The Hippo signaling is an evolutionary conserved pathway that inhibits cell proliferation by contact inhibition, and whose loss leads to organ growth and cancer development. The Yes‐associated protein (YAP) transcription co‐activator is a key regulator of the Hippo pathway. Phosphorylation‐dependent YAP translocation is a well‐known intracellular mechanism of the Hippo pathway, however the responsible molecular effectors by which the YAP leads cytosolic translocation remain undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses canonical Wnt activity.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. Mutational inactivation of the nuclear export signal in DVL leads to nuclear YAP retention, with increases TEAD transcriptional activity. DVL is also required for YAP intracellular dynamics induced by E‐cadherin, α‐catenin, or AMPK activation. Importantly, the nuclear‐cytoplasmic trafficking is largely dependent on the p53‐Lats2 or LKB1‐AMPK tumor suppressor axes, which determine YAP phosphorylation status. Conversely, loss of p53 or LKB1 relieves DVL‐linked reciprocal inhibition between the canonical Wnt pathway and nuclear YAP activity. Our observations provide novel mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.Support or Funding InformationNFR‐2017R1A2B3002241 funded by the Korean government (MSIP) andBK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.