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Optogenetic control of YAP cellular localisation and function

YAP, an effector of the Hippo signalling pathway, promotes organ growth and regeneration. Prolonged YAP activation results in uncontrolled proliferation and cancer. Therefore, exogenous regulation of YAP activity has potential translational applications. We present a versatile optogenetic construct...

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Autores principales: Toh, Pearlyn J Y, Lai, Jason K H, Hermann, Anke, Destaing, Olivier, Sheetz, Michael P, Sudol, Marius, Saunders, Timothy E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9442306/
https://www.ncbi.nlm.nih.gov/pubmed/35876586
http://dx.doi.org/10.15252/embr.202154401
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author Toh, Pearlyn J Y
Lai, Jason K H
Hermann, Anke
Destaing, Olivier
Sheetz, Michael P
Sudol, Marius
Saunders, Timothy E
author_facet Toh, Pearlyn J Y
Lai, Jason K H
Hermann, Anke
Destaing, Olivier
Sheetz, Michael P
Sudol, Marius
Saunders, Timothy E
author_sort Toh, Pearlyn J Y
collection PubMed
description YAP, an effector of the Hippo signalling pathway, promotes organ growth and regeneration. Prolonged YAP activation results in uncontrolled proliferation and cancer. Therefore, exogenous regulation of YAP activity has potential translational applications. We present a versatile optogenetic construct (optoYAP) for manipulating YAP localisation, and consequently its activity and function. We attach a LOV2 domain that photocages a nuclear localisation signal (NLS) to the N‐terminus of YAP. In 488 nm light, the LOV2 domain unfolds, exposing the NLS, which shuttles optoYAP into the nucleus. Nuclear import of optoYAP is reversible and tuneable by light intensity. In cell culture, activated optoYAP promotes YAP target gene expression and cell proliferation. Similarly, optofYap can be used in zebrafish embryos to modulate target genes. We demonstrate that optoYAP can override a cell's response to substrate stiffness to generate anchorage‐independent growth. OptoYAP is functional in both cell culture and in vivo, providing a powerful tool to address basic research questions and therapeutic applications in regeneration and disease.
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spelling pubmed-94423062022-09-09 Optogenetic control of YAP cellular localisation and function Toh, Pearlyn J Y Lai, Jason K H Hermann, Anke Destaing, Olivier Sheetz, Michael P Sudol, Marius Saunders, Timothy E EMBO Rep Resource YAP, an effector of the Hippo signalling pathway, promotes organ growth and regeneration. Prolonged YAP activation results in uncontrolled proliferation and cancer. Therefore, exogenous regulation of YAP activity has potential translational applications. We present a versatile optogenetic construct (optoYAP) for manipulating YAP localisation, and consequently its activity and function. We attach a LOV2 domain that photocages a nuclear localisation signal (NLS) to the N‐terminus of YAP. In 488 nm light, the LOV2 domain unfolds, exposing the NLS, which shuttles optoYAP into the nucleus. Nuclear import of optoYAP is reversible and tuneable by light intensity. In cell culture, activated optoYAP promotes YAP target gene expression and cell proliferation. Similarly, optofYap can be used in zebrafish embryos to modulate target genes. We demonstrate that optoYAP can override a cell's response to substrate stiffness to generate anchorage‐independent growth. OptoYAP is functional in both cell culture and in vivo, providing a powerful tool to address basic research questions and therapeutic applications in regeneration and disease. John Wiley and Sons Inc. 2022-07-25 /pmc/articles/PMC9442306/ /pubmed/35876586 http://dx.doi.org/10.15252/embr.202154401 Text en © 2022 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Resource
Toh, Pearlyn J Y
Lai, Jason K H
Hermann, Anke
Destaing, Olivier
Sheetz, Michael P
Sudol, Marius
Saunders, Timothy E
Optogenetic control of YAP cellular localisation and function
title Optogenetic control of YAP cellular localisation and function
title_full Optogenetic control of YAP cellular localisation and function
title_fullStr Optogenetic control of YAP cellular localisation and function
title_full_unstemmed Optogenetic control of YAP cellular localisation and function
title_short Optogenetic control of YAP cellular localisation and function
title_sort optogenetic control of yap cellular localisation and function
topic Resource
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9442306/
https://www.ncbi.nlm.nih.gov/pubmed/35876586
http://dx.doi.org/10.15252/embr.202154401
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