Regulation of LKB1/STRAD localization and function by E-cadherin.
LKB1 kinase is a tumor suppressor that is causally linked to Peutz-Jeghers syndrome. In complex with the pseudokinase STRAD and the scaffolding protein MO25, LKB1 phosphorylates and activates AMPK family kinases, which mediate many cellular processes. The prototypical family member AMPK regulates cell energy metabolism and epithelial apicobasal polarity. This latter event is also dependent on E-cadherin-mediated adherens junctions (AJs) at lateral borders. Strikingly, overexpression of LKB1/STRAD can also trigger establishment of epithelial polarity in the absence of cell-cell or cell-matrix contacts. 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.
Sebbagh
Michael
M
Cardiovascular Research Center and Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA. michael.sebbagh@inserm.fr
Santoni
Marie-Josée
MJ
Hall
Brian
B
Borg
Jean-Paul
JP
Schwartz
Martin A
MA
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism*; D015153:Blotting, Western; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism*; D002458:Cell Fractionation; D017931:DNA Primers / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D033942:Adaptor Proteins, Vesicular Transport; D015820:Cadherins; D017931:DNA Primers; D046912:Multiprotein Complexes; C476400:STRADA protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases