Cited by 1,381Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

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

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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·2004·The EMBO Journal

DOI 10.1038/sj.emboj.7600110PMC PMC381014

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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.

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Authors: Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., & Alessi, D. R.
Affiliations: University of Dundee (GB)
University of Helsinki (FI)
Corresponding author: Alessi, Dario R
ORCID: Göransson, Olga
Toth, Rachel
Udd, Lina
Mäkelä, Tomi P
Hardie, D Grahame
Alessi, Dario R
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2004-02-19
Volume: 23
Issue: 4
Pages: 833-843
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1038/sj.emboj.7600110
PMC: PMC381014
OpenAlex: W2138319716
Cited by: 1,381
References: 53
Citations by year: 2026: 41 · 2025: 44 · 2024: 57 · 2023: 38 · 2022: 56 · 2021: 70 · 2020: 60 · 2019: 51 · 2018: 52 · 2017: 56 · 2016: 61 · 2015: 68 · 2014: 91 · 2013: 82 · 2012: 88
FWCI: 23.49
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Pfizer
AstraZeneca
GlaxoSmithKline
University of Dundee
Merck KGaA
Wellcome Trust (01488, QLG1-CT-2001-01488)
Diabetes UK
European Commission
Medical Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: LKB1, AMPK-related kinases, kinase activation, T-loop phosphorylation, STRAD, MO25, MARK kinases, MELK
MeSH terms: AMP-Activated Protein Kinase Kinases, Amino Acid Sequence, Cell Line, Enzyme Activation, Fibroblasts, Humans, Molecular Sequence Data, Multienzyme Complexes, Mutation, Peptides, Phosphorylation, Protein Binding, Substrate Specificity, Protein Serine-Threonine Kinases, Protein Subunits, Adaptor Proteins, Vesicular Transport, AMP-Activated Protein Kinases

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

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