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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.
Abstract:
The neuregulins and their ErbB/HER receptors play essential roles in mammalian development and tissue homeostasis. In addition, deregulation of their function has been linked to the pathogenesis of diseases such as cancer or schizophrenia. These circumstances have stimulated research into the biology of this ligand-receptor system. Here we show the identification of programmed cell death protein-4 (PDCD4) as a novel neuregulin-ErbB signaling mediator. Phosphoproteomic analyses identified PDCD4 as protein whose phosphorylation increased in cells treated with neuregulin. Mutagenesis experiments defined serine 67 of PDCD4 as a site whose phosphorylation increased upon activation of neuregulin receptors. Phosphorylation of that site promoted degradation of PDCD4 by the proteasome, which depended on exit of PDCD4 from the nucleus to the cytosol. Mechanistic studies defined mTORC1 and ERK1/2 as routes implicated in neuregulin-induced serine 67 phosphorylation and PDCD4 degradation. Functionally, PDCD4 regulated several important biological functions of neuregulin, such as proliferation, migration, or invasion.
Insights
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.
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.
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