LKB1-AMPK pathway: metabolism and growth control in tumor suppression

LKB1 in complex with its two regulatory subunits STRAD and Mo25 directly phosphorylates and activates a family of 14 AMPK-related kinases. These kinases in turn directly phosphorylate a number of downstream substrates to mediate effects on cell polarity, metabolism, and growth control. All well-established substrates of AMPK and its related family members are shown, and those for which further in vivo data is needed are shown with a question mark. It is important to note that many of the known substrates are expressed in a tissue-specific manner and may not explain ubiquitous effects of LKB1 and its downstream kinases in all cell types. Bottom: The sequences flanking the best-characterized phosphorylation site in each substrate with those residues selected for from in vitro peptide library and alanaine scanning peptide mutagenesis studies highlighted. Importantly, to date there is no substantive mutational data from human tumors to specifically support any of the downstream kinases, including the two AMPK catalytic genes, as being a particularly critical target of LKB1 in tumor suppression. One confounding issue with the lack of mutations found in these downstream kinases is that there is a great deal of redundancy among them, suggesting that loss of any one of them may be compensated for by other family members, unlike the case for LKB1 for which no other specific kinase has been shown to compensate in vivo.

Publication

The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. () David B. Shackelford, et al. Nat Rev Cancer. ;9(8):563-575. Figure: F2. All organisms Homo sapiens Drosophila melanogaster

Disease mentions