Distinct phosphorylation patterns underlie Akt activation by different survival factors in neurons

The survival of cultured cerebellar granule neurons can be maintained by depolarizing levels of potassium (high K(+), HK), insulin-like growth factor (IGF-1), cyclic AMP or lithium. We examined the possibility that the signaling pathways activated by these different factors converge and that Akt might represent such a point of convergence. Consistent with this possibility, we find that Akt is phosphorylated and activated by all four survival factors. The pattern of Akt phosphorylation induced by the four survival factors, however, shows differences. While IGF-1 induces phosphorylation of Akt at both Ser473 and Thr308, HK and cyclic AMP stimulate phosphorylation at Thr308 only. Lithium increases phosphorylation at Ser473 but not at Thr308. Our results are consistent with the possibility that Akt is a central component of different survival-promoting pathways in granule neurons. The different phosphorylation patterns, however, point to a previously unappreciated complexity in the regulation of Akt activity in neurons. Finally, we provide evidence indicating that SGK, a kinase that is structurally related to Akt, is also activated by the four survival factors.