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, Len R. Stephens

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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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    Malek, M., Kielkowska, A., Chessa, T., Anderson, K. E., Barneda, D., Pir, P., Nakanishi, H., Eguchi, S., Koizumi, A., Sasaki, J., Juvin, V., Kiselev, V. Y., Niewczas, I., Gray, A., Valayer, A., Spensberger, D., Imbert, M., Felisbino, S., Habuchi, T., ... Stephens, L. R. (2017). PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K. Molecular Cell, 68(3), 566-580.e10. https://doi.org/10.1016/j.molcel.2017.09.024