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

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LEE Y. KIM N.H. CHO E.S. YANG J.H. CHA Y.H. KANG H.E. YUN J.S. CHO S.B. LEE S.H. PACLÍKOVÁ Petra RADASZKIEWICZ Tomasz Witold BRYJA Vítězslav KANG C.G. YUK Y.S. CHA S.Y. KIM S.Y. KIM H.S. YOOK J.I.

Rok publikování 2018
Druh Článek v odborném periodiku
Časopis / Zdroj Nature Communications
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://www.nature.com/articles/s41467-018-04757-w
Doi http://dx.doi.org/10.1038/s41467-018-04757-w
Klíčová slova ACTIVATED PROTEIN-KINASE; PLANAR CELL POLARITY; ORGAN SIZE CONTROL; HIPPO PATHWAY; BETA-CATENIN; ENERGY STRESS; CONTACT INHIBITION; SIGNALING-PATHWAY; CANCER; LKB1
Popis 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.
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