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PI3K-mediated PDGFRα signaling regulates survival and proliferation in skeletal development through p53-dependent

Katherine A Fantauzzo1, Philippe Soriano

  • 1Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Genes & Development
|May 3, 2014
PubMed

Insights

Platelet-derived growth factor receptor alpha (PDGFRα) signaling, mediated by phosphatidylinositol 3-kinase (PI3K), is crucial for skeletal development. This study identifies p53 as a novel downstream effector regulating cell survival and proliferation during this process.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Phosphatidylinositol 3-kinase (PI3K) is a key downstream effector of Platelet-Derived Growth Factor Receptor alpha (PDGFRα) signaling in murine skeletal development.
  • Mutant mice lacking PI3K binding to PDGFRα exhibit significant skeletal defects, including issues with palatal shelves, shoulder girdle, vertebrae, and sternum.

Purpose of the Study:

  • To identify proteins phosphorylated by Akt downstream of PI3K-mediated PDGFRα signaling.
  • To elucidate the role of these identified proteins in skeletal development, focusing on cell survival and proliferation.

Main Methods:

  • Immunoprecipitation of Akt phosphorylation substrates from PDGF-AA-treated primary mouse embryonic palatal mesenchyme (MEPM) lysates.
  • Analysis of immunoprecipitated peptides using nanoliquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS).
  • Assessment of MEPM cell survival with PI3K inhibitors and proliferation in response to PDGF-AA in mutant cells; investigation of Ybox1-p53 interaction and Trp53 expression; analysis of vertebral defects in Trp53-null mutant mice.

Main Results:

  • A list of 56 proteins, including 10 involved in cell survival and proliferation, was identified as Akt phosphorylation substrates.
  • MEPM cell survival was impaired by PI3K inhibition, and mutant cells showed no proliferation in response to PDGF-AA.
  • Ybox1 was identified as a regulator of cell survival via p53, binding the Trp53 promoter and p53 protein, with decreased Trp53 expression observed upon PDGF-AA treatment.
  • Introduction of a Trp53-null allele mitigated vertebral defects in the PDGFRα mutant mice.

Conclusions:

  • p53 is identified as a novel effector downstream of PI3K-engaged PDGFRα signaling.
  • This pathway regulates cell survival and proliferation essential for skeletal development in vivo.
  • Targeting this pathway could offer therapeutic strategies for skeletal development disorders.
Keywords:
PDGFRαPI3Kp53proliferationskeletonsurvival

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