Glial Cell Line-derived Neurotrophic Factor-stimulated Phosphatidylinositol 3-Kinase and Akt Activities Exert Opposing Effects on the ERK Pathway

Abstract

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 ␣1/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.

A Truncated Kringle Domain of Human Apolipoprotein(a) Inhibits the Activation of Extracellular Signal-regulated Kinase 1 and 2 through a Tyrosine Phosphatase-dependent Pathway

“…In this study we have consistently shown that selective inhibition of either ERK or PI3-K/Akt signaling, using U0126 or LY294002, almost completely prevented endothelial cell migration. Furthermore, although cross-talk between these adjacent signaling pathways has been reported previously (17), here activation of ERK and PI3-K/Akt signaling induced by bFGF, VEGF, or HGF appeared to occur without any cross-talk, because PI3-K inhibitors had no effect on ERK but abolished Akt phosphorylation, whereas MEK inhibitors significantly inhibited ERK activation without affecting Akt phosphorylation.…”

Signal Pathways in Up-regulation of Chemokines by Tyrosine Kinase MER/NYK in Prostate Cancer Cells

“…The activation of IL-8 by the tyrosine kinase RET was found to be augmented by PI3K inhibition (49). This is likely due to the opposing effects of AKT and ERK (50). It was reported that activated AKT is able to phosphorylate either c-Raf or B-Raf and negatively regulates Raf kinase activity, which in turn has a negative effect on signaling through Ras/MEK/ ERK to AP-1 (51,52).…”

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

“…36 These new evidences may explain the reduction of cell proliferation and tumor growth suppression induced by Gas1 in our model. Previous results have shown that GDNF and Ret are highly expressed in C6 cells, 37,38 and that GDNF exerts a powerful proliferative effect on them. 39 Therefore, we propose that the effects of GDNF on the proliferation of C6 cells is antagonized by the overexpression of gas1 and results in cell death (in preparation).…”