The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.
The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an u...
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doaj-1c1a795a50ae4782ad49dfdef46b4e3e2021-07-01T04:31:39ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-02-01192e300112210.1371/journal.pbio.3001122The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.Ruyuan ZhouQirou WuMengqiu WangSeema IraniXiao LiQian ZhangFansen MengShengduo LiuFei ZhangLiming WuXia LinXiaojian WangJian ZouHai SongJun QinTingbo LiangXin-Hua FengYan Jessie ZhangPinglong XuThe Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.https://doi.org/10.1371/journal.pbio.3001122 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ruyuan Zhou Qirou Wu Mengqiu Wang Seema Irani Xiao Li Qian Zhang Fansen Meng Shengduo Liu Fei Zhang Liming Wu Xia Lin Xiaojian Wang Jian Zou Hai Song Jun Qin Tingbo Liang Xin-Hua Feng Yan Jessie Zhang Pinglong Xu |
spellingShingle |
Ruyuan Zhou Qirou Wu Mengqiu Wang Seema Irani Xiao Li Qian Zhang Fansen Meng Shengduo Liu Fei Zhang Liming Wu Xia Lin Xiaojian Wang Jian Zou Hai Song Jun Qin Tingbo Liang Xin-Hua Feng Yan Jessie Zhang Pinglong Xu The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. PLoS Biology |
author_facet |
Ruyuan Zhou Qirou Wu Mengqiu Wang Seema Irani Xiao Li Qian Zhang Fansen Meng Shengduo Liu Fei Zhang Liming Wu Xia Lin Xiaojian Wang Jian Zou Hai Song Jun Qin Tingbo Liang Xin-Hua Feng Yan Jessie Zhang Pinglong Xu |
author_sort |
Ruyuan Zhou |
title |
The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. |
title_short |
The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. |
title_full |
The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. |
title_fullStr |
The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. |
title_full_unstemmed |
The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. |
title_sort |
protein phosphatase ppm1a dephosphorylates and activates yap to govern mammalian intestinal and liver regeneration. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2021-02-01 |
description |
The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration. |
url |
https://doi.org/10.1371/journal.pbio.3001122 |
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