Abstract
We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.
Highlights
We hypothesize that in neurodegenerative disorders such as Alzheimer’s disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3 (GSK3), a pathway important in determining cell fate
FGF1 Regulation of GSK3 Activity Is Dependent on the phosphatidylinositol 3-kinase (PI3K)-Acknowledgments—We thank Dr Kenneth Walsh (Akt) Pathway—Since time course experiments (Fig. 1) suggested that the effects of FGF1 on GSK3 might be mediated via either the PI3K-Akt or the ERK signaling pathways, further analysis of the molecular events was conducted by treating cells with the PI3K inhibitor LY294002 or the ERK inhibitors U0126 and PD98059 prior to FGF1 stimulation
Inhibitors of the ERK pathway completely blocked FGF1-mediated ERK phosphorylation with only slight effects on Akt and GSK3 phosphorylation (Fig. 3). Taken together these results indicate that phosphorylation of GSK3 by FGF1 stimulation is mediated via the PI3K-Akt pathway but is independent of ERK
Summary
We hypothesize that the neurotrophic effects of FGF1 might involve regulation of other signaling cascades such as the glycogen synthase kinase-3 (GSK3) pathway, which is important in determining cell fate [18, 19]. Supporting this possibility, a recent study showed that FGF2-mediated tau hyperphosphorylation was inhibited by lithium, an inhibitor of GSK3, but not by inhibitors of ERK or the cyclin-dependent kinases [20]. Our results suggest that the neuroprotective properties of FGF1 might involve phosphorylation-mediated inactivation of GSK3 via the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway
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