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- Title
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.
- Authors
Lizcano, Jose M; Göransson, Olga; Toth, Rachel; Deak, Maria; Morrice, Nick A; Boudeau, Jérôme; Hawley, Simon A; Udd, Lina; Mäkelä, Tomi P; Hardie, D Grahame; Alessi, Dario R
- Abstract
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.
- Publication
The EMBO journal, 2004, Vol 23, Issue 4, p833
- ISSN
0261-4189
- Publication type
Journal Article
- DOI
10.1038/sj.emboj.7600110