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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Bibliographic Details
Published in:Molecular biology of the cell 2021-09, Vol.32 (19), p.1807-1817
Main Authors: Peng, Hualing, Zhang, Jingyi, Ya, Amanda, Ma, Winston, Villa, Sammy, Sukenik, Shahar, Ge, Xuecai
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
Brief Reports
Cell Line, Tumor
Cell Proliferation - genetics
Cells, Cultured
Centrosome - metabolism
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics
Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
HEK293 Cells
Humans
Mice
Microscopy, Fluorescence - methods
NIH 3T3 Cells
Protein Binding
RNA Interference
Signal Transduction
Time-Lapse Imaging - methods
Zinc Finger Protein Gli2 - genetics
Zinc Finger Protein Gli2 - metabolism
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E21-02-0064