Hedgehog (Hh) signaling is essential for embryonic development and adult homeostasis. How its signaling activity is fine-tuned in response to fluctuated Hh gradient is less known. Here, we identify protein phosphatase V (PpV), the catalytic subunit of protein phosphatase 6, as a homeostatic regulator of Hh signaling. PpV is genetically upstream of widerborst (wdb), which encodes a regulatory subunit of PP2A that modulates high-level Hh signaling. We show that PpV negatively regulates Wdb stability independent of phosphatase activity of PpV, by competing with the catalytic subunit of PP2A for Wdb association, leading to Wdb ubiquitination and subsequent proteasomal degradation. Thus, regulated Wdb stability, maintained through competition between two closely related phosphatases, ensures graded Hh signaling. Interestingly, PpV expression is regulated by Hh signaling. Therefore, PpV functions as a Hh activity sensor that regulates Wdb-mediated PP2A activity through feedback mechanisms to maintain Hh signaling homeostasis.
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1 February 2021
Article|
December 29 2020
Competition between two phosphatases fine-tunes Hedgehog signaling
Min Liu
,
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
2
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
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Aiguo Liu
,
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
2
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
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Jie Wang
,
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
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Yansong Zhang
,
Yansong Zhang
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
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Yajuan Li
,
Yajuan Li
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
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Ying Su
,
3
Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China
Correspondence to Ying Su: suying@ouc.edu.cn
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Alan Jian Zhu
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
2
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
Alan Jian Zhu: zhua@pku.edu.cn
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Min Liu
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
2
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
Aiguo Liu
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
2
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
Jie Wang
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
Yansong Zhang
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
Yajuan Li
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
Ying Su
3
Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, China
Alan Jian Zhu
1
Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
2
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
Correspondence to Ying Su: suying@ouc.edu.cn
Alan Jian Zhu: zhua@pku.edu.cn
*
M. Liu, A. Liu, and J. Wang contributed equally to this paper.
Received:
October 14 2020
Revision Received:
November 26 2020
Accepted:
December 02 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
National Institutes of Health
(P40OD018537)
National Natural Science Foundation of China
(31725019)
Peking University
(NO AWARD)
© 2020 Liu et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (2): e202010078.
Article history
Received:
October 14 2020
Revision Received:
November 26 2020
Accepted:
December 02 2020
Citation
Min Liu, Aiguo Liu, Jie Wang, Yansong Zhang, Yajuan Li, Ying Su, Alan Jian Zhu; Competition between two phosphatases fine-tunes Hedgehog signaling. J Cell Biol 1 February 2021; 220 (2): e202010078. doi: https://doi.org/10.1083/jcb.202010078
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