LKB1 and AMPK maintain epithelial cell polarity under energetic stress.
LKB1 is mutated in both familial and spontaneous tumors, and acts as a master kinase that activates the PAR-1 polarity kinase and the adenosine 5'monophosphate-activated kinase (AMPK). This has led to the hypothesis that LKB1 acts as a tumor suppressor because it is required to maintain cell polarity and growth control through PAR-1 and AMPK, respectively. However, the genetic analysis of LKB1-AMPK signaling in vertebrates has been complicated by the existence of multiple redundant AMPK subunits. We describe the identification of mutations in the single Drosophila melanogaster AMPK catalytic subunit AMPKalpha. Surprisingly, ampkalpha mutant epithelial cells lose their polarity and overproliferate under energetic stress. LKB1 is required in vivo for AMPK activation, and lkb1 mutations cause similar energetic stress-dependent phenotypes to ampkalpha mutations. Furthermore, lkb1 phenotypes are rescued by a phosphomimetic version of AMPKalpha. Thus, LKB1 signals through AMPK to coordinate epithelial polarity and proliferation with cellular energy status, and this might underlie the tumor suppressor function of LKB1.
Mirouse
Vincent
V
The Gurdon Institute, Department of Genetics, University of Cambridge, Cambridge, England, UK.
Swick
Lance L
LL
Kazgan
Nevzat
N
St Johnston
Daniel
D
Brenman
Jay E
JE
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D020134:Catalytic Domain / Q000502:physiology; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004734:Energy Metabolism / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D009097:Multienzyme Complexes; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C495775:LKB1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases