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Published on: June 15, 2017
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
Summary
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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