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Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

Mutations in the hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma (MB), one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our...

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Autores principales: Peng, Hualing, Zhang, Jingyi, Ya, Amanda, Ma, Winston, Villa, Sammy, Sukenik, Shahar, Ge, Xuecai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684712/
https://www.ncbi.nlm.nih.gov/pubmed/34260267
http://dx.doi.org/10.1091/mbc.E21-02-0064
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author Peng, Hualing
Zhang, Jingyi
Ya, Amanda
Ma, Winston
Villa, Sammy
Sukenik, Shahar
Ge, Xuecai
author_facet Peng, Hualing
Zhang, Jingyi
Ya, Amanda
Ma, Winston
Villa, Sammy
Sukenik, Shahar
Ge, Xuecai
author_sort Peng, Hualing
collection PubMed
description Mutations in the hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma (MB), one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study, we found that a specific isoform PDE4D3 is tethered to the centrosome by Myomegalin (Mmg), a centrosome/Golgi-associated protein. Mmg loss dislocates PDE4D3 from the centrosome, leading to local PKA overactivation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Mmg loss suppresses the proliferation of granule neuron precursors and blocks the growth of MB in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.
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spelling pubmed-86847122021-12-21 Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome Peng, Hualing Zhang, Jingyi Ya, Amanda Ma, Winston Villa, Sammy Sukenik, Shahar Ge, Xuecai Mol Biol Cell Brief Reports Mutations in the hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma (MB), one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study, we found that a specific isoform PDE4D3 is tethered to the centrosome by Myomegalin (Mmg), a centrosome/Golgi-associated protein. Mmg loss dislocates PDE4D3 from the centrosome, leading to local PKA overactivation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Mmg loss suppresses the proliferation of granule neuron precursors and blocks the growth of MB in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects. The American Society for Cell Biology 2021-09-01 /pmc/articles/PMC8684712/ /pubmed/34260267 http://dx.doi.org/10.1091/mbc.E21-02-0064 Text en © 2021 Peng et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. https://creativecommons.org/licenses/by-nc-sa/3.0/This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Brief Reports
Peng, Hualing
Zhang, Jingyi
Ya, Amanda
Ma, Winston
Villa, Sammy
Sukenik, Shahar
Ge, Xuecai
Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
title Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
title_full Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
title_fullStr Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
title_full_unstemmed Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
title_short Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
title_sort myomegalin regulates hedgehog pathway by controlling pde4d at the centrosome
topic Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684712/
https://www.ncbi.nlm.nih.gov/pubmed/34260267
http://dx.doi.org/10.1091/mbc.E21-02-0064
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