Interrogating Lkb1 function | Nature Cell Biology
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The kinase Lkb1 regulates cell polarity and is mutated or deleted in many cancers. Lkb1 substrates include the kinase AMPK, but whether AMPK is a relevant Lkb1 target in polarity and
tumorigenesis remains unclear. Mellman and colleagues now use elegant chemical genetics approaches to address this issue (J. Cell Biol. 199, 1117–1130; 2012).
The authors generated a knock-in mouse expressing an analogue-sensitive kinase allele (ASKA) of Lkb1; this strategy enables Lkb1 to be inhibited by the compound 1NMPP1. Mice homozygous for
mutant Lkb1 were embryonic lethal, but embryonic tissues harvested from these mice could be used for ex vivo analyses. Acute Lkb1 inhibition in the lung led to branching defects but not loss
of apical–basal polarity. Pancreatic explants similarly retained apical–basal polarity following Lkb1 inhibition, but formed dynamic cysts lined with rapidly proliferating epithelial cells.
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