PTEN Regulates PI(3,4)P 2 Signaling Downstream of Class I PI3K

Mol Cell. 2017 Nov 2;68(3):566-580.e10. doi: 10.1016/j.molcel.2017.09.024. Epub 2017 Oct 19.

Abstract

The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P2 in the phenotype caused by loss-of-function mutations or deletions in PTEN.

Keywords: INPP4B; PI(3,4)P(2); PI(3,4,5)P(3); PI3K; PTEN; SHIP2; cancer; invadopodia; prostate.

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Epidermal Growth Factor / pharmacology
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phenotype
  • Phosphatidylinositols / metabolism*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Second Messenger Systems* / drug effects
  • Time Factors

Substances

  • Phosphatidylinositols
  • phosphoinositide-3,4-bisphosphate
  • Epidermal Growth Factor
  • Class I Phosphatidylinositol 3-Kinases
  • Phosphoric Monoester Hydrolases
  • phosphatidylinositol-3,4-bisphosphate 4-phosphatase
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse