Glial cell line-derived neurotrophic factor-stimulated phosphatidylinositol 3-kinase and Akt activities exert opposing effects on the ERK pathway - Importance for the rescue of neuroectodermic cells

Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in rescuing neural crest cells from apoptosis during their migration in the fo regut. This survival factor binds to the heterodimer GDNF family receptor a lpha1/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 th eir importance in neuroectodermic cell survival still remain elusive. Using the neuroectodermic SK-N-MC cell line, we found that the Ret tyrosine kina se activity is essential for GDNF to induce phosphatidylinositol 3-kinase ( PI3K)/Akt and ERK pathways as well as cell rescue. We demonstrate that acti vation of PI3K is mandatory for GDNF-induced cell survival. In addition, ev idence 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 procaspas e-3 cleavage. Altogether, these findings underscore the importance of the R et/PI3K/Akt pathway in GDNF-induced neuroectodermic cell survival.