Maintaining Polarity in the Face of Energetic Stress

Science's STKE  15 May 2007:
Vol. 2007, Issue 386, pp. tw166
DOI: 10.1126/stke.3862007tw166

The serine-threonine LKB1 is a tumor suppressor, and mutations in the encoding gene cause epithelial tissue-derived tumors. Two targets of LKB1 are the polarity-stimulating kinase PAR-1 and a kinase that is activated under conditions of energy depletion, AMPK. Drosophila represents a simpler system than mammalian ones to investigate the role of LKB1 and AMPK in epithelial cell function, because there is only a single AMPK complex (not the multiple isoforms found in mammals). Mirouse et al. created Drosophila mutants of the gene encoding the α subunit of the AMPK complex (ampkα) and found that the follicle epithelial cells of the ovary exhibited normal polarity under energy-replete conditions but showed disrupted polarity under conditions of glucose deprivation. In the latter case, apical markers were decreased in abundance and mislocalized, whereas basal markers were more broadly distributed. However, intercellular adhesion did not appear to be affected, because E-cadherin was enriched in adherens junctions. The localization of a tagged form of AMPKα, as well as the LKB1-phosphorylated form of AMPK, showed that AMPK was distributed throughout the cytoplasm and was not enriched at either apical or basal sides of the cells. However, LKB1 appears to be important for the polarity-regulating activity of AMPK under conditions of glucose deprivation. LKB1 functions in energy-replete conditions in the stem cells that produce the follicular epithelium, and when these cells have the lkb1 mutation, a large cell with disrupted polarity is formed. Mirouse et al. showed that small cells that formed after the epithelium was formed that had the lkb1 mutation did not have polarity defects under energy-replete conditions but did show disruption of polarity in response to glucose deprivation. An activated form of AMPK rescued the polarity defects that occurred in the lkb1 cells in response to energetic stress. Thus, AMPK appears to serve a role in maintaining polarity under conditions of energy stress, whereas LKB1 appears to participate in both this maintenance pathway and the pathway that establishes epithelial polarity.

V. Mirouse, L. L. Swick, N. Kazgan, D. St. Johnston, J. E. Brenman, LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J. Cell Biol. 177, 387-392 (2007). [Abstract] [Full Text]