Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

被引：65

作者：

Lee, Yoonmi ^{[1
,2
]}

Kim, Nam Hee ^{[2
]}

Cho, Eunae Sandra ^{[1
]}

Yang, Ji Hye ^{[1
]}

Cha, Yong Hoon ^{[3
]}

Kang, Hee Eun ^{[1
]}

Yun, Jun Seop ^{[1
]}

Cho, Sue Bean ^{[2
]}

Lee, Seon-Hyeong ^{[4
]}

Paclikova, Petra ^{[5
]}

Radaszkiewicz, Tomasz W. ^{[5
]}

Bryja, Vitezslav ^{[5
]}

Kang, Chi Gu ^{[1
]}

Yuk, Young Soo ^{[1
]}

Cha, So Young ^{[1
]}

Kim, Soo-Youl ^{[4
]}

Kim, Hyun Sil ^{[2
]}

Yook, Jong In ^{[1
]}

机构：

[1] Yonsei Univ, Coll Dent, Dept Oral Pathol, Seoul 03722, South Korea

[2] Yonsei Univ, Coll Dent, Oral Canc Res Inst, Seoul 03722, South Korea

[3] Yonsei Univ, Coll Dent, Dept Oral & Maxillofacial Surg, Seoul 03722, South Korea

[4] Natl Canc Ctr, Canc Cell & Mol Biol Branch, Ilsan 10408, South Korea

[5] Masaryk Univ, Fac Sci, Inst Expt Biol, Brno 62500, Czech Republic

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

新加坡国家研究基金会;

关键词：

PLANAR CELL POLARITY; ORGAN SIZE CONTROL; HIPPO PATHWAY; BETA-CATENIN; CONTACT INHIBITION; SIGNALING-PATHWAY; CANCER; LKB1; PHOSPHORYLATION; LOCALIZATION;

D O I：

10.1038/s41467-018-04757-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, a-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.

引用

页数：16

共 69 条

[1] Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases [J].