In mammals, large tumor suppressor (Lats)1/2 serine/threonine kinase phosphorylates at multiple sites on YAP, including Ser127, resulting in cytoplasmic translocation from the nucleus1,5,6
In mammals, large tumor suppressor (Lats)1/2 serine/threonine kinase phosphorylates at multiple sites on YAP, including Ser127, resulting in cytoplasmic translocation from the nucleus1,5,6. 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. Introduction The Hippo signaling is an evolutionary conserved pathway that inhibits cell proliferation by contact inhibition, its loss leading to both organ growth and cancer development. The Yes-associated protein (YAP) transcription co-activator is a key regulator of the Hippo pathway1,2. Inhibition of the Hippo pathway leads to increased nuclear YAP abundance and TEAD transcriptional activity, resulting in increased organ size as well as overgrowth of cancer3,4. Conversely, activation of the Hippo pathway induced by cell-to-cell contact leads to phosphorylation and inhibition of nuclear YAP. In mammals, large tumor suppressor (Lats)1/2 serine/threonine kinase phosphorylates at multiple sites on YAP, including Ser127, resulting in cytoplasmic translocation from the nucleus1,5,6. Recently, AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate YAP, resulting in cytoplasmic retention and suppression of nuclear YAP activity7,8. While the phosphorylation-dependent YAP shuttling is critically important in the Hippo pathway and/or in metabolic regulation, the molecular effector of the dynamic intracellular shuttling is not known. The canonical Wnt pathway comprises fundamental extracellular signaling involving diverse developmental process, and deregulation of components involved in the Wnt/-catenin pathway has been implicated in a wide spectrum of diseases, particularly human cancers9. Highly conserved in metazoan, the Wnt signaling is critically important for coordinative regulation of cell-to-cell adhesion from cell membrane to transcriptional activity in the nucleus. The -catenin, a key mediator of Wnt signaling, functions both as intercellular adhesion complex through binding to cytoplasmic domain of E-cadherin and as transcriptional co-activator in the nucleus with T-cell factor/lymphoid enhancer factor (TCF/LEF)9,10. Because the Hippo and Wnt pathways similarly regulate intercellular adhesion and nuclear transcriptional activity11, elucidating a reciprocal link between the two pathways may reveal an important molecular mechanism in human cancer and other diseases. Although the co-activation of Wnt signaling and YAP activity are commonly observed in human cancer, recent findings point to a dilemma in that YAP suppresses canonical Wnt via binding to Dishevelled (DVL) and/or -catenin2,12C15. Although a Rabbit Polyclonal to MDM2 (phospho-Ser166) large body of studies have focused on YAP Batimastat sodium salt regulation of canonical Wnt activity in development and cancer12C14, the upstream function and molecular mechanisms enabling reciprocal regulations between YAP and Wnt signaling are largely unknown16. In this study, 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. Furthermore, oncogenic inactivation of p53/Lats2 and the liver kinase B1 (LKB1)/AMPK tumor suppressor axes, two most commonly observed genetic alterations in human cancer, abolish DVLs function on YAP nuclear export. The loss of tumor suppressor function allows co-activation of the canonical Wnt pathway and nuclear YAP activity by DVL. 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. Results DVL interacts with YAP in a phosphorylation-dependent manner Because the YAP antagonizes Wnt activity via binding to DVL in Batimastat sodium salt development and human cancer2,13, we focused on roles of enigmatic DVL on YAP activity in this study. As Batimastat sodium salt a key scaffolding protein of the Wnt pathway, DVL in mammal consists of three highly similar homolog genes, in Dsh while there is highly conserved NES at the distal region of the DEP domain in.