The LKB1 complex-AMPK pathway: the tree that hides the forest

Abstract

Initially identified as the Caenorhabditis elegans PAR-4 homologue, the serine threonine kinase LKB1 is conserved throughout evolution and ubiquitously expressed. In humans, LKB1 is causally linked to the Peutz-Jeghers syndrome and is one of the most commonly mutated genes in several cancers like lung and cervical carcinomas. These observations have led to classify LKB1 as tumour suppressor gene. Although, considerable dark zones remain, an impressive leap in the understanding of LKB1 functions has been done during the last decade. Role of LKB1 as a major actor of the AMPK/mTOR pathway connecting cellular metabolism, cell growth and tumorigenesis has been extensively studied probably to the detriment of other functions of equal importance. This review will discuss about LKB1 activity regulation, its effectors and clues on their involvement in cell polarity.

Fig. 1

(A) Scheme of human LKB1 spliced variants, STRAD and Mo25 paralogues. Tilted and underline residues considered as autophosphorylation sites. Phosphorylated residues targeted by mentioned kinases (arrow). NLS for nuclear localization sequence. CAAX for the site of farnesylation. (B) Schematic representation of active and functional complex.

Fig. 2

Domain organization of AMPK-related kinases activated by LKB1 complexes. Kinase domain in light gray, ubiquitin associated domain in checked motif. Usual and alternative names, molecular weight and main identified functions, respectively from left to right.