As highly conserved signaling cascades of multicellular organisms, Wnt and Hippo pathways control a wide range of cellular activities, including cell adhesion, fate determination, cell cycle, motility, polarity, and metabolism. Dysregulation of those pathways are implicated in many human diseases, including cancer. Similarly to β-catenin in the Wnt pathway, the YAP transcription co-activator is a major player in Hippo. Although the intracellular dynamics of YAP are well-known to largely depend on phosphorylation by LATS and AMPK kinases, the molecular effector of YAP cytosolic translocation remains unidentified. Recently, we reported that the Dishevelled (DVL), a key scaffolding protein between canonical and non-canonical Wnt pathway, is responsible for nuclear export of phosphorylated YAP. The DVL is also required for YAP intracellular trafficking induced by E-cadherin, α-catenin, or metabolic stress. Note that the p53/LATS2 and LKB1/AMPK tumor suppressor axes, commonly inactivated in human cancer, govern the reciprocal inhibition between DVL and YAP. Conversely, loss of the tumor suppressor allows co-activation of YAP and Wnt independent of epithelial polarity or contact inhibition in human cancer. These observations provide novel mechanistic insight into (1) a tight molecular connection merging the Wnt and Hippo pathways, and (2) the importance of tumor suppressor contexts with respect to controlled proliferation and epithelial polarity regulated by cell adhesion.
Bibliographical noteFunding Information:
We thank E. Tunkle for preparation of the manuscript. This work was supported by grants from the National Research Foundation of Korea (NFR-2017R1A2B3002241, NRF-2016R 1E1A1A01942724, NRF-2014R1A6A3A04055110) funded by the Korean government (MSIP) and a grant from the Korea Health Industry Development Institute (KHIDI) funded by the Ministry for Health & Welfare Korea (HI17C2586)
© 2018 by the The Korean Society for Biochemistry and Molecular Biology.
All Science Journal Classification (ASJC) codes
- Molecular Biology