The Tumor Suppressor LKB1 Kinase Directly Activates AMP-activated Kinase and Regulates Apoptosis in Response to Energy Stress

Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35. doi: 10.1073/pnas.0308061100. Epub 2004 Feb 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multienzyme Complexes
  • Proteins
  • Recombinant Proteins
  • STK11IP protein, human
  • Stk11ip protein, mouse
  • Tumor Suppressor Proteins
  • Threonine
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • STK11 protein, human
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases