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Cbl negatively regulates JNK activation and cell death

Andrew A Sproul1, Zhiheng Xu, Michael Wilhelm

  • 1Department of Biological Sciences, Columbia University, New York, New York, USA.

Cell Research
|June 24, 2009
PubMed

Insights

Cbl proteins (c-Cbl and Cbl-b) normally protect neurons from apoptosis by inhibiting mixed lineage kinase (MLK) 3 signaling. Loss of Cbl proteins unleashes MLK3, activating JNK signaling and promoting neuronal cell death.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Cbl proteins (c-Cbl and Cbl-b) are known regulators of cellular signaling.
  • Neuronal apoptosis is a critical process implicated in neurodegenerative diseases.
  • The precise role of Cbl proteins in neuronal apoptosis remains incompletely understood.

Purpose of the Study:

  • To investigate the function of Cbl proteins in regulating neuronal apoptosis.
  • To elucidate the molecular mechanisms by which Cbl proteins influence neuronal cell death pathways.

Main Methods:

  • Utilized nerve growth factor (NGF) deprivation and DNA damage models of neuronal apoptosis.
  • Employing small interfering RNA (siRNA) to knockdown c-Cbl and Cbl-b expression.
  • Investigated interactions between Cbl proteins and c-Jun N-terminal kinase (JNK) pathway components, including mixed lineage kinase (MLK) 3 and POSH.
  • Assessed JNK pathway activity and neuronal cell viability.

Main Results:

  • Cellular levels of c-Cbl and Cbl-b decreased prior to neuronal cell death in both apoptosis models.
  • NGF deprivation led to a loss of c-Cbl tyrosine phosphorylation and activation.
  • siRNA-mediated knockdown of c-Cbl and Cbl-b sensitized neurons to apoptosis.
  • Cbl proteins were found to interact with MLK3 and POSH, inhibiting JNK pathway activation.
  • Overexpression of c-Cbl protected neurons from MLK-induced death but not from downstream JNK activators.

Conclusions:

  • Cbl proteins act as crucial suppressors of neuronal apoptosis.
  • Cbl proteins inhibit MLK-mediated activation of JNK signaling, thereby preventing cell death.
  • Loss or inactivation of Cbl proteins removes a critical brake on JNK signaling, promoting neuronal apoptosis.

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