LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1
Author
Summary, in English
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.
Department/s
Publishing year
2004
Language
English
Pages
833-843
Publication/Series
EMBO Journal
Volume
23
Issue
4
Document type
Journal article
Publisher
Oxford University Press
Topic
- Biochemistry and Molecular Biology
Keywords
- diabetes
- PAR1/MARK kinase
- cancer
- cell polarity
- TOF–TOF mass spectrometry
- Peutz–Jeghers syndrome
Status
Published
Research group
- Insulin Signal Transduction
ISBN/ISSN/Other
- ISSN: 1460-2075