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

ABSTRACT: 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, ?-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.

SUBMITTER: Lee Y

PROVIDER: S-EPMC5997650 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Lee Yoonmi Y Kim Nam Hee NH Cho Eunae Sandra ES Yang Ji Hye JH Cha Yong Hoon YH Kang Hee Eun HE Yun Jun Seop JS Cho Sue Bean SB Lee Seon-Hyeong SH Paclikova Petra P Radaszkiewicz Tomasz W TW Bryja Vitezslav V Kang Chi Gu CG Yuk Young Soo YS Cha So Young SY Kim Soo-Youl SY Kim Hyun Sil HS Yook Jong In JI

Nature communications 20180612 1

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 re ...[more]

PMID: 29895829

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Dataset Information

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

Publications

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

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