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Glial Cell Line-derived Neurotrophic Factor-stimulated Phosphatidylinositol 3-Kinase and Akt Activities Exert Opposing Effects on the ERK Pathway
Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in rescuing neural crest cells from apoptosis during their migration in the foregut. This survival factor binds to the heterodimer GDNF family receptor α1/Ret, inducing the Ret tyrosine kinase activity. ret loss-of-function mut...
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Published in: | The Journal of biological chemistry 2001-11, Vol.276 (48), p.45307-45319 |
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Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in rescuing neural crest cells from apoptosis during
their migration in the foregut. This survival factor binds to the heterodimer GDNF family receptor α1/Ret, inducing the Ret
tyrosine kinase activity. ret loss-of-function mutations result in Hirschsprung's disease, a frequent developmental defect of the enteric nervous system.
Although critical to enteric nervous system development, the intracellular signaling cascades activated by GDNF and their
importance in neuroectodermic cell survival still remain elusive. Using the neuroectodermic SK-N-MC cell line, we found that
the Ret tyrosine kinase activity is essential for GDNF to induce phosphatidylinositol 3-kinase (PI3K)/Akt and ERK pathways
as well as cell rescue. We demonstrate that activation of PI3K is mandatory for GDNF-induced cell survival. In addition, evidence
is provided for a critical up-regulation of the ERK pathway by PI3K at the level of Raf-1. Conversely, Akt inhibits the ERK
pathway. Thus, both PI3K and Akt act in concert to finely regulate the level of ERK. We found that Akt activation is indispensable
for counteracting the apoptotic signal on mitochondria, whereas ERK is partially involved in precluding procaspase-3 cleavage.
Altogether, these findings underscore the importance of the Ret/PI3K/Akt pathway in GDNF-induced neuroectodermic cell survival. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M101220200 |