Complexes between the LKB1 tumor suppressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade

Simon A. Hawley, Jerome Boudeau, Jennifer L. Reid, Kirsty J. Mustard, Lina Udd, Tomi P. Makela, Dario R. Alessi, D. Grahame Hardie

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    1272 Citations (Scopus)

    Abstract

    Background: The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a ‘metabolic master switch’ and inhibits cell proliferation. Activation requires phosphorylation of Thr172 of AMPK within the activation loop by upstream kinases (AMPKKs) that have not been identified. Recently, we identified three related protein kinases acting upstream of the yeast homolog of AMPK. Although they do not have obvious mammalian homologs, they are related to LKB1, a tumor suppressor that is mutated in the human Peutz-Jeghers cancer syndrome. We recently showed that LKB1 exists as a complex with two accessory subunits, STRAD / and MO25 / . Results: We report the following observations. First, two AMPKK activities purified from rat liver contain LKB1, STRAD and MO25 , and can be immunoprecipitated using anti-LKB1 antibodies. Second, both endogenous and recombinant complexes of LKB1, STRAD / and MO25 / activate AMPK via phosphorylation of Thr172. Third, catalytically active LKB1, STRAD or STRAD and MO25 or MO25 are required for full activity. Fourth, the AMPK-activating drugs AICA riboside and phenformin do not activate AMPK in HeLa cells (which lack LKB1), but activation can be restored by stably expressing wild-type, but not catalytically inactive, LKB1. Fifth, AICA riboside and phenformin fail to activate AMPK in immortalized fibroblasts from LKB1-knockout mouse embryos. Conclusions: These results provide the first description of a physiological substrate for the LKB1 tumor suppressor and suggest that it functions as an upstream regulator of AMPK. Our findings indicate that the tumors in Peutz-Jeghers syndrome could result from deficient activation of AMPK as a consequence of LKB1 inactivation
    Original languageEnglish
    Pages (from-to)28
    Number of pages1
    JournalJournal of Biology
    Volume2
    Issue number4
    DOIs
    Publication statusPublished - Sep 2003

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