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Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury

The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). The canonical pathway topology is characterized by sequential phosphorylation of kinases in the...

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Autores principales: Wehling, Lilija, Keegan, Liam, Fernández-Palanca, Paula, Hassan, Reham, Ghallab, Ahmed, Schmitt, Jennifer, Tang, Yingyue, Le Marois, Maxime, Roessler, Stephanie, Schirmacher, Peter, Kummer, Ursula, Hengstler, Jan G, Sahle, Sven, Breuhahn, Kai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578710/
https://www.ncbi.nlm.nih.gov/pubmed/36255405
http://dx.doi.org/10.7554/eLife.78540
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author Wehling, Lilija
Keegan, Liam
Fernández-Palanca, Paula
Hassan, Reham
Ghallab, Ahmed
Schmitt, Jennifer
Tang, Yingyue
Le Marois, Maxime
Roessler, Stephanie
Schirmacher, Peter
Kummer, Ursula
Hengstler, Jan G
Sahle, Sven
Breuhahn, Kai
author_facet Wehling, Lilija
Keegan, Liam
Fernández-Palanca, Paula
Hassan, Reham
Ghallab, Ahmed
Schmitt, Jennifer
Tang, Yingyue
Le Marois, Maxime
Roessler, Stephanie
Schirmacher, Peter
Kummer, Ursula
Hengstler, Jan G
Sahle, Sven
Breuhahn, Kai
author_sort Wehling, Lilija
collection PubMed
description The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). The canonical pathway topology is characterized by sequential phosphorylation of kinases in the cytoplasm that defines the subcellular localization of YAP and TAZ. However, the molecular mechanisms controlling the nuclear/cytoplasmic shuttling dynamics of both factors under physiological and tissue-damaging conditions are poorly understood. By implementing experimental in vitro data, partial differential equation modeling, as well as automated image analysis, we demonstrate that nuclear phosphorylation contributes to differences between YAP and TAZ localization in the nucleus and cytoplasm. Treatment of hepatocyte-derived cells with hepatotoxic acetaminophen (APAP) induces a biphasic protein phosphorylation eventually leading to nuclear protein enrichment of YAP but not TAZ. APAP-dependent regulation of nuclear/cytoplasmic YAP shuttling is not an unspecific cellular response but relies on the sequential induction of reactive oxygen species (ROS), RAC-alpha serine/threonine-protein kinase (AKT, synonym: protein kinase B), as well as elevated nuclear interaction between YAP and AKT. Mouse experiments confirm this sequence of events illustrated by the expression of ROS-, AKT-, and YAP-specific gene signatures upon APAP administration. In summary, our data illustrate the importance of nuclear processes in the regulation of Hippo pathway activity. YAP and TAZ exhibit different shuttling dynamics, which explains distinct cellular responses of both factors under physiological and tissue-damaging conditions.
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spelling pubmed-95787102022-10-19 Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury Wehling, Lilija Keegan, Liam Fernández-Palanca, Paula Hassan, Reham Ghallab, Ahmed Schmitt, Jennifer Tang, Yingyue Le Marois, Maxime Roessler, Stephanie Schirmacher, Peter Kummer, Ursula Hengstler, Jan G Sahle, Sven Breuhahn, Kai eLife Computational and Systems Biology The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). The canonical pathway topology is characterized by sequential phosphorylation of kinases in the cytoplasm that defines the subcellular localization of YAP and TAZ. However, the molecular mechanisms controlling the nuclear/cytoplasmic shuttling dynamics of both factors under physiological and tissue-damaging conditions are poorly understood. By implementing experimental in vitro data, partial differential equation modeling, as well as automated image analysis, we demonstrate that nuclear phosphorylation contributes to differences between YAP and TAZ localization in the nucleus and cytoplasm. Treatment of hepatocyte-derived cells with hepatotoxic acetaminophen (APAP) induces a biphasic protein phosphorylation eventually leading to nuclear protein enrichment of YAP but not TAZ. APAP-dependent regulation of nuclear/cytoplasmic YAP shuttling is not an unspecific cellular response but relies on the sequential induction of reactive oxygen species (ROS), RAC-alpha serine/threonine-protein kinase (AKT, synonym: protein kinase B), as well as elevated nuclear interaction between YAP and AKT. Mouse experiments confirm this sequence of events illustrated by the expression of ROS-, AKT-, and YAP-specific gene signatures upon APAP administration. In summary, our data illustrate the importance of nuclear processes in the regulation of Hippo pathway activity. YAP and TAZ exhibit different shuttling dynamics, which explains distinct cellular responses of both factors under physiological and tissue-damaging conditions. eLife Sciences Publications, Ltd 2022-10-18 /pmc/articles/PMC9578710/ /pubmed/36255405 http://dx.doi.org/10.7554/eLife.78540 Text en © 2022, Wehling et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Wehling, Lilija
Keegan, Liam
Fernández-Palanca, Paula
Hassan, Reham
Ghallab, Ahmed
Schmitt, Jennifer
Tang, Yingyue
Le Marois, Maxime
Roessler, Stephanie
Schirmacher, Peter
Kummer, Ursula
Hengstler, Jan G
Sahle, Sven
Breuhahn, Kai
Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury
title Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury
title_full Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury
title_fullStr Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury
title_full_unstemmed Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury
title_short Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury
title_sort spatial modeling reveals nuclear phosphorylation and subcellular shuttling of yap upon drug-induced liver injury
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578710/
https://www.ncbi.nlm.nih.gov/pubmed/36255405
http://dx.doi.org/10.7554/eLife.78540
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