Fibroblast Growth Factor 1 Regulates Signaling via the Glycogen Synthase Kinase-3β Pathway

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-3␤ (GSK3␤), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3␤ by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3␤ 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 ␤-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3␤ recombinant adenovirus-associated virus increased activity of GSK3␤ and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3␤ inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3␤ by a pathway involving activation of the PI3K-Akt cascades.Neurotrophic factors are capable of maintaining particular neuronal populations during cellular stress. While some factors, such as nerve growth factor, support a narrowly defined neuronal population (e.g. cholinergic neurons), other factors such as fibroblast growth factor (FGF) 1 support more diverse populations (1). Among the more than 20 members of the FGF family (2, 3), FGF1 (or acidic FGF) is abundant in sensory and motor neurons, and FGF2 (or basic FGF) is primarily produced by astrocytes, although it can be taken up by neurons and translocated to the nucleus (4). Of the four FGF receptors (FGFRs), three are found in the brain: FGFR1 is mainly expressed on neurons, while FGFR2 and FGFR3 are found on glial cells (1, 2, 6, 7). Binding of FGF leads to dimerization of FGFR followed by tyrosine kinase activation (2). FGF2 promotes survival of cortical and hippocampal neurons (8, 9) and is also capable of rescuing neurons from denervation and injury (1). Similarly, FGF1 protects selective neuronal populations against the neurotoxic effects of molecules involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (10, 11) and HIV encephalitis (12).FGF1 and -2 are potent regulators of central nervous system development (13, 14) and maintenance after neuronal injury (1). However, there is no consensus as to the signal transduction pathways initiated by FGF during neuronal differentiation or during neuroprotection. Some studies suggest that during FGF2-induced neuronal differentiation (i) activation of a mitogen-activated protein kinase, such as extracellular signal-regulated kinases (ERK1 and ERK2), is neither necessary nor sufficient, (ii) activatio...

β-Synuclein Regulates Akt Activity in Neuronal Cells

“…Kinase activity assays were performed as previously described with some modifications (35). Briefly, for the Akt and PDK-1 assays, the cells were rinsed twice with cold phosphate-buffered saline and incubated for 20 min on ice in lysis buffer.…”

“…Cell viability was evaluated by MTT assay and trypan blue exclusion assay. MTT assays were performed as previously described (35). Briefly, 2.5 ϫ 10 3 cells/well were plated in 100 l of Dulbecco's modified Eagle's medium with 10% fetal calf serum in 96-well microtiter plates.…”

FGF1 inhibits p53-dependent apoptosis and cell cycle arrest via an intracrine pathway

“…FGF activities are usually transduced in cells by tyrosine kinase receptors. Exogenous FGF induces FGF-R phosphorylation, which may initiate various intracellular transduction pathways, such as those involving Ras/ MAP kinases, PLC-g and PI3K/Akt pathways (Johnson and Williams, 1993;Powers et al, 2000;Ong et al, 2001;Hashimoto et al, 2002). However, FGF1, like FGF2, lacks a secretion signal peptide, suggesting that neither of these factors are secreted by the classical secretion mechanism, consistent with their primarily intracellular distribution.…”

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

“…Previous work in our laboratory (21) and by others (22) using recombinant aFGF was able to increase the survival of neurons and increase the intrinsic capacity of mature neurons for regrowth; as a result, paraplegic rats showed remarkable functional recovery. Although a previous study has illustrated that aFGF is able to protect PC12 cells from glutamate-induced toxicity via the phosphatidylinositol 3-kinase (PI3K)/Akt kinase signaling pathway in vitro (23), the molecular intracellular signaling pathways of aFGF-induced functional recovery in injured spinal cord in vivo are still not clearly or fully understood. To further advance this area of study, it is of great importance to reveal the underlying molecular mechanisms involved in this vital functional recovery process.…”