PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K

  • Mol Cell. 2017 Nov 2;68(3):566-580.e10. doi: 10.1016/j.molcel.2017.09.024.
Mouhannad Malek  1 ,  Anna Kielkowska  1 ,  Tamara Chessa  1 ,  Karen E Anderson  1 ,  David Barneda  2 ,  Pınar Pir  1 ,  Hiroki Nakanishi  3 ,  Satoshi Eguchi  3 ,  Atsushi Koizumi  4 ,  Junko Sasaki  3 ,  Véronique Juvin  1 ,  Vladimir Y Kiselev  1 ,  Izabella Niewczas  1 ,  Alexander Gray  5 ,  Alexandre Valayer  1 ,  Dominik Spensberger  1 ,  Marine Imbert  1 ,  Sergio Felisbino  6 ,  Tomonori Habuchi  4 ,  Soren Beinke  7 ,  Sabina Cosulich  8 ,  Nicolas Le Novère  1 ,  Takehiko Sasaki  3 ,  Jonathan Clark  1 ,  Phillip T Hawkins  9 ,  Len R Stephens  10
Affiliations
  • 1. Signalling Programme, Babraham Institute, Cambridge, UK.
  • 2. Signalling Programme, Babraham Institute, Cambridge, UK; AstraZeneca R&D Cambridge, CRUK Cambridge Institute, Cambridge, UK.
  • 3. Department of Medical Biology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Japan.
  • 4. Department of Urology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Japan.
  • 5. School of Life Sciences, University of Dundee, Dow St., Dundee, UK.
  • 6. Department of Morphology, Institute of Biosciences of Botucatu, Sao Paulo State University - UNESP, Botucatu, Sao Paulo, Brazil.
  • 7. Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
  • 8. AstraZeneca R&D Cambridge, CRUK Cambridge Institute, Cambridge, UK.
  • 9. Signalling Programme, Babraham Institute, Cambridge, UK. Electronic address: [email protected].
  • 10. Signalling Programme, Babraham Institute, Cambridge, UK. Electronic address: [email protected].
PMID: 29056325 DOI: 10.1016/j.molcel.2017.09.024
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.
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