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Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Radha Mukherjee1, Kiran G Vanaja2, Jacob A Boyer1

  • 1Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Molecular Cell
|February 19, 2021
PubMed

Insights

The PI3K pathway

Area of Science:

  • Cellular signaling and cancer biology.
  • Molecular mechanisms of cancer progression and treatment resistance.

Background:

  • The phosphoinositide 3-kinase (PI3K) pathway is crucial for cell functions, and its aberrant activation is prevalent in various cancers.
  • PTEN acts as a key negative regulator of the PI3K pathway, maintaining cellular homeostasis.

Purpose of the Study:

  • To investigate the role of PTEN regulation in controlling PI3K pathway signaling duration and output.
  • To elucidate the impact of PTEN regulation on the efficacy of PI3K pathway inhibitors in cancer treatment.

Main Methods:

  • Analysis of PTEN expression in response to PI3K pathway activation (physiologic and oncogenic).
  • Investigation of the translational control of PTEN by mTOR/4E-BP1.
  • Assessment of PI3K pathway activity and inhibitor efficacy in models with altered PTEN and 4E-BP1 levels.

Main Results:

  • Both physiologic and oncogenic PI3K activation upregulate PTEN expression, limiting pathway signaling duration.
  • Inhibition of the PI3K pathway leads to decreased PTEN levels, contributing to pathway rebound and reduced efficacy of PI3K inhibitors.
  • mTOR/4E-BP1-dependent translational control of PTEN is identified as a major homeostatic mechanism, which is lost upon 4E-BP1 deletion.
  • Tumor cells with concurrent PI3K mutation and PTEN loss exhibit hyperactivated pathway output.

Conclusions:

  • Translational regulation of PTEN is a critical homeostatic mechanism for PI3K signaling.
  • This PTEN regulation influences the response to oncogenic PI3K activation and the effectiveness of PI3K inhibitors.
  • Understanding PTEN's role in PI3K pathway regulation is vital for developing more effective cancer therapies.
Keywords:
4E-BPBYL-719PI3K signalingPTEN regulationPTEN translationcomputational model of PI3K signalinggrowth factor signalingmTORnegative feedbackresistance to PI3K inhibition

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