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.

To determine if these defects resulted from aberrant Lkb1–AMPK signalling, the authors applied an allosteric AMPK activator, A-769662, to lung and pancreatic explants. A-769662 suppressed the lung branching defects but not pancreatic cyst formation, suggesting that this phenotype is independent of AMPK. Furthermore, prolonged Lkb1 inhibition in pancreatic explants elicited lesions resembling early-stage pancreatic intraepithelial neoplasias. These data reveal the power of chemical genetics approaches and ex vivo analyses in understanding protein function, and suggest that Lkb1 affects morphology and tumorigenesis through AMPK-dependent and -independent pathways.