LKB1 and AMPK maintain epithelial cell polarity under energetic stress

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 AMPKα. Surprisingly, ampkα 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 ampkα mutations. Furthermore, lkb1 phenotypes are rescued by a phosphomimetic version of AMPKα. 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.

AMP-activated protein kinase (AMPK) beyond metabolism

“…[87][88][89] An early glimpse into the importance of AMPK in cytokinesis and cell proliferation was observed in Drosophila melanogaster, where mutation of the α-catalytic subunit of AMPK led to disruptions in cell polarity and enhanced cell proliferation under metabolic stress. 88 Another Drosophila study suggested that the enzyme supports the fidelity of cell division in early stages of development since AMPK-null germ-line clones exhibited gross mitotic defects, such as lagging chromosomes in anaphase, failure to complete cytokinesis, polyploidy, and embryonic lethality. 90 In flies, AMPK was found to phosphorylate non-muscle myosin regulatory light chain (MRLC; also known as MRLC2) on Ser22, a protein that interacts with actin to facilitate changes in the actin cytoskeleton that are required for the maintenance of cell polarity.…”

The Caenorhabditis elegans AMP-activated Protein Kinase AAK-2 Is Phosphorylated by LKB1 and Is Required for Resistance to Oxidative Stress and for Normal Motility and Foraging Behavior

“…Mammalian LKB1 kinase, a deficiency in which is associated with Peutz-Jeghers syndrome, a disease that shows increased susceptibility to certain cancers (12), and its Drosophila homologue are the major upstream Ser/Thr kinases acting on AMPK (7,8,(13)(14)(15)(16). In addition, the ␤ isoform of Ca 2ϩ /calmodulindependent protein kinase kinase ␤ also phosphorylates and activates AMPK in mammalian cells (17,18).…”

Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

“…Among the LKB1 downstream kinases, AMPKs, MARK/ PAR-1 kinases and BRSK1 and 2 have been linked to regulation of cell polarity in a context-dependent manner (figure 2). Findings in Drosophila have suggested that LKB1 may use AMPK to signal cell polarity [79]. In Drosophila follicular epithelial cells, ampk-a null mutants exhibit normal epithelial polarity in a nutrient-rich environment but in culture media deprived of sugars, conditions where AMPK normally is maximally active, apico-basal cell polarity of these cells is disrupted.…”