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Mol Pharmacol. 2005 Apr;67(4):1195-205. Epub 2004 Dec 30.

Involvement of G i/o proteins in nerve growth factor-stimulated phosphorylation and degradation of tuberin in PC-12 cells and cortical neurons.

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  • 1Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.


Tuberin is a critical translation regulator whose role in nerve growth factor (NGF)-promoted neuronal survival has not been documented. In the present study, we examined the ability of NGF to regulate tuberin in PC-12 cells and primary cortical neurons. Incubation of serum-deprived cells with NGF stimulated tuberin phosphorylation and induced proteosome-mediated tuberin degradation. Inhibition of the phosphatidylinositol-3-kinase (PI3K) by wortmannin or overexpression of the kinase dead Akt mutant completely blocked the NGF-induced tuberin phosphorylation and degradation. It is interesting that the NGF-induced tuberin phosphorylation was partially blocked by pertussis toxin or overexpression of regulators of G protein signaling (regulator of G protein signaling Z1 and Galpha-interacting protein), suggesting the participation of G(i/o) proteins. The use of transducin as a Gbetagamma scavenger indicated that Gbetagamma subunits rather than Galpha(i/o) acted as the signal transducer. Epidermal growth factor can similarly induce tuberin phosphorylation and degradation via a PI3K/Akt pathway in PC-12 cells, but these responses were insensitive to pertussis toxin treatment. Treatment of PC-12 cells with a specific agonist to the G(i)-coupled alpha(2)-adrenoceptor also stimulated tuberin phosphorylation transiently, further demonstrating the involvement of G(i/o) signaling in tuberin regulation in PC-12 cells. Finally, overexpression of nonphosphorylable tuberin attenuated NGF-promoted survival of PC-12 cells, suggesting that the phosphorylation and degradation of tuberin are important for NGF-promoted cell survival. Together, this study demonstrates the regulatory effect of NGF and G(i/o) signaling on tuberin.

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