The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration

Autor: Jun Qin, Yan Jessie Zhang, Qirou Wu, Xiaojian Wang, Xin-Hua Feng, Fansen Meng, Pinglong Xu, Mengqiu Wang, Liming Wu, Shengduo Liu, Xia Lin, Fei Zhang, Seema Irani, Xiao Li, Jian Zou, Tingbo Liang, Ruyuan Zhou, Hai Song, Qian Zhang
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Biochemistry
0302 clinical medicine
Cell Signaling
Medicine and Health Sciences
Biology (General)
Organ Cultures
Post-Translational Modification
Phosphorylation
Tissue homeostasis
Cells
Cultured
Mice
Knockout
Kinase
General Neuroscience
Signaling cascades
Colitis
Liver regeneration
Cell biology
Enzymes
Organoids
Intestines
Protein Phosphatase 2C
Biological Cultures
Anatomy
General Agricultural and Biological Sciences
Research Article
Signal Transduction
Cell signaling
QH301-705.5
Phosphatase
Gastroenterology and Hepatology
Biology
Research and Analysis Methods
Transfection
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Animals
Humans
Regeneration
Molecular Biology Techniques
Molecular Biology
Adaptor Proteins
Signal Transducing
Cell Proliferation
General Immunology and Microbiology
Cell growth
Regeneration (biology)
Inflammatory Bowel Disease
Phosphatases
Biology and Life Sciences
Proteins
YAP-Signaling Proteins
Cell Biology
Liver Regeneration
Gastrointestinal Tract
Mice
Inbred C57BL
030104 developmental biology
TGF-beta signaling cascade
Enzymology
Digestive System
030217 neurology & neurosurgery
Transcription Factors
Zdroj: PLoS Biology
PLoS Biology, Vol 19, Iss 2, p e3001122 (2021)
ISSN: 1545-7885
1544-9173
Popis: 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.
This study identifies PPM1A as a phosphatase which dephosphorylates Yap, a key effector of Hippo signaling. This dephosphorylation event governs the regeneration of intestine and liver upon injury, and therefore represents a candidate therapeutic target for the treatment of Hippo signaling-related diseases such as colitis.
Databáze: OpenAIRE
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