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The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase
Fabien Llambi1, Filipe Calheiros Lourenço, Devrim Gozuacik
1Apoptosis, Cancer and Development Laboratory, Equipe labellisée La Ligue, CNRS FRE2870, Centre Leon Berard, Lyon, France.
The EMBO Journal
|February 25, 2005
Summary
Netrin-1 receptor UNC5H2 interacts with DAP-kinase, influencing cell death pathways. This interaction regulates DAP-kinase activity, suggesting a role in controlling cell fate.
Area of Science:
- Molecular Biology
- Neuroscience
- Cell Biology
Background:
- Netrin-1 receptors (UNC5H1-4) were initially linked to axonal guidance.
- UNC5H receptors function as dependence receptors, inducing apoptosis without netrin-1.
- These receptors are investigated for their potential as tumor suppressors.
Purpose of the Study:
- To investigate the interaction between UNC5H2 and death-associated protein kinase (DAP-kinase).
- To elucidate the role of this interaction in UNC5H2-mediated apoptosis and DAP-kinase activity.
- To understand how netrin-1 modulates this interaction and subsequent cell fate.
Main Methods:
- Co-immunoprecipitation assays in cell culture and embryonic mouse brains.
- Analysis of UNC5H2-induced apoptosis using dominant-negative DAP-kinase mutants.
- Assessment of DAP-kinase autophosphorylation and catalytic activity in the presence and absence of netrin-1.
Main Results:
- UNC5H2 physically interacts with DAP-kinase via their death domains.
- UNC5H2-induced apoptosis is partially dependent on DAP-kinase activity.
- Netrin-1 absence enhances UNC5H2-mediated DAP-kinase activation (reduced autophosphorylation, increased catalytic activity).
- Netrin-1 presence inhibits this activation.
Conclusions:
- The netrin-1/UNC5H2 pair regulates cell fate by modulating DAP-kinase's proapoptotic activity.
- This interaction provides a novel mechanism linking netrin signaling to apoptosis regulation.