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. 2007 May 7;177(3):387-92.
doi: 10.1083/jcb.200702053. Epub 2007 Apr 30.

LKB1 and AMPK maintain epithelial cell polarity under energetic stress

Vincent Mirouse  1 , Lance L Swick, Nevzat Kazgan, Daniel St Johnston, Jay E Brenman
Affiliations

LKB1 and AMPK maintain epithelial cell polarity under energetic stress

Vincent Mirouse et al. J Cell Biol. .

Retraction in

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 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.

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Figures

Figure 1.
Figure 1.
Identification of mutations within the single D. melanogaster ampkα gene. (A) Schematic domain representation of AMPKα and corresponding genetic lesions in mutants. The serine/threonine kinase domain (black, aa 39–280) and T-Loop (gray, aa 167–194) are shown with the sites of mutations, S211L, Q295STOP, and Y141STOP, for ampkα1 , ampkα2 , and ampkα3 , respectively. (B) Representative image of wild-type da neurons expressing an Actin∷GFP fusion transgene in a second instar larva. (C) ampkα mutants display enlarged plasma membrane domains (arrows) in sensory neuron dendrites, but not axons. (D) A wild-type ampkα transgene expressed autonomously within da neurons completely rescues the dendrite phenotype. (B–D) Background genotypes are w; Gal4109(2)80, UAS-actin∷GFP. Anterior at left and dorsal at top. Bars, 20 μm.
Figure 2.
Figure 2.
ampkα is required to maintain epithelial polarity under energetic stress. (A) ampkα3 mutant follicle cell clones under normal (left) or energetic stress conditions (right). Mutant cells are marked by the absence of GFP (green). Markers are indicated to the left, as follows: F-actin, red; Dlg, red; aPKC, blue; Crb, red; Cora, blue; DECad, red; and Dg, blue. The apical domain is at the top and faces the oocyte, which also contains a layer of cortical actin (top). (B) ampkα3 clone stained for DNA (blue) and Baz (red). Baz is usually present at the apical domain of mutant cells, but is lost in the most severely affected clones that lose their epithelial organization and form multiple layers. (C) ampkα3 clone stained for DNA (blue) and Dlg (red). Large ampkα3 clones at the anterior or posterior poles of the egg chamber overproliferate to form tumorlike structures composed of unpolarized cells. (D) tend mutant cells stained for aPKC (blue) and Dlg (red). Cells maintain normal epithelial polarity. (E) ampkα3 clone from a female fed on a glucose-only diet stained for aPKC (blue) and Dlg (red). These conditions of protein and lipid starvation do not affect the polarity of ampkα3 mutant cells. The stage (st) of the egg chamber is indicated on each picture.
Figure 3.
Figure 3.
AMPKα activation is not polarized. (A) Follicle cells expressing Cherry-AMPKα (left) and GFP-LKB1 (right). (B) Wild-type follicle cells (green) adjacent to ampkα3 (left) or lkb14A4-2 (right) mutant cells marked by the loss of GFP stained for PhosphoT184-AMPKα (red, top; white, bottom).
Figure 4.
Figure 4.
LKB1 is required to maintain epithelial polarity under energetic starvation conditions. (A) lkb14A mutant follicle cell clones under normal (left) or energetic stress conditions (right). Mutant cells are marked by the absence of GFP (green) and visualized with the same markers (at left) as described in Fig. 2 A. (B) lkb4 clone stained for DNA (blue) and Dlg (red, left) or DECad (red, right). Large mutant clones at the anterior or posterior poles of the egg chamber overproliferate to form tumorlike aggregates of unpolarized cells.
Figure 5.
Figure 5.
The AMPKα-T184D phosphomimetic transgene rescues the starvation-dependent lkb1 phenotypes. lkb1 mutant cells marked by the absence of GFP (green) expressing the UAS-AMPKα-T184D transgene. The expression of the phosphomimetic AMPKα transgene (T184D) rescues the lkb1 energetic stress–dependent phenotypes, as indicated by the normal distribution of various polarity markers (indicated to the left or right of the images). (top) F-actin and DECad, red; DG, blue. (bottom) Dlg and Crb, red; aPKC and Cora, blue.
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