Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
| Autor: | Xuecai Ge, Shahar Sukenik, Amanda Ya, Jingyi Zhang, Winston Ma, Hualing Peng, Sammy Villa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Scaffold protein
Gene isoform Zinc Finger Protein Gli2 Biology Time-Lapse Imaging Mice 03 medical and health sciences symbols.namesake 0302 clinical medicine Cell Line Tumor medicine Animals Humans Hedgehog Proteins education Molecular Biology Hedgehog Cells Cultured Adaptor Proteins Signal Transducing Cell Proliferation 030304 developmental biology Centrosome Medulloblastoma 0303 health sciences education.field_of_study Phosphodiesterase Cell Biology Golgi apparatus medicine.disease Cyclic AMP-Dependent Protein Kinases Hedgehog signaling pathway Cyclic Nucleotide Phosphodiesterases Type 4 3. Good health Cell biology Cytoskeletal Proteins HEK293 Cells Myomegalin Microscopy Fluorescence Cytoplasm NIH 3T3 Cells symbols Brief Reports RNA Interference 030217 neurology & neurosurgery Protein Binding Signal Transduction |
| Zdroj: | Molecular Biology of the Cell |
| DOI: | 10.1101/2020.04.24.059923 |
| Popis: | Mutations in the Hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma, 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, a centrosome/Golgi associated protein. Myomegalin loss dislocates PDE4D3 from the centrosome, leading to local PKA over-activation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Myomegalin loss suppresses the proliferation of granule neuron precursors, and blocks the growth of medulloblastoma 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. |
| Databáze: | OpenAIRE |
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