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Insulin-like growth factor 1 inhibits extracellular signal-regulated kinase to promote neuronal survival via the phosphatidylinositol 3-kinase/protein kinase A/c-Raf pathway
- Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience. 25(11)
- Publication Year :
- 2005
-
Abstract
- Extracellular signal-regulated kinase (ERK) activation has been shown to promote neuronal death in various paradigms. We demonstrated previously that the late and sustained ERK activation in cerebellar granule neurons (CGNs) cultured in low potassium predominantly promotes plasma membrane (PM) damage. Here, we examined the effects of a well established neuronal survival factor, insulin-like growth factor 1 (IGF-1), on the ERK cell death pathway. Stimulation of CGNs with IGF-1 induced an early and transient ERK activation but abrogated the appearance of late and sustained ERK. Withdrawal or readdition of IGF-1 after 4 h in low potassium failed to prevent sustained ERK activation and cell death. IGF-1 activated the protein kinase A (PKA) to mediate ERK inhibition via c-Raf phosphorylation at an inhibitory site (Ser259). Phosphatidylinositol 3-kinase (PI3K) or PKA inhibitors, but not a specific Akt inhibitor, abrogated PKA signaling. This suggests that the PI3K/PKA/c-Raf-Ser259 pathway mediates ERK inhibition by IGF-1 independent of Akt. In addition, adenoviral-mediated expression of constitutively active MEK (mitogen-activated protein kinase kinase) or Sindbis viral-mediated expression of mutant Raf Ser259Ala both attenuated IGF-1-mediated prevention of PM damage. Activation of caspase-3 promoted DNA damage. Its inhibition by IGF-1 was both PI3K and Akt dependent but PKA independent. 8-Br-cAMP, an activator of PKA, induced phosphorylation of c-Raf-Ser259 and inhibited ERK activation without affecting caspase-3. This indicates a selective role for PKA in ERK inhibition through c-Raf-Ser259 phosphorylation. Together, these data demonstrate that IGF-1 can positively and negatively regulate the ERK pathway in the same neuronal cell, and provide new insights into the PI3K/Akt/PKA signaling pathways in IGF-1-mediated neuronal survival.
- Subjects :
- MAPK/ERK pathway
Indoles
Time Factors
Cell Survival
Blotting, Western
Green Fluorescent Proteins
8-Bromo Cyclic Adenosine Monophosphate
Enzyme-Linked Immunosorbent Assay
Mitogen-activated protein kinase kinase
Transfection
Gene Expression Regulation, Enzymologic
Potassium Chloride
Phosphatidylinositol 3-Kinases
Cerebellum
In Situ Nick-End Labeling
Serine
Animals
Drug Interactions
c-Raf
RNA, Messenger
Enzyme Inhibitors
Insulin-Like Growth Factor I
Rats, Wistar
Protein kinase A
Extracellular Signal-Regulated MAP Kinases
Protein kinase B
PI3K/AKT/mTOR pathway
Cells, Cultured
Neurons
MAP kinase kinase kinase
Dose-Response Relationship, Drug
Akt/PKB signaling pathway
Chemistry
Reverse Transcriptase Polymerase Chain Reaction
General Neuroscience
Cyclic AMP-Dependent Protein Kinases
Immunohistochemistry
Cell biology
Rats
Enzyme Activation
Proto-Oncogene Proteins c-raf
Animals, Newborn
Signal Transduction
Cellular/Molecular
Subjects
Details
- ISSN :
- 15292401
- Volume :
- 25
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Accession number :
- edsair.doi.dedup.....b045e8e864e9f499ddc520afc368162e