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Nerve growth factor, but not epidermal growth factor, increases Fra-2 expression and alters Fra-2/JunD binding to

V Boss1, J D Roback, A N Young

  • 1Departments of Pharmacology and Pathology, Emory University School of Medicine, Atlanta, Georgia 30329, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|January 11, 2001
PubMed

Insights

Nerve growth factor (NGF) and epidermal growth factor (EGF) trigger distinct cellular responses. Researchers identified a specific protein complex, Fra-2/JunD, activated by NGF but not EGF, suggesting its role in NGF-driven gene expression.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Nerve growth factor (NGF) and epidermal growth factor (EGF) activate similar signaling pathways in pheochromocytoma (PC12) cells.
  • Despite pathway similarity, NGF induces differentiation, while EGF promotes cell proliferation (mitogenesis).
  • Understanding the molecular basis for these divergent outcomes is crucial for cell signaling research.

Purpose of the Study:

  • To identify transcription factor activities unique to NGF signaling compared to EGF signaling.
  • To elucidate the specific molecular mechanisms underlying NGF-induced differentiation versus EGF-induced mitogenesis.
  • To characterize novel protein-DNA interactions in response to growth factor stimulation.

Main Methods:

  • Utilized a DNA recognition library with random oligonucleotide clones to isolate specific DNA-binding proteins from PC12 nuclear extracts.
  • Employed gel mobility shift assays and supershift assays to identify protein complexes and their DNA-binding partners.
  • Conducted time course experiments analyzing ERK phosphorylation, c-fos induction, and Fra-1/Fra-2 protein levels via Western blotting.

Main Results:

  • Identified a protein complex, Fra-2/JunD, with increased DNA binding activity specifically in NGF-treated cells, but not in EGF-treated cells.
  • Observed that NGF elicits a more delayed and sustained ERK phosphorylation compared to EGF.
  • NGF specifically increases Fra-1 and Fra-2 levels, with enhanced phosphorylation of Fra-2, suggesting its critical role in NGF signaling.

Conclusions:

  • Prolonged alterations in Fra-2 levels and Fra-2/JunD complex formation are key to NGF-specific gene expression programs.
  • The Fra-2/JunD complex's binding to AP-1 and CREB elements may orchestrate NGF-driven differentiation.
  • These findings highlight distinct downstream signaling events differentiating NGF and EGF actions in PC12 cells.

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