A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway.
A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway.
复制标题
DOI：
10.1038/ncb2884
复制
发表时间：
2014-01
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
Hippo/YAP通路是一个新兴的信号级联，参与干细胞活性和器官大小的调节。Hippo信号的改变也是人类上皮恶性肿瘤的一个共同特征，尽管这种错误调控的分子基础尚不清楚。由于目前的大部分知识都来自果蝇的研究，我们对哺乳动物河马/YAP信号的理解仍然不完整。为了确定这一途径的新成分，我们在人类细胞中进行了基于rnai的kinome筛选。我们的筛选发现了几个先前与Hippo信号不相关的激酶，它们强烈地调节Hippo换能器YAP的活性。其中一些激酶控制应激反应、边界形成、细胞周期和粘附等过程，并反映可能影响Hippo信号传导和生长控制的新输入。其中一个靶点LKB1（也称为Stk11）是一种常见的肿瘤抑制因子，其作用机制仅部分了解。我们证明LKB1通过其PAR-1家族底物（MARK1-4）调节基底-外侧极性复合物的定位和核心Hippo激酶的活性。小鼠和人类缺乏lkb1的肿瘤表现为基侧决定因子Scribble的错误定位，Hippo激酶活性降低，yap驱动的转录增强。通过异种移植试验和遗传分析，我们证明YAP对LKB1的肿瘤抑制作用具有重要的功能。我们的研究结果确定了一个重要的信号轴，将YAP激活与LKB1突变联系起来，并对LKB1突变人类恶性肿瘤的治疗具有重要意义。此外，我们的研究结果对Hippo/YAP信号级联的输入性质提供了新的见解。
The Hippo/YAP pathway is an emerging signaling cascade involved in the regulation of stem cell activity and organ size. Alterations in Hippo signaling are also a common feature of human epithelial malignancies, although the molecular bases for this misregulation are unclear. As most of the current knowledge has been derived from work in the fruit fly, our understanding of mammalian Hippo/YAP signaling is still incomplete. To identify novel components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signaling that strongly regulate the activity of the Hippo transducer YAP. Some of these kinases control processes such as response to stress, boundary formation, cell cycle and adhesion, and reflect novel inputs that may impinge on Hippo signaling and growth control. One of the hits, LKB1 (also known as Stk11), is a common tumor suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the PAR-1 family (MARK1-4) to regulate the localization of the baso-lateral polarity complex and the activity of the core Hippo kinases. Murine and human LKB1-deficient tumors exhibit mislocalization of the basolateral determinant Scribble, reduced Hippo kinase activity, and enhanced YAP-driven transcription. Using xenograft assays and genetic analysis, we demonstrate that YAP is functionally important for the tumor suppressive effects of LKB1. Our results identify an important signaling axis that links YAP activation with LKB1 mutations, and have significant implications for the treatment of LKB1-mutant human malignancies. Additionally, our findings provide novel insight into the nature of inputs that speak to the Hippo/YAP signaling cascade.
登录
查看更多内容
影响因子：
30.8
作者：
Stark, Mitchell S.;Woods, Susan L.;Gartside, Michael G.;Bonazzi, Vanessa F.;Dutton-Regester, Ken;Aoude, Lauren G.;Chow, Donald;Sereduk, Chris;Niemi, Natalie M.;Tang, Nanyun;Ellis, Jonathan J.;Reid, Jeffrey;Zismann, Victoria;Tyagi, Sonika;Muzny, Donna;Newsham, Irene;Wu, YuanQing;Palmer, Jane M.;Pollak, Thomas;Youngkin, David;Brooks, Bradford R.;Lanagan, Catherine;Schmidt, Christopher W.;Kobe, Bostjan;MacKeigan, Jeffrey P.;Yin, Hongwei;Brown, Kevin M.;Gibbs, Richard;Trent, Jeffrey;Hayward, Nicholas K.
通讯作者：
Hayward, Nicholas K.
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
11.2
作者：
Chen F
通讯作者：
Chen F
影响因子：
1.2
作者：
Parsons, Linda M.;Grzeschik, Nicola A.;Richardson, Helena E.
通讯作者：
Richardson, Helena E.