The phosphatidylinositol-3 kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12 cells

Genes Cells. 2003 Aug;8(8):657-69. doi: 10.1046/j.1365-2443.2003.00663.x.

Abstract

Background: Previous studies have shown that phosphatidylinositol-3 kinase (PI3K) plays an important role in NGF (nerve growth factor)-induced neurite elongation. However, the roles of the PI3K pathway in neurite branch formation were not fully understood. Also, it was not clear where the PI3K pathway is activated during branch formation.

Results: We found that the treatment of PC12 cells with the PI3K inhibitor LY294002 resulted in a marked increase in the number of neurite branch points, suggesting a suppressive role of PI3K in neurite branch formation. Expression of a constitutively active form of Akt, a downstream effector of PI3K, decreased the number of branch points, whereas that of a dominant-negative form of Akt increased it. In contrast, inhibition of neither Rac, mTOR nor GSK3, other effectors of PI3K, promoted branch formation. Importantly, the phosphorylated form of endogenous Akt was localized at the tips of growth cones, but devoid of small branches in NGF-treated PC12 cells. A GFP-fusion protein of the plekstrin-homology (PH) domain of Akt was also localized at the tips of growth cones.

Conclusions: The PI3K-Akt pathway thus plays a key role in suppression of neurite branch formation in NGF-treated PC12 cells.

MeSH terms

  • Animals
  • Chromones / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Genes, Dominant
  • Green Fluorescent Proteins
  • Immunosuppressive Agents / pharmacology
  • Luminescent Proteins / metabolism
  • Morpholines / pharmacology
  • Nerve Growth Factor / pharmacology*
  • Neurites / physiology*
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • rac GTP-Binding Proteins / metabolism

Substances

  • Chromones
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Luminescent Proteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Green Fluorescent Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Nerve Growth Factor
  • Protein Kinases
  • mTOR protein, rat
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases
  • rac GTP-Binding Proteins
  • Sirolimus