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The LKB1 tumor suppressor negatively regulates mTOR signaling

Reuben J Shaw1, Nabeel Bardeesy, Brendan D Manning

  • 1Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.

Cancer Cell
|July 21, 2004
PubMed

Insights

Loss of LKB1 function impairs mTOR repression, leading to elevated signaling in hamartomatous syndromes. This suggests mTOR inhibitors may treat Peutz-Jeghers syndrome.

Area of Science:

  • Cellular signaling pathways
  • Tumor suppressor genes
  • Metabolic regulation

Background:

  • Germline mutations in LKB1, TSC2, and PTEN cause hamartomatous syndromes with similar tumor characteristics.
  • LKB1 activates AMP-activated protein kinase (AMPK), which inhibits mTOR via TSC2.

Purpose of the Study:

  • To investigate the biochemical and biological relationship between LKB1 and mTOR regulation.
  • To determine if LKB1 is essential for mTOR repression under low ATP conditions.

Main Methods:

  • Utilized cultured cells and mouse embryonic fibroblasts (MEFs) lacking LKB1.
  • Analyzed signaling pathways downstream of mTOR in Lkb1 null MEFs and gastrointestinal polyps from Lkb1 mutant mice.

Main Results:

  • LKB1 is necessary for repressing mTOR under low ATP conditions, dependent on AMPK and TSC2.
  • Lkb1 null MEFs and Lkb1 mutant mouse polyps exhibit increased signaling downstream of mTOR.
  • Aberrant mTOR activation is implicated in the pathogenesis of these germline neoplastic conditions.

Conclusions:

  • Aberrant mTOR activation is a central mechanism in LKB1, TSC2, and PTEN-related hamartomatous syndromes.
  • mTOR inhibitors represent a potential therapeutic strategy for Peutz-Jeghers syndrome.

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