Document Type
Article
Publication Date
3-9-2004
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
Department
Geisel School of Medicine
Additional Department
Department of Biological Sciences
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.
DOI
10.1073/pnas.0308061100
Original Citation
Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. 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. PMID: 14985505; PMCID: PMC373461.
Dartmouth Digital Commons Citation
Shaw, Reuben J.; Kosmatka, Monica; Bardeesy, Nabeel; Hurley, Rebecca L.; Witters, Lee A.; DePinho, Ronald A.; and Cantley, Lewis C., "The Tumor Suppressor LKB1 Kinase Directly Activates AMP-Activated Kinase and Regulates Apoptosis in Response to Energy Stress" (2004). Dartmouth Scholarship. 1584.
https://digitalcommons.dartmouth.edu/facoa/1584
