Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome

  1. Michael N. Corradetti1,2,5,
  2. Ken Inoki1,2,5,6,
  3. Nabeel Bardeesy4,
  4. Ronald A. DePinho4, and
  5. Kun-Liang Guan1,2,3,7
  1. 1Life Sciences Institute, 2Department of Biological Chemistry, and 3Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109, USA; 4Department of Adult Oncology, Dana-Farber Cancer Institute, and Departments of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

Abstract

Tuberous sclerosis complex (TSC) and Peutz-Jeghers syndrome (PJS) are dominantly inherited benign tumor syndromes that share striking histopathological similarities. Here we show that LKB1, the gene mutated in PJS, acts as a tumor suppressor by activating TSC2, the gene mutated in TSC. Like TSC2, LKB1 inhibits the phosphorylation of the key translational regulators S6K and 4EBP1. Furthermore, we show that LKB1 activates TSC2 through the AMP-dependent protein kinase (AMPK), indicating that LKB1 plays a role in cell growth regulation in response to cellular energy levels. Our results suggest that PJS and other benign tumor syndromes could be caused by dysregulation of the TSC2/mTOR pathway.

Keywords

Footnotes

  • Supplemental material is available at http://www.genesdev.org.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1199104.

  • ↵5 These authors contributed equally to this work.

  • Corresponding authors.

  • ↵6 E-MAIL inokik{at}umich.edu; FAX (734) 647-9702.

  • ↵7 E-MAIL kunliang{at}umich.edu; FAX (734) 647-9702.

    • Accepted April 27, 2004.
    • Received February 29, 2004.
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  1. doi: 10.1101/gad.1199104 Genes & Dev. 18: 1533-1538 Cold Spring Harbor Laboratory Press

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