Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4-phosphatase-1

EMBO Rep. 2009 May;10(5):487-93. doi: 10.1038/embor.2009.28. Epub 2009 Mar 27.

Abstract

Akt is a crucial phosphoinositide 3-kinase (PI(3)K) effector that regulates cell proliferation and survival. PI(3)K-generated signals, PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2), direct Akt plasma membrane engagement. Pathological Akt plasma membrane association promotes oncogenesis. PtdIns(3,4)P(2) is degraded by inositol polyphosphate 4-phosphatase-1 (4-ptase-1) forming PtdIns(3)P; however, the role of 4-ptase-1 in regulating the activation and function of Akt is unclear. In mouse embryonic fibroblasts lacking 4-ptase-1 ((-/-)MEFs), the Akt-pleckstrin homology (PH) domain was constitutively membrane-associated both in serum-starved and agonist-stimulated cells, in contrast to (+/+)MEFs, in which it was detected only at the plasma membrane following serum stimulation. Epidermal growth factor (EGF) stimulation resulted in increased Ser(473) and Thr(308)-Akt phosphorylation and activation of Akt-dependent signalling in (-/-)MEFs, relative to (+/+)MEFs. Significantly, loss of 4-ptase-1 resulted in increased cell proliferation and decreased apoptosis. SV40-transformed (-/-)MEFs showed increased anchorage-independent cell growth and formed tumours in nude mice. This study provides the first evidence, to our knowledge, that 4-ptase-1 controls the activation of Akt and thereby cell proliferation, survival and tumorigenesis.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Staurosporine / pharmacology

Substances

  • Epidermal Growth Factor
  • Cycloheximide
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • inositol-1,4-bisphosphate 1-phosphatase
  • Staurosporine