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The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress.

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.

Pubmed ID: 14985505


  • Shaw RJ
  • Kosmatka M
  • Bardeesy N
  • Hurley RL
  • Witters LA
  • DePinho RA
  • Cantley LC


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 9, 2004

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK35712
  • Agency: NCI NIH HHS, Id: P01CA89021
  • Agency: NIGMS NIH HHS, Id: R01 GM056203
  • Agency: NIGMS NIH HHS, Id: R01 GM56203

Mesh Terms

  • AMP-Activated Protein Kinases
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Carrier Proteins
  • Cell Line
  • Energy Metabolism
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • LLC-PK1 Cells
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Multienzyme Complexes
  • Phosphorylation
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Recombinant Proteins
  • Swine
  • Threonine
  • Tumor Suppressor Proteins