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

doi:10.15252/embr.202050103

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 journal › Article › peer-review

8 Citations (Scopus)

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 language	English
Article number	e50103
Journal	EMBO Reports
Volume	21
Issue number	9
DOIs	https://doi.org/10.15252/embr.202050103
Publication status	Published - 2020 Sept 3

Bibliographical note

Funding Information:
This work was supported by the grants from the National Research Foundation of Korea to E‐hJ (2016R1A5A1010764, 2017M3A9B4062421, and 2020R1A2C3013746), and from the Swiss National Science Foundation to VLK (31003A_175658). BOW and ZAZ are supported by the Van Andel Institute. We thank David Nadziejka for editorial assistance.

Funding Information:
This work was supported by the grants from the National Research Foundation of Korea to E-hJ (2016R1A5A1010764, 2017M3A9B4062421, and 2020R1A2C3013746), and from the Swiss National Science Foundation to VLK (31003A_175658). BOW and ZAZ are supported by the Van Andel Institute. We thank David Nadziejka for editorial assistance.

Publisher Copyright:
© 2020 The Authors

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Genetics

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10.15252/embr.202050103

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@article{5dc02ac6927d4af0a41642e17e5f8a33,

title = "LDL receptor-related protein LRP6 senses nutrient levels and regulates Hippo signaling",

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.",

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

note = "Funding Information: This work was supported by the grants from the National Research Foundation of Korea to E‐hJ (2016R1A5A1010764, 2017M3A9B4062421, and 2020R1A2C3013746), and from the Swiss National Science Foundation to VLK (31003A_175658). BOW and ZAZ are supported by the Van Andel Institute. We thank David Nadziejka for editorial assistance. Funding Information: This work was supported by the grants from the National Research Foundation of Korea to E-hJ (2016R1A5A1010764, 2017M3A9B4062421, and 2020R1A2C3013746), and from the Swiss National Science Foundation to VLK (31003A_175658). BOW and ZAZ are supported by the Van Andel Institute. We thank David Nadziejka for editorial assistance. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = sep,

day = "3",

doi = "10.15252/embr.202050103",

language = "English",

volume = "21",

journal = "EMBO Reports",

issn = "1469-221X",

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T1 - LDL receptor-related protein LRP6 senses nutrient levels and regulates Hippo signaling

AU - Jeong, Wonyoung

AU - Kim, Soyoung

AU - Lee, Ukjin

AU - Zhong, Zhendong A.

AU - Savitsky, Mikhail

AU - Kwon, Hyeryun

AU - Kim, Jiyoung

AU - Lee, Taebok

AU - Cho, Jin Won

AU - Williams, Bart O.

AU - Katanaev, Vladimir L.

AU - Jho, Eek hoon

N1 - Funding Information: This work was supported by the grants from the National Research Foundation of Korea to E‐hJ (2016R1A5A1010764, 2017M3A9B4062421, and 2020R1A2C3013746), and from the Swiss National Science Foundation to VLK (31003A_175658). BOW and ZAZ are supported by the Van Andel Institute. We thank David Nadziejka for editorial assistance. Funding Information: This work was supported by the grants from the National Research Foundation of Korea to E-hJ (2016R1A5A1010764, 2017M3A9B4062421, and 2020R1A2C3013746), and from the Swiss National Science Foundation to VLK (31003A_175658). BOW and ZAZ are supported by the Van Andel Institute. We thank David Nadziejka for editorial assistance. Publisher Copyright: © 2020 The Authors

PY - 2020/9/3

Y1 - 2020/9/3

N2 - 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.

AB - 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.

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DO - 10.15252/embr.202050103

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JO - EMBO Reports

JF - EMBO Reports

IS - 9

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ER -

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

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