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Circling back to PTEN: Fumarate inhibits canonical tumor suppressor

Sally E Claridge1, Benjamin D Hopkins1

  • 1Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.

Molecular Cell
|April 8, 2022
PubMed

Insights

Fumarate modifies PTEN, an important tumor suppressor, revealing a new link between cell metabolism and PI3K signaling. This discovery suggests a feedforward loop regulating cell growth and metabolism.

Area of Science:

  • Biochemistry
  • Cellular Signaling
  • Metabolic Regulation

Background:

  • Phosphatase and tensin homolog (PTEN) is a critical tumor suppressor.
  • PTEN regulates the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, crucial for cell growth and survival.
  • Dysregulation of PTEN and PI3K signaling is implicated in various cancers.

Purpose of the Study:

  • To investigate the regulatory mechanisms of PTEN.
  • To explore the integration of cellular metabolism and PI3K signaling.
  • To identify novel post-translational modifications of PTEN.

Main Methods:

  • Biochemical assays to detect PTEN modification.
  • Analysis of fumarate levels in cellular contexts.
  • Investigation of the PI3K-glucose-fumarate-PTEN signaling axis.

Main Results:

  • Fumarate directly modifies PTEN at cysteine 211 (C211).
  • This modification inhibits PTEN activity.
  • A feedforward regulatory mechanism is proposed, linking PI3K signaling, glucose metabolism, and PTEN activity.

Conclusions:

  • Fumarate-mediated inhibition of PTEN represents a novel post-translational modification.
  • This finding provides insight into the crosstalk between cellular metabolism and oncogenic signaling pathways.
  • The identified PI3K-glucose-fumarate-PTEN axis offers a potential therapeutic target for cancer treatment.

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