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.

中文翻译：

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低密度脂蛋白受体相关蛋白 LRP6 感知营养水平并调节河马信号。

受控的细胞生长和增殖对于组织稳态和发育至关重要。Wnt 和 Hippo 信号分别是众所周知的细胞增殖的正负调节因子。已经显示了 Wnt 通路对 Hippo 信号传导的调节，但 Wnt 信号传导的哪些成分和如何参与营养饥饿期间 Hippo 信号传导的激活尚不清楚。在这里，我们报告说，营养饥饿期间低密度脂蛋白受体相关蛋白 6 (LRP6) 水平的降低会诱导 YAP 的磷酸化和细胞质定位，从而抑制 YAP 依赖性转录。通过丢失 LRP6 导致的 YAP 磷酸化由大型肿瘤抑制激酶 1/2 (LATS1/2) 和 Merlin 介导。我们发现OLRP6 的 GlcNAcylation 减少，并且 LRP6 的总量通过在营养饥饿期间内吞作用介导的溶酶体降解而减少。Merlin 与 LRP6 结合；当 LRP6 的O- GlcNAcylated较少时，Merlin 与其解离并能够与 LATS1 相互作用以诱导 YAP 的磷酸化。我们的数据表明 LRP6 作为营养传感器和 Hippo 信号调节器具有意想不到的作用。