Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

Hualing Peng; Jingyi Zhang; Amanda Ya; Winston Ma; Sammy Villa; Shahar Sukenik; Xuecai Ge

doi:10.1091/mbc.E21-02-0064

Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

Mol Biol Cell. 2021 Sep 1;32(19):1807-1817. doi: 10.1091/mbc.E21-02-0064. Epub 2021 Jul 14.

Authors

Hualing Peng¹, Jingyi Zhang¹, Amanda Ya¹, Winston Ma¹, Sammy Villa¹, Shahar Sukenik², Xuecai Ge¹

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Merced, Merced, CA 95340.
² Department of Chemistry and Chemical Biology, University of California, Merced, Merced, CA 95340.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
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*
HEK293 Cells
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism*
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

Substances

Adaptor Proteins, Signal Transducing
Cytoskeletal Proteins
Hedgehog Proteins
PDE4DIP protein, human
Zinc Finger Protein Gli2
Cyclic AMP-Dependent Protein Kinases
Cyclic Nucleotide Phosphodiesterases, Type 4

Grants and funding

R15 CA235749/CA/NCI NIH HHS/United States