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Intact Ras function is required for sustained activation and nuclear translocation of extracellular signal-regulated

G Boglári1, P Erhardt, G M Cooper

  • 1Department of Medical Biology, University Medical School of Pécs, Hungary.

European Journal of Cell Biology
|April 2, 1998
PubMed

Insights

Nerve growth factor (NGF) triggers neurite outgrowth in PC12 cells via sustained extracellular signal-regulated kinase (ERK) activation and nuclear translocation. Inhibiting Ras protein disrupts this process, highlighting ERK signaling

Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • PC12 pheochromocytoma cells are a model system for studying neuronal differentiation.
  • Nerve growth factor (NGF) is a key signaling molecule that induces neurite outgrowth in PC12 cells.
  • Mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinases (ERKs), are involved in cellular signaling and differentiation.

Purpose of the Study:

  • To investigate the role of Ras protein in modulating NGF-induced MAPK activation and neuritogenesis in PC12 cells.
  • To determine the relationship between ERK activation, nuclear translocation, and neurite outgrowth.
  • To elucidate the necessity of sustained ERK signaling for neuronal differentiation.

Main Methods:

  • Utilized PC12 cell lines engineered to express varying levels of dominant-negative Ha-Ras Asn-17.
  • Administered NGF to stimulate signaling pathways.
  • Monitored ERK activation, nuclear translocation, and neurite outgrowth using biochemical and imaging techniques.

Main Results:

  • NGF rapidly stimulated ERK activation in wild-type PC12 cells, leading to sustained activation, nuclear translocation, and neurite outgrowth.
  • High levels of dominant-negative Ras significantly inhibited NGF-induced ERK activation and nuclear translocation.
  • Low levels of dominant-negative Ras resulted in transient ERK activation that was not followed by nuclear translocation, and blocked neurite formation.

Conclusions:

  • Sustained activation of ERKs is crucial for NGF-induced neuronal differentiation in PC12 cells.
  • Nuclear translocation of ERKs is an essential downstream event for neuritogenesis.
  • The Ras pathway plays a critical role in regulating the duration and efficacy of ERK signaling during NGF-induced differentiation.

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