Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner.
Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner.
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DOI：
10.1038/s41467-018-04757-w
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发表时间：
2018-06-12
影响因子：
16.6
通讯作者：
Yook JI
中科院分区：
文献类型：
--
作者：
Lee Y;Kim NH;Cho ES;Yang JH;Cha YH;Kang HE;Yun JS;Cho SB;Lee SH;Paclikova P;Radaszkiewicz TW;Bryja V;Kang CG;Yuk YS;Cha SY;Kim SY;Kim HS;Yook JI
磷酸化依赖性YAP易位是Hippo通路的一种众所周知的细胞内机制；然而，调控YAP细胞质易位的分子效应仍不明确。最近的研究结果表明，致癌YAP矛盾地抑制Wnt活性。在这里，我们发现Wnt脚手架蛋白disheveled （DVL）负责磷酸化YAP的细胞质易位。嵌入在DVL中的核输出信号的突变失活导致核YAP保留，并增加TEAD转录活性。由E-cadherin、α-catenin或AMPK激活诱导的YAP亚细胞定位也需要DVL。重要的是，核细胞质运输依赖于p53-Lats2或LKB1-AMPK肿瘤抑制轴，它们决定YAP磷酸化状态。体内和临床数据支持p53或LKB1的缺失减轻了与dvl相关的Wnt和核YAP活性之间的相互抑制。我们的观察结果提供了在发育和人类癌症过程中与上皮极性耦合的受控增殖的机制见解。河马和Wnt通路对癌症的发展很重要，它们可以相互作用；然而，这种联系背后的机制尚不清楚。在这里，作者表明，在特定的肿瘤抑制背景下，DVL （Wnt通路中的支架蛋白）调节YAP （Hippo通路的关键成分）在细胞质和细胞核之间的穿梭。
Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer. Hippo and Wnt pathways are important for cancer development, and they can cross talk; however, the mechanisms behind this connection are unknown. Here the authors show that DVL (a scaffold protein in the Wnt pathway) regulates the shuttling of YAP (a key component of the Hippo pathway) between cytoplasm and nucleus in specific tumor suppressor contexts.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Kim NH;Kim HS;Kim NG;Lee I;Choi HS;Li XY;Kang SE;Cha SY;Ryu JK;Na JM;Park C;Kim K;Lee S;Gumbiner BM;Yook JI;Weiss SJ
通讯作者：
Weiss SJ
影响因子：
8
作者：
Aylon, Y.;Yabuta, N.;Besserglick, H.;Buganim, Y.;Rotter, V.;Nojima, H.;Oren, M.
通讯作者：
Oren, M.
影响因子：
2.6
作者：
Klingensmith, J;Yang, Y;Sussman, DJ
通讯作者：
Sussman, DJ
影响因子：
10.5
作者：
Cai J;Maitra A;Anders RA;Taketo MM;Pan D
通讯作者：
Pan D