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Analysis of Retinoic Acid-induced Neural Differentiation of Mouse Embryonic Stem Cells in Two and Three-dimensional Embryoid Bodies
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Abrogation of nerve growth factor-induced terminal differentiation by ret oncogene involves perturbation of nuclear

G L Colucci-D'Amato1, A D'Alessio, D Califano

  • 1Centro di Endocrinologia ed Oncologia Sperimentale del CNR "G. Salvatore," c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, via S. Pansini 5, Naples, Italy.

The Journal of Biological Chemistry
|June 20, 2000
PubMed

Insights

Oncogenic RET variants disrupt nerve growth factor (NGF) signaling in neuroendocrine tumors by impairing ERK activation. This leads to uncontrolled cell proliferation and prevents differentiation, highlighting MKP-3

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Oncogenic RET variants are implicated in neuroendocrine tumors, such as multiple endocrine neoplasia type 2.
  • These RET alterations likely interfere with antiproliferative and differentiative extracellular signals.
  • Nerve growth factor (NGF) signaling pathways are crucial for neuronal differentiation and survival.

Purpose of the Study:

  • To investigate the role of ERK signaling impairment in RET-induced NGF unresponsiveness.
  • To elucidate the molecular mechanisms by which oncogenic RET affects NGF-mediated cellular responses.
  • To understand how RET variants contribute to the loss of antiproliferative and differentiative signals in neuroendocrine cells.

Main Methods:

  • Utilized two rat pheochromocytoma-derived cell lines (PC12/MEN2A and PC12/MEN2B) stably transfected with active RET oncogenes.
  • Assessed ERK signaling activity, MKP-3 expression, and nuclear translocation of ERKs upon NGF stimulation.
  • Investigated the effect of forced MEK-1 expression on gene transcription and cell proliferation.

Main Results:

  • RET-transfected cells exhibit chronic ERK activity and elevated MKP-3 (an ERK-specific phosphatase) levels.
  • NGF stimulation fails to induce nuclear translocation of ERKs and immediate-early gene transcription in these cells.
  • Forced expression of active MEK-1 restores ERK nuclear translocation, c-fos promoter activity, and inhibits proliferation.

Conclusions:

  • MKP-3-mediated negative feedback on ERK signaling is a key mechanism abrogating NGF-induced terminal differentiation in RET-driven cancers.
  • Impaired ERK nuclear translocation due to MKP-3 activity contributes to uncontrolled proliferation in neuroendocrine tumors.
  • Targeting the MKP-3/ERK pathway may offer therapeutic strategies for RET-associated neuroendocrine neoplasms.

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