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PDCD4 limits prooncogenic neuregulin-ErbB signaling.

Juan Carlos Montero1, Atanasio Pandiella2

  • 1Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC) and CIBERONC, Campus Miguel de Unamuno, 37007, Salamanca, Spain. jcmon@usal.es.

Cellular and Molecular Life Sciences : CMLS
|August 18, 2020
PubMed
Summary

Programmed cell death protein-4 (PDCD4) is identified as a novel mediator in neuregulin-ErbB signaling. Its phosphorylation promotes PDCD4 degradation, impacting neuregulin-driven cell proliferation, migration, and invasion.

Keywords:
Breast cancerErbB receptorsNeuregulinPDCD4

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Neuregulins and ErbB/HER receptors are crucial for mammalian development and tissue homeostasis.
  • Dysregulation of this signaling pathway is implicated in diseases like cancer and schizophrenia.

Purpose of the Study:

  • To identify novel mediators of the neuregulin-ErbB signaling pathway.
  • To elucidate the functional role of PDCD4 in neuregulin signaling.

Main Methods:

  • Phosphoproteomic analysis to identify differentially phosphorylated proteins.
  • Site-directed mutagenesis to pinpoint key phosphorylation sites.
  • Proteasome inhibition and subcellular localization studies.
  • Mechanistic studies involving mTORC1 and ERK1/2 signaling pathways.

Main Results:

  • Programmed cell death protein-4 (PDCD4) was identified as a novel neuregulin-ErbB signaling mediator.
  • Neuregulin treatment increased PDCD4 phosphorylation at serine 67, promoting its proteasomal degradation.
  • PDCD4 nuclear-to-cytosolic exit was essential for its degradation.
  • mTORC1 and ERK1/2 pathways were implicated in PDCD4 phosphorylation and degradation.
  • PDCD4 regulates neuregulin-mediated cell proliferation, migration, and invasion.

Conclusions:

  • PDCD4 acts as a key regulator in the neuregulin-ErbB signaling pathway.
  • Phosphorylation-dependent degradation of PDCD4 influences critical cellular processes.
  • This finding provides new insights into the molecular mechanisms underlying neuregulin signaling in normal physiology and disease.