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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.

The EMBO journal | Feb 25, 2004

We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function.

Pubmed ID: 14976552 RIS Download

Mesh terms: AMP-Activated Protein Kinases | Adaptor Proteins, Vesicular Transport | Amino Acid Sequence | Cell Line | Enzyme Activation | Fibroblasts | Humans | Molecular Sequence Data | Multienzyme Complexes | Mutation | Peptides | Phosphorylation | Protein Binding | Protein Subunits | Protein-Serine-Threonine Kinases | Substrate Specificity