2. Academic Validation
  3. PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K

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

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: phillip.hawkins@babraham.ac.uk.
  • 10 Signalling Programme, Babraham Institute, Cambridge, UK. Electronic address: len.stephens@babraham.ac.uk.
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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