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TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction
1The Burnham Institute, La Jolla, California 92037, USA.
Abstract:
The common neurotrophin receptor, p75(NTR), has been shown to signal in the absence of Trk tyrosine kinase receptors, including induction of neural apoptosis and activation of NF-kappaB. However, the mechanisms by which p75(NTR) initiates these intracellular signal transduction pathways are unknown. Here we report interactions between p75(NTR) and the six members of TRAF (tumor necrosis factor receptor-associated factors) family proteins. The binding of different TRAF proteins to p75(NTR) was mapped to distinct regions in p75(NTR). Furthermore, TRAF4 interacted with dimeric p75(NTR), whereas TRAF2 interacted preferentially with monomeric p75(NTR). TRAF2-p75(NTR), TRAF4-p75(NTR), and TRAF6-p75(NTR) interactions modulated p75(NTR)-induced cell death and NF-kappaB activation with contrasting effects. Coexpression of TRAF2 with p75(NTR) enhanced cell death, whereas coexpression of TRAF6 was cytoprotective. Furthermore, overexpression of TRAF4 abrogated the ability of dimerization to prevent the induction of apoptosis normally mediated by monomeric p75(NTR). TRAF4 also inhibited the NF-kappaB response, whereas TRAF2 and TRAF6 enhanced p75(NTR)-induced NF-kappaB activation. These results demonstrate that TRAF family proteins interact with p75(NTR) and differentially modulate its NF-kappaB activation and cell death induction.
Insights
Tumor necrosis factor receptor-associated factors (TRAFs) interact with the neurotrophin receptor p75(NTR), influencing neural cell death and NF-kappaB activation. These TRAF proteins differentially modulate p75(NTR) signaling pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- The p75 neurotrophin receptor (p75(NTR)) mediates intracellular signaling, including neural apoptosis and NF-kappaB activation, independently of Trk receptors.
- The precise molecular mechanisms underlying p75(NTR)-initiated signaling remain largely unelucidated.
Purpose of the Study:
- To investigate the interactions between p75(NTR) and the six members of the TRAF (tumor necrosis factor receptor-associated factors) protein family.
- To determine how these interactions modulate p75(NTR)-mediated signaling pathways, specifically cell death and NF-kappaB activation.
Main Methods:
- Mapping of TRAF protein binding sites to distinct regions of p75(NTR).
- Analysis of TRAF2, TRAF4, and TRAF6 interactions with monomeric and dimeric forms of p75(NTR).
- Assessment of the effects of TRAF-p75(NTR) interactions on p75(NTR)-induced apoptosis and NF-kappaB activation via coexpression studies.
Main Results:
- Specific TRAF proteins bind to distinct regions of p75(NTR).
- TRAF4 binds to dimeric p75(NTR), while TRAF2 preferentially binds to monomeric p75(NTR).
- TRAF2 enhances p75(NTR)-induced cell death, TRAF6 is cytoprotective, and TRAF4 inhibits apoptosis. TRAF2 and TRAF6 enhance NF-kappaB activation, while TRAF4 inhibits it.
Conclusions:
- TRAF family proteins physically interact with p75(NTR).
- These interactions differentially regulate p75(NTR)-induced cell death and NF-kappaB activation.
- TRAF proteins serve as crucial mediators in p75(NTR) signaling pathways, with distinct functional outcomes.