LDL receptor-related protein LRP6 senses nutrient levels and regulates Hippo signaling.

Controlled cell growth and proliferation are essential for tissue homeostasis and development. Wnt and Hippo signaling are well known as positive and negative regulators of cell proliferation, respectively. The regulation of Hippo signaling by the Wnt pathway has been shown, but how and which components of Wnt signaling are involved in the activation of Hippo signaling during nutrient starvation are unknown. Here, we report that a reduction in the level of low-density lipoprotein receptor-related protein 6 (LRP6) during nutrient starvation induces phosphorylation and cytoplasmic localization ofYAP, inhibitingYAP-dependent transcription. Phosphorylation ofYAPvia loss ofLRP6 is mediated by large tumor suppressor kinases 1/2 (LATS1/2) and Merlin. We found thatO-GlcNAcylation ofLRP6 was reduced, and the overall amount ofLRP6 was decreased via endocytosis-mediated lysosomal degradation during nutrient starvation. Merlin binds toLRP6; whenLRP6 is lessO-GlcNAcylated, Merlin dissociates from it and becomes capable of interacting withLATS1 to induce phosphorylation ofYAP. Our data suggest thatLRP6 has unexpected roles as a nutrient sensor and Hippo signaling regulator.