Regulation of LKB1/STRAD Localization and Function by E-Cadherin

LKB1 kinase is a tumor suppressor that is causally linked to Peutz-Jeghers syndrome [1]. In complex with the pseudokinase STRAD and the scaffolding protein MO25, LKB1 phosphorylates and activates AMPK family kinases, which mediate many cellular processes [2, 3]. The prototypical family member AMPK regulates cell energy metabolism [4] and epithelial apicobasal polarity [5, 6]. This latter event is also dependent on E-cadherin-mediated adherens junctions (AJs) at lateral borders [7, 8]. Strikingly, overexpression of LKB1/STRAD can also trigger establishment of epithelial polarity in the absence of cell-cell or cell-matrix contacts [9]. However, the upstream factors that normally govern LKB1/STRAD function are unknown. Here we show by immunostaining and fluorescence resonance energy transfer that active LKB1/STRAD kinase complex colocalizes with E-cadherin at AJs. LKB1/STRAD localization and AMPK phosphorylation require E-cadherin-dependent maturation of AJs. However, LKB1/STRAD complex kinase activity is E-cadherin independent. These data suggest that in polarized epithelial cells, E-cadherin regulates AMPK phosphorylation by controlling the localization of the LKB1 complex. The LKB1 complex therefore appears to function downstream of E-cadherin in tumor suppression.