Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis Journal Article

Authors: Mukherjee, R.; Vanaja, K. G.; Boyer, J. A.; Gadal, S.; Solomon, H.; Chandarlapaty, S.; Levchenko, A.; Rosen, N.
Article 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. © 2021 Elsevier Inc. Mukherjee et al. show that PI3K pathway homeostasis is mediated by its control of translation of PTEN, its negative regulator. Perturbations of the pathway are buffered by changes in PTEN expression, thus limiting the effects of physiologic and oncogenic pathway activation and reducing the therapeutic effects of pathway inhibitors. © 2021 Elsevier Inc.
Keywords: negative feedback; mtor; growth factor signaling; pi3k signaling; 4e-bp; byl-719; computational model of pi3k signaling; pten regulation; pten translation; resistance to pi3k inhibition
Journal Title: Molecular Cell
Volume: 81
Issue: 4
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2021-02-18
Start Page: 708
End Page: 723.e5
Language: English
DOI: 10.1016/j.molcel.2021.01.033
PROVIDER: scopus
PUBMED: 33606974
PMCID: PMC8384339
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Neal Rosen
    412 Rosen
  2. Sunyana   Gadal
    3 Gadal
  3. Jacob Andrew Boyer
    4 Boyer