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

Mouhannad Malek, Anna Kielkowska, Tamara Chessa, Karen E. Anderson, David Barneda, Pınar Pir, Hiroki Nakanishi, Satoshi Eguchi, Atsushi Koizumi, Junko Sasaki, Véronique Juvin, Vladimir Y Kiselev, Izabella Niewczas, Alexander Gray, Alexandre Valayer, Dominik Spensberger, Marine Imbert, Sergio Felisbino, Tomonori Habuchi, Soren BeinkeSabina C. Cosulich, Nicolas Le Novère, Takehiko Sasaki, Jonathan Clark, Phillip T. Hawkins (Lead / Corresponding author), Len R. Stephens (Lead / Corresponding author)

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129 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)566-580.e10
Number of pages25
JournalMolecular Cell
Volume68
Issue number3
Early online date17 Oct 2017
DOIs
Publication statusPublished - 2 Nov 2017

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