@article{128d4b9b39324c4eadc858afc2b8c68b,
title = "Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis",
abstract = "The PI3K pathway regulates cell metabolism, proliferation, and migration, and its dysregulation is common in cancer. We now show that both physiologic and oncogenic activation of PI3K signaling increase the expression of its negative regulator PTEN. This limits the duration of the signal and output of the pathway. Physiologic and pharmacologic inhibition of the pathway reduces PTEN and contributes to the rebound in pathway activity in tumors treated with PI3K inhibitors and limits their efficacy. Regulation of PTEN is due to mTOR/4E-BP1-dependent control of its translation and is lost when 4E-BP1 is deleted. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the pathway activation by oncogenic PIK3CA mutants and the antitumor activity of PI3K pathway inhibitors. However, pathway output is hyperactivated in tumor cells with coexistent PI3K mutation and loss of PTEN function.",
keywords = "4E-BP, BYL-719, PI3K signaling, PTEN regulation, PTEN translation, computational model of PI3K signaling, growth factor signaling, mTOR, negative feedback, resistance to PI3K inhibition",
author = "Radha Mukherjee and Vanaja, {Kiran G.} and Boyer, {Jacob A.} and Sunyana Gadal and Hilla Solomon and Sarat Chandarlapaty and Andre Levchenko and Neal Rosen",
note = "Funding Information: We thank the Memorial Sloan Kettering (MSK) Anti-tumor Assessment core for assistance with experiments and the Gene Editing and Screening Core for reagents. We thank the Britta Weigelt, John Blenis, Elizabeth Henske, and Josh Lauring labs for providing cell lines. N.R. and R.M. have been funded by grants from the National Institutes of Health (NIH) (R35 CA210085 and P01 CA094060 ); and from the Breast Cancer Research Foundation ( BCRF-20-141 ). They were also funded in part through the NIH/ NCI MSKCC Cancer Center Support Grant P30 CA008748 . A.L. and K.G.V. are funded by NIH grants R01 GM072024 and U54 CA209992 . We would like to acknowledge the support of the Arlene and Joseph Taub Foundation and of P. and T. McInerney, without whom this work would not have been possible. Funding Information: N.R. is on the scientific advisory boards (SABs) of and owns equity in BeiGene, Zai Lab, MAPCure, Ribon Therapeutics, and Fortress; is on the SABs of AstraZeneca and Chugai; consults with Novartis, Boehringer Ingelheim, RevMed, Eli Lilly, and Array-Pfizer; owns equity in Kura; and receives research support from Boehringer Ingelheim, AstraZeneca, and RevMed. S.C. has consulted with Eli Lilly, Novartis, Bristol Myers Squibb, Sermonix, and Paige.AI and receives research funding from Daiichi Sankyo. Funding Information: We thank the Memorial Sloan Kettering (MSK) Anti-tumor Assessment core for assistance with experiments and the Gene Editing and Screening Core for reagents. We thank the Britta Weigelt, John Blenis, Elizabeth Henske, and Josh Lauring labs for providing cell lines. N.R. and R.M. have been funded by grants from the National Institutes of Health (NIH) (R35 CA210085 and P01 CA094060); and from the Breast Cancer Research Foundation (BCRF-20-141). They were also funded in part through the NIH/NCI MSKCC Cancer Center Support Grant P30 CA008748. A.L. and K.G.V. are funded by NIH grants R01 GM072024 and U54 CA209992. We would like to acknowledge the support of the Arlene and Joseph Taub Foundation and of P. and T. McInerney, without whom this work would not have been possible. R.M. and N.R. designed the project, analyzed the data, and wrote the manuscript. K.G.V. and A.L. designed the computational model and wrote the manuscript. R.M. designed and performed the laboratory experiments. J.A.B. performed the translation assay and made the 4E-BP1KO and 4E-BP1-4A cell lines. S.G. performed the migration assay. S.C. analyzed experimental data and critically reviewed the work. N.R. is on the scientific advisory boards (SABs) of and owns equity in BeiGene, Zai Lab, MAPCure, Ribon Therapeutics, and Fortress; is on the SABs of AstraZeneca and Chugai; consults with Novartis, Boehringer Ingelheim, RevMed, Eli Lilly, and Array-Pfizer; owns equity in Kura; and receives research support from Boehringer Ingelheim, AstraZeneca, and RevMed. S.C. has consulted with Eli Lilly, Novartis, Bristol Myers Squibb, Sermonix, and Paige.AI and receives research funding from Daiichi Sankyo. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = feb,
day = "18",
doi = "10.1016/j.molcel.2021.01.033",
language = "English (US)",
volume = "81",
pages = "708--723.e5",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}