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J. Cell Biol. 177 (3): 387-392

Copyright © 2007 by the Rockefeller University Press.

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LKB1 and AMPK maintain epithelial cell polarity under energetic stress

Vincent Mirouse1,2, Lance L. Swick3, Nevzat Kazgan3, Daniel St Johnston1,2, , and Jay E. Brenman3

1 The Gurdon Institute and the 2 Department of Genetics, University of Cambridge, Cambridge CB2 1QN, England, UK
3 Cell and Developmental Biology and Neuroscience Center, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27599

Correspondence to J. Brenman: brenman{at}med.unc.edu

Abstract: 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 AMPK{alpha}. Surprisingly, ampk{alpha} 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 ampk{alpha} mutations. Furthermore, lkb1 phenotypes are rescued by a phosphomimetic version of AMPK{alpha}. 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.

V. Mirouse and L.L. Swick contributed equally to this paper.

Abbreviations used in this paper: AMPK, AMP-activated kinase; aPKC, atypical PKC; MARK, microtubule affinity-regulating kinase.

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