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 Beinke; Sabina C. Cosulich; Nicolas Le Novère; Takehiko Sasaki; Jonathan Clark; Phillip T. Hawkins; Len R. Stephens

doi:10.1016/j.molcel.2017.09.024

PTEN Regulates PI(3,4)P₂Signaling 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 Beinke

Sabina C. Cosulich, Nicolas Le Novère, Takehiko Sasaki, Jonathan Clark, Phillip T. Hawkins (Lead / Corresponding author), Len R. Stephens (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	566-580.e10
Number of pages	25
Journal	Molecular Cell
Volume	68
Issue number	3
Early online date	17 Oct 2017
DOIs	https://doi.org/10.1016/j.molcel.2017.09.024
Publication status	Published - 2 Nov 2017

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Copyright 2017 The Authors. Published by Elsevier Inc. This article is available under the terms of the Creative Commons Attribution License (CC BY). You may copy and distribute the article, create extracts, abstracts and new works from the article, alter and revise the article, text or data mine the article and otherwise reuse the article commercially (including reuse and/or resale of the article) without permission from Elsevier. You must give appropriate credit to the original work, together with a link to the formal publication through the relevant DOI and a link to the Creative Commons user license above. You must indicate if any changes are made but not in any way that suggests the licensor endorses you or your use of the work. Permission is not required for this type of reuse.
Final published version, 4.79 MBLicence: CC BY

Gray, Alexander
- Leverhulme Research Centre for Forensic Science - Principal Investigator
Person: Research

Cite this

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)P₂Signaling Downstream of Class I PI3K. Molecular Cell, 68(3), 566-580.e10. https://doi.org/10.1016/j.molcel.2017.09.024

@article{b785f16867bb4d3e8393f2b523d77d58,

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

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.",

author = "Mouhannad Malek and Anna Kielkowska and Tamara Chessa and Anderson, \{Karen E.\} and David Barneda and Pınar Pir and Hiroki Nakanishi and Satoshi Eguchi and Atsushi Koizumi and Junko Sasaki and V{\'e}ronique Juvin and Kiselev, \{Vladimir Y\} and Izabella Niewczas and Alexander Gray and Alexandre Valayer and Dominik Spensberger and Marine Imbert and Sergio Felisbino and Tomonori Habuchi and Soren Beinke and Cosulich, \{Sabina C.\} and \{Le Nov{\`e}re\}, Nicolas and Takehiko Sasaki and Jonathan Clark and Hawkins, \{Phillip T.\} and Stephens, \{Len R.\}",

note = "N.L.N., L.R.S. and P.T.H. acknowledge financial support from the BBSRC (BB/J004456/1, BB/I003428/1, and BB/I003916/1) and The Wellcome Trust (WT085889MA). T.S. acknowledges financial support from the Japan Society for the Promotion of Science (JSPS) (KAKENHI grant JP15H05899) and the Japan Agency for Medical Research and Development (AMED) (grant 16gm0710002h0304). A. Kielkowska is in receipt of a BBSRC-CASE PhD studentship with GSK. ",

year = "2017",

month = nov,

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doi = "10.1016/j.molcel.2017.09.024",

language = "English",

volume = "68",

pages = "566--580.e10",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "3",

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Malek, M, Kielkowska, A, Chessa, T, Anderson, KE, Barneda, D, Pir, P, Nakanishi, H, Eguchi, S, Koizumi, A, Sasaki, J, Juvin, V, Kiselev, VY, Niewczas, I, Gray, A, Valayer, A, Spensberger, D, Imbert, M, Felisbino, S, Habuchi, T, Beinke, S, Cosulich, SC, Le Novère, N, Sasaki, T, Clark, J, Hawkins, PT & Stephens, LR 2017, 'PTEN Regulates PI(3,4)P₂Signaling Downstream of Class I PI3K', Molecular Cell, vol. 68, no. 3, pp. 566-580.e10. https://doi.org/10.1016/j.molcel.2017.09.024

TY - JOUR

T1 - PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K

AU - Malek, Mouhannad

AU - Kielkowska, Anna

AU - Chessa, Tamara

AU - Anderson, Karen E.

AU - Barneda, David

AU - Pir, Pınar

AU - Nakanishi, Hiroki

AU - Eguchi, Satoshi

AU - Koizumi, Atsushi

AU - Sasaki, Junko

AU - Juvin, Véronique

AU - Kiselev, Vladimir Y

AU - Niewczas, Izabella

AU - Gray, Alexander

AU - Valayer, Alexandre

AU - Spensberger, Dominik

AU - Imbert, Marine

AU - Felisbino, Sergio

AU - Habuchi, Tomonori

AU - Beinke, Soren

AU - Cosulich, Sabina C.

AU - Le Novère, Nicolas

AU - Sasaki, Takehiko

AU - Clark, Jonathan

AU - Hawkins, Phillip T.

AU - Stephens, Len R.

N1 - N.L.N., L.R.S. and P.T.H. acknowledge financial support from the BBSRC (BB/J004456/1, BB/I003428/1, and BB/I003916/1) and The Wellcome Trust (WT085889MA). T.S. acknowledges financial support from the Japan Society for the Promotion of Science (JSPS) (KAKENHI grant JP15H05899) and the Japan Agency for Medical Research and Development (AMED) (grant 16gm0710002h0304). A. Kielkowska is in receipt of a BBSRC-CASE PhD studentship with GSK.

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2017.09.024

DO - 10.1016/j.molcel.2017.09.024

M3 - Article

C2 - 29056325

SN - 1097-2765

VL - 68

SP - 566-580.e10

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -

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

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PTEN Regulates PI(3,4)P₂Signaling Downstream of Class I PI3K