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.

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