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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

Academic Article
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Overview

authors

  • Subramaniam, Srinivasa
  • Shahani, N.
  • Strelau, J.
  • Laliberte, C.
  • Brandt, R.
  • Kaplan, D.
  • Unsicker, K.

publication date

  • March 2005

journal

  • Journal of Neuroscience  Journal

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.

subject areas

  • 8-Bromo Cyclic Adenosine Monophosphate
  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Cell Survival
  • Cells, Cultured
  • Cerebellum
  • Cyclic AMP-Dependent Protein Kinases
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation
  • Enzyme Inhibitors
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases
  • Gene Expression Regulation, Enzymologic
  • Green Fluorescent Proteins
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Indoles
  • Insulin-Like Growth Factor I
  • Neurons
  • Phosphatidylinositol 3-Kinases
  • Potassium Chloride
  • Proto-Oncogene Proteins c-raf
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine
  • Signal Transduction
  • Time Factors
  • Transfection
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Research

keywords

  • ERK
  • PI3K
  • PKA
  • Raf-S259A
  • Sindbis virus
  • neuronal death
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Identity

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.5060-04.2005

PubMed ID

  • 15772344
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Additional Document Info

start page

  • 2838

end page

  • 2852

volume

  • 25

issue

  • 11

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