Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection.
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.
Hashimoto
Makoto
M
Department of Neurosciences, University of California San Diego, La Jolla, California 92093-0624, USA.
Sagara
Yutaka
Y
Langford
Dianne
D
Everall
Ian P
IP
Mallory
Margaret
M
Everson
Analisa
A
Digicaylioglu
Murat
M
Masliah
Eliezer
E
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D053938:DNA Fragmentation; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism / Q000494:pharmacology*; D005822:Genetic Vectors; D018698:Glutamic Acid / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D016220:Fibroblast Growth Factor 1; D018698:Glutamic Acid; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D019763:Heparin Lyase; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D012694:Serine; D015534:Trans-Activators; D051176:beta Catenin; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat