Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade

摘要: The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation Thr172 AMPK within the activation loop by upstream kinases (AMPKKs) have not been identified. Recently, we identified three related acting yeast homolog AMPK. Although they do obvious mammalian homologs, are to LKB1, tumor suppressor mutated in human Peutz-Jeghers cancer syndrome. We recently showed LKB1 exists complex with two accessory subunits, STRADα/β MO25α/β. report following observations. First, AMPKK activities purified from rat liver contain STRADα MO25α, can be immunoprecipitated using anti-LKB1 antibodies. Second, both endogenous recombinant complexes MO25α/β activate via Thr172. Third, catalytically active or STRADβ MO25α MO25β required for full activity. Fourth, AMPK-activating drugs AICA riboside phenformin HeLa cells (which lack LKB1), but restored stably expressing wild-type, inactive, LKB1. Fifth, fail immortalized fibroblasts LKB1-knockout mouse embryos. These results provide first description physiological substrate suggest it functions an regulator Our findings indicate tumors syndrome could result deficient consequence inactivation.