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

Wonyoung Jeong, Soyoung Kim, Ukjin Lee, Zhendong A. Zhong, Mikhail Savitsky, Hyeryun Kwon, Jiyoung Kim, Taebok Lee, Jin Won Cho, Bart O. Williams, Vladimir L. Katanaev, Eek hoon Jho

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 of YAP, inhibiting YAP-dependent transcription. Phosphorylation of YAP via loss of LRP6 is mediated by large tumor suppressor kinases 1/2 (LATS1/2) and Merlin. We found that O-GlcNAcylation of LRP6 was reduced, and the overall amount of LRP6 was decreased via endocytosis-mediated lysosomal degradation during nutrient starvation. Merlin binds to LRP6; when LRP6 is less O-GlcNAcylated, Merlin dissociates from it and becomes capable of interacting with LATS1 to induce phosphorylation of YAP. Our data suggest that LRP6 has unexpected roles as a nutrient sensor and Hippo signaling regulator.

Original languageEnglish
Article numbere50103
JournalEMBO Reports
Volume21
Issue number9
DOIs
StatePublished - 3 Sep 2020

Keywords

  • Hippo signaling
  • LRP6
  • O-GlcNAcylation
  • Starvation
  • YAP

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