morgan AA;Gong Y;Fischbein MP;Robbins RC;Naesens M;Butte AJ;Sarwal MM
通讯作者：
Sarwal MM
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
30.8
作者：
Jonkers, J;Meuwissen, R;Berns, A
通讯作者：
Berns, A