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p75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity in protection from enediyne
Chaohua Yan1, Ye Liang, Karen D Nylander
1The Pediatric Center for Neuroscience, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Abstract:
Growth factors, including nerve growth factor (NGF), have been hypothesized to play a role in resistance to chemotherapeutic agent-induced apoptosis. Induction by NGF of resistance to apoptosis is primarily thought to be the result of its binding to its high-affinity receptor, TrkA. The low-affinity NGF receptor, p75, has long been thought merely to facilitate NGF binding to TrkA. However, we have previously shown that the binding of NGF to its low-affinity receptor, p75, protects neuroblastoma cells that do not express TrkA against apoptosis induced by enediyne chemotherapeutic agents. In cells that express both receptors, it is not clear what determines which receptor is responsible for the protective effect of NGF. We now show that, in enediyne-treated SH-SY5Y neuroblastoma transfectants with native levels of p75 and a low TrkA/p75 ratio (1/100), the anti-apoptotic effect of NGF requires binding to p75. In contrast, in transfectants with native levels of p75 and a high TrkA/p75 ratio (100/100), NGF treatment prevents enediyne-induced apoptosis by a mechanism independent of p75 binding. Treatment of low TrkA/p75 ratio cells with NGF results in activation and nuclear translocation of NF-kappaB and tyrosine phosphorylation of TrkA. Analogous treatment of high TrkA/p75 ratio cells results only in phosphorylation of TrkA even though nuclear factor (NF)-kappaB signaling is not inactive and can be initiated by other ligands. The ratio of TrkA/p75 in cells that express both receptors probably contributes to the determination of which of the two known roles of p75 (i.e., TrkA independent or TrkA facilitatory) are responsible for NGF-mediated protection from enediyne-induced apoptosis.
Insights
Nerve growth factor (NGF) protects neuroblastoma cells from chemotherapy-induced apoptosis. The specific NGF receptor (TrkA or p75) involved depends on the TrkA/p75 ratio, influencing cell survival pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Nerve growth factor (NGF) is implicated in resistance to chemotherapy-induced apoptosis.
- NGF's anti-apoptotic effects are primarily attributed to its high-affinity receptor, TrkA.
- The low-affinity receptor, p75, was thought to only facilitate TrkA binding, but has shown independent protective roles.
Purpose of the Study:
- To investigate the role of TrkA/p75 receptor ratio in mediating NGF's protective effects against enediyne chemotherapeutic agents in neuroblastoma cells.
- To elucidate the signaling pathways activated by NGF binding to TrkA versus p75 in cells with different receptor ratios.
Main Methods:
- Utilized SH-SY5Y neuroblastoma transfectants with varying TrkA/p75 ratios (1/100 and 100/100).
- Treated cells with enediyne chemotherapeutic agents and NGF.
- Assessed apoptosis, receptor binding, NF-kappaB activation, and TrkA tyrosine phosphorylation.
Main Results:
- In cells with a low TrkA/p75 ratio (1/100), NGF's anti-apoptotic effect required p75 binding and activated NF-kappaB signaling.
- In cells with a high TrkA/p75 ratio (100/100), NGF prevented apoptosis independently of p75, primarily through TrkA phosphorylation.
- NF-kappaB signaling remained inducible in high TrkA/p75 cells, but was not the primary mediator of NGF's protective effect.
Conclusions:
- The ratio of TrkA to p75 receptors dictates the mechanism of NGF-mediated protection from enediyne-induced apoptosis in neuroblastoma.
- p75 mediates NGF's anti-apoptotic effects via NF-kappaB in low TrkA/p75 expressing cells.
- TrkA activation, independent of p75, confers protection in high TrkA/p75 expressing cells, highlighting context-dependent receptor function.