LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Open accessAbstract
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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LKB-1 phosphorylates and activates PAR-1, but also phosphorylates the inactivating Ser-9 on GSK-3β and may be the elusive GSK-3β kinase activated by Wnt signaling.
“LKB-1 phosphorylates and activates PAR-1 (120,122,123), but also phosphorylates the inactivating Ser-9 on GSK-3β and may be the elusive GSK-3β kinase activated by Wnt signaling (124).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [122]
Citation (124) is attached to the GSK-3β clause. The paper’s ‘Phosphorylation and activation of the MARK kinases by LKB1’ section reports phosphorylation of MARK kinases, but no passage found for GSK-3β Ser-9 phosphorylation or an LKB1 kinase role activated by Wnt signaling (searched: GSK3, Ser-9, and Wnt signaling). (LLM, conf=0.75)
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The molecular targets of resveratrol
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“It was, hence, exciting to see that the Liver Kinase B1 (LKB1), the main upstream kinase for AMPK activation [89,90], was a target for SIRT1 deacetylation in cultured cells and rodent tissues [85].”
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AMPK: restoring metabolic homeostasis over space and time
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AMPK: A Target for Drugs and Natural Products With Effects on Both Diabetes and Cancer
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Self-citationThe Glycogen-Binding Domain on the AMPK β Subunit Allows the Kinase to Act as a Glycogen Sensor
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AMP-Activated Protein Kinase as a Drug Target
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Self-citationThe tuberous sclerosis complex
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LKB1 and SAD Kinases Define a Pathway Required for the Polarization of Cortical Neurons
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Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice
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Self-citationThe Lkb1 metabolic sensor maintains haematopoietic stem cell survival
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AMPK inhibition in health and disease
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AMP-activated protein kinase: new regulation, new roles?
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AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern
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Self-citationStructure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation
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LKB1/STRAD Promotes Axon Initiation During Neuronal Polarization
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The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator
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LKB1 and AMPK and the cancer-metabolism link - ten years after
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The Warburg effect and drug resistance
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A genetic screen identifies an LKB1–MARK signalling axis controlling the Hippo–YAP pathway
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Deregulated MYC expression induces dependence upon AMPK-related kinase 5
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Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase
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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
- Venue
- The EMBO Journal
- Published
- 2004-02-19
- Volume
- 23
- Issue
- 4
- Pages
- 833-843
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- 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
- 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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