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The Yes-associated protein controls the cell density regulation of Hedgehog signaling

The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for correct embryogenesis and is misregulated in several malignancies. In cell culture, Hh-sensitive cells display a striking dependence on cell density with active Hh signaling requiring cell-to-cell contact. As the Hippo/YAP...

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Autores principales: Tariki, M, Dhanyamraju, P K, Fendrich, V, Borggrefe, T, Feldmann, G, Lauth, M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189961/
https://www.ncbi.nlm.nih.gov/pubmed/25111861
http://dx.doi.org/10.1038/oncsis.2014.27
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author Tariki, M
Dhanyamraju, P K
Fendrich, V
Borggrefe, T
Feldmann, G
Lauth, M
author_facet Tariki, M
Dhanyamraju, P K
Fendrich, V
Borggrefe, T
Feldmann, G
Lauth, M
author_sort Tariki, M
collection PubMed
description The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for correct embryogenesis and is misregulated in several malignancies. In cell culture, Hh-sensitive cells display a striking dependence on cell density with active Hh signaling requiring cell-to-cell contact. As the Hippo/YAP system is tightly linked to cell density control and contact inhibition, we investigated the cross-talk between the two pathways. Our data reveal that the suppression of Hh signaling in the absence of cellular contacts is independent of primary cilia and is mediated by the YAP oncogene. Overexpression of YAP blocks Hh signaling whereas RNA interference-mediated knockdown of YAP enhances Hh/GLI activity. Despite this negative regulation, Hh signaling promotes YAP activity through post-transcriptional mechanisms, resulting in a negative feedback loop. In vivo, we found strong nuclear YAP immunoreactivity restricted to compartments with low Hh pathway activity in human and mouse pancreatic cancer. Finally, we identified protease-activated receptors (PARs) as molecules being able to override the inverse Hippo/Hh regulation, potentially giving tumors a mechanism to utilize both oncogenic pathways in parallel.
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spelling pubmed-51899612017-01-13 The Yes-associated protein controls the cell density regulation of Hedgehog signaling Tariki, M Dhanyamraju, P K Fendrich, V Borggrefe, T Feldmann, G Lauth, M Oncogenesis Short Communication The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for correct embryogenesis and is misregulated in several malignancies. In cell culture, Hh-sensitive cells display a striking dependence on cell density with active Hh signaling requiring cell-to-cell contact. As the Hippo/YAP system is tightly linked to cell density control and contact inhibition, we investigated the cross-talk between the two pathways. Our data reveal that the suppression of Hh signaling in the absence of cellular contacts is independent of primary cilia and is mediated by the YAP oncogene. Overexpression of YAP blocks Hh signaling whereas RNA interference-mediated knockdown of YAP enhances Hh/GLI activity. Despite this negative regulation, Hh signaling promotes YAP activity through post-transcriptional mechanisms, resulting in a negative feedback loop. In vivo, we found strong nuclear YAP immunoreactivity restricted to compartments with low Hh pathway activity in human and mouse pancreatic cancer. Finally, we identified protease-activated receptors (PARs) as molecules being able to override the inverse Hippo/Hh regulation, potentially giving tumors a mechanism to utilize both oncogenic pathways in parallel. Nature Publishing Group 2014-08 2014-08-11 /pmc/articles/PMC5189961/ /pubmed/25111861 http://dx.doi.org/10.1038/oncsis.2014.27 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Short Communication
Tariki, M
Dhanyamraju, P K
Fendrich, V
Borggrefe, T
Feldmann, G
Lauth, M
The Yes-associated protein controls the cell density regulation of Hedgehog signaling
title The Yes-associated protein controls the cell density regulation of Hedgehog signaling
title_full The Yes-associated protein controls the cell density regulation of Hedgehog signaling
title_fullStr The Yes-associated protein controls the cell density regulation of Hedgehog signaling
title_full_unstemmed The Yes-associated protein controls the cell density regulation of Hedgehog signaling
title_short The Yes-associated protein controls the cell density regulation of Hedgehog signaling
title_sort yes-associated protein controls the cell density regulation of hedgehog signaling
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189961/
https://www.ncbi.nlm.nih.gov/pubmed/25111861
http://dx.doi.org/10.1038/oncsis.2014.27
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