2. Academic Validation
  3. Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

  • Mol Cell. 2021 Feb 18;81(4):708-723.e5. doi: 10.1016/j.molcel.2021.01.033.
Radha Mukherjee 1,  Kiran G Vanaja 2,  Jacob A Boyer 1,  Sunyana Gadal 1,  Hilla Solomon 1,  Sarat Chandarlapaty 3,  Andre Levchenko 4,  Neal Rosen 5
Affiliations

Affiliations

  • 1 Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Yale Systems Biology Institute, Yale University, Orange, CT 06477, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
  • 3 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Yale Systems Biology Institute, Yale University, Orange, CT 06477, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. Electronic address: [email protected].
  • 5 Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 33606974 DOI: 10.1016/j.molcel.2021.01.033
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.

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