Nogo-A interacts with TrkA to alter nerve growth factor signaling in Nogo-A-overexpressing PC12 cells

Nogo-A interacts with TrkA to alter nerve growth factor signaling in Nogo-A-overexpressing PC12... The Nogo-A protein, originally discovered as a potent myelin-associated inhibitor of neurite outgrowth, is also expressed by certain neurons, especially during development and after injury, but its role in neuronal function is not completely known. In this report, we overexpressed Nogo-A in PC12 cells to use as a model to identify potential neuronal signaling pathways affected by endogenously expressed Nogo-A. Unexpectedly, our results show that viability of Nogo-A-overexpressing cells was reduced progressively due to apoptotic cell death following NGF treatment, but only after 24 h. Inhibitors of neutral sphingomyelinase prevented this loss of viability, suggesting that NGF induced the activation of a ceramide-dependent cell death pathway. Nogo-A over-expression also changed NGF-induced phosphorylation of TrkA at tyrosines 490 and 674/675 from sustained to transient, and prevented the regulated intramembrane proteolysis of p75NTR, indicating that Nogo-A was altering the function of the two neurotrophin receptors. Co-immunoprecipitation studies revealed that there was a physical association between TrkA and Nogo-A which appeared to be dependent on interactions in the Nogo-A-specific region of the protein. Taken together, our results indicate that Nogo-A influences NGF-mediated mechanisms involving the activation of TrkA and its interaction with p75NTR. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cellular Signalling Elsevier

Nogo-A interacts with TrkA to alter nerve growth factor signaling in Nogo-A-overexpressing PC12 cells

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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier Ltd
ISSN
0898-6568
eISSN
1873-3913
D.O.I.
10.1016/j.cellsig.2018.01.003
Publisher site
See Article on Publisher Site

Abstract

The Nogo-A protein, originally discovered as a potent myelin-associated inhibitor of neurite outgrowth, is also expressed by certain neurons, especially during development and after injury, but its role in neuronal function is not completely known. In this report, we overexpressed Nogo-A in PC12 cells to use as a model to identify potential neuronal signaling pathways affected by endogenously expressed Nogo-A. Unexpectedly, our results show that viability of Nogo-A-overexpressing cells was reduced progressively due to apoptotic cell death following NGF treatment, but only after 24 h. Inhibitors of neutral sphingomyelinase prevented this loss of viability, suggesting that NGF induced the activation of a ceramide-dependent cell death pathway. Nogo-A over-expression also changed NGF-induced phosphorylation of TrkA at tyrosines 490 and 674/675 from sustained to transient, and prevented the regulated intramembrane proteolysis of p75NTR, indicating that Nogo-A was altering the function of the two neurotrophin receptors. Co-immunoprecipitation studies revealed that there was a physical association between TrkA and Nogo-A which appeared to be dependent on interactions in the Nogo-A-specific region of the protein. Taken together, our results indicate that Nogo-A influences NGF-mediated mechanisms involving the activation of TrkA and its interaction with p75NTR.

Journal

Cellular SignallingElsevier

Published: Apr 1, 2018

References

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