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, 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.
Highlights
Phosphorylation-dependent Yes-associated protein (YAP) translocation is a well-known intracellular mechanism of the Hippo pathway; the molecular effectors governing YAP cytoplasmic translocation remains undefined
We found that DVL, a scaffolding protein of the Wnt pathway as well as a key regulator of Wnt-independent epithelial polarity, is a molecular effector for nuclear-cytoplasmic shuttling of YAP in a YAP phosphorylation-dependent manner
Because the YAP antagonizes Wnt activity via binding to DVL in development and human cancer[2,13], we focused on roles of enigmatic DVL on YAP activity in this study
Summary
Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; the molecular effectors governing YAP cytoplasmic translocation remains undefined. Because the Hippo and Wnt pathways regulate intercellular adhesion and nuclear transcriptional activity[11], elucidating a reciprocal link between the two pathways may reveal an important molecular mechanism in human cancer and other diseases. We found that DVL, a scaffolding protein of the Wnt pathway as well as a key regulator of Wnt-independent epithelial polarity, is a molecular effector for nuclear-cytoplasmic shuttling of YAP in a YAP phosphorylation-dependent manner. Oncogenic inactivation of p53/Lats[2] and the liver kinase B1 (LKB1)/AMPK tumor suppressor axes, two most commonly observed genetic alterations in human cancer, abolish DVL’s function on YAP nuclear export. Our observations demonstrate molecular mechanisms for the dynamic regulation of YAP activity via subcellular trafficking by DVL as well as the importance of p53 and LKB1 tumor suppressor contexts in the reciprocal control between the canonical Wnt and Hippo pathways
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