Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells

Xie, Zhonglin; Dong, Yunzhou; Scholz, Roland; Neumann, Dietbert; Zou, Ming-Hui

doi:10.1161/circulationaha.107.744490

Cited by 273Metabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancer

Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells

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Xie, Zhonglin, Dong, Yunzhou, Scholz, Roland, Neumann, Dietbert, Zou, Ming-Hui·2008·Circulation

DOI 10.1161/circulationaha.107.744490PMC PMC2862466

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Abstract

BACKGROUND: Metformin, one of most commonly used antidiabetes drugs, is reported to exert its therapeutic effects by activating AMP-activated protein kinase (AMPK); however, the mechanism by which metformin activates AMPK is poorly defined. The objective of the present study was to determine how metformin activates AMPK in endothelial cells. METHODS AND RESULTS: Exposure of human umbilical vein endothelial cells or bovine aortic endothelial cells to metformin significantly increased AMPK activity and the phosphorylation of both AMPK at Thr172 and LKB1 at Ser428, an AMPK kinase, which was paralleled by increased activation of protein kinase C (PKC)-zeta, as evidenced by increased activity, phosphorylation (Thr410/403), and nuclear translocation of PKC-zeta. Consistently, either pharmacological or genetic inhibition of PKC-zeta ablated metformin-enhanced phosphorylation of both AMPK-Thr172 and LKB1-Ser428, suggesting that PKC-zeta might act as an upstream kinase for LKB1. Furthermore, adenoviral overexpression of LKB1 kinase-dead mutants abolished but LKB1 wild-type overexpression enhanced the effects of metformin on AMPK in bovine aortic endothelial cells. In addition, metformin increased the phosphorylation and nuclear export of LKB1 into the cytosols as well as the association of AMPK with LKB1 in bovine aortic endothelial cells. Similarly, overexpression of LKB1 wild-type but not LKB1 S428A mutants (serine replaced by alanine) restored the effects of metformin on AMPK in LKB1-deficient HeLa-S3 cells, suggesting that Ser428 phosphorylation of LKB1 is required for metformin-enhanced AMPK activation. Moreover, LKB1 S428A, like kinase-dead LKB1 D194A, abolished metformin-enhanced LKB1 translocation as well as the association of LKB1 with AMPK in HeLa-S3 cells. Finally, inhibition of PKC-zeta abolished metformin-enhanced coimmunoprecipitation of LKB1 with both AMPKalpha1 and AMPKalpha2. CONCLUSIONS: We conclude that PKC-zeta phosphorylates LKB1 at Ser428, resulting in LKB1 nuclear export and hence AMPK activation.

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In endothelial cells, metformin enhances phosphorylation and increases the activity of LKB1.
“In endothelial cells, metformin has been shown to enhance phosphorylation and increase the activity of LKB1 (122).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [122]

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Resveratrol Prevents the Prohypertrophic Effects of Oxidative Stress on LKB1
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Resveratrol prevents hypertension and cardiac hypertrophy in hypertensive rats and mice
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Effects of Metformin in Experimental Stroke
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Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa‐2a plus ribavirin†‡
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AMPK: A cellular metabolic and redox sensor. A minireview
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Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease
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Acute Exposure to Low Glucose Rapidly Induces Endothelial Dysfunction and Mitochondrial Oxidative Stress
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7-Ketocholesterol Induces Autophagy in Vascular Smooth Muscle Cells through Nox4 and Atg4B
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Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress
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Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells
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AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response
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Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems
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Uncoupling of the LKB1-AMPKα Energy Sensor Pathway by Growth Factors and Oncogenic BRAFV600E
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AMPK-Dependent Metabolic Regulation by PPAR Agonists
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Melatonin ameliorates high fat diet‐induced diabetes and stimulates glycogen synthesis via a PKCζ‐Akt‐GSK3β pathway in hepatic cells
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The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic-acid Methyl Ester Has Potent Anti-diabetic Effects in Diet-induced Diabetic Mice and Lepr Mice
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Targeting LKB1 signaling in cancer
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Efficacy of sauchinone as a novel AMPK-activating lignan for preventing iron-induced oxidative stress and liver injury
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Targeting Energy Metabolic and Oncogenic Signaling Pathways in Triple-negative Breast Cancer by a Novel Adenosine Monophosphate-activated Protein Kinase (AMPK) Activator
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Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis
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PKA/AMPK signaling in relation to adiponectin’s antiproliferative effect on multiple myeloma cells
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Taurine supplementation improves liver glucose control in normal protein and malnourished mice fed a high‐fat diet
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Regulation of bile canalicular network formation and maintenance by AMP-activated protein kinase and LKB1
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Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell Angiogenesis
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Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling
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Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies
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Farnesoid X Receptor Protects Hepatocytes From Injury by Repressing miR-199a-3p, Which Increases Levels of LKB1
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Arsenic Inhibits Neurite Outgrowth by Inhibiting the LKB1–AMPK Signaling Pathway
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TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise
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Reactive Nitrogen Species Is Required for the Activation of the AMP-activated Protein Kinase by Statin in Vivo
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Mechanism and Role of High Density Lipoprotein-induced Activation of AMP-activated Protein Kinase in Endothelial Cells
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Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation
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Perivascular fat, AMP ‐activated protein kinase and vascular diseases
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Endothelium-Selective Activation of AMP-Activated Protein Kinase Prevents Diabetes Mellitus–Induced Impairment in Vascular Function and Reendothelialization via Induction of Heme Oxygenase-1 in Mice
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Ablation of CD44 induces glycolysis-to-oxidative phosphorylation transition via modulation of the c-Src–Akt–LKB1–AMPKα pathway
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CD4 + T-Cell Endogenous Cystathionine γ Lyase–Hydrogen Sulfide Attenuates Hypertension by Sulfhydrating Liver Kinase B1 to Promote T Regulatory Cell Differentiation and Proliferation
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Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels
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Reactive oxygen species are produced at low glucose and contribute to the activation of AMPK in insulin-secreting cells
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Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.
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The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 β cells
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The Inositol Phosphate System—A Coordinator of Metabolic Adaptability
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Genistein-induced LKB1–AMPK activation inhibits senescence of VSMC through autophagy induction
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APPL1 Mediates Adiponectin-Induced LKB1 Cytosolic Localization Through the PP2A-PKCζ Signaling Pathway
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Endothelial Cell–Specific Liver Kinase B1 Deletion Causes Endothelial Dysfunction and Hypertension in Mice In Vivo
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Protective effects of AMP‐activated protein kinase in the cardiovascular system
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AMPK Suppresses Vascular Inflammation In Vivo by Inhibiting Signal Transducer and Activator of Transcription-1
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Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids
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Metformin: Insights into its anticancer potential with special reference to AMPK dependent and independent pathways
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Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration
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Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons
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C-terminal Phosphorylation of LKB1 Is Not Required for Regulation of AMP-activated Protein Kinase, BRSK1, BRSK2, or Cell Cycle Arrest
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Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway
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Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase
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Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities
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PKC-Dependent Human Monocyte Adhesion Requires AMPK and Syk Activation
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Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism
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Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation
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Sepsis-Induced Alterations in Protein-Protein Interactions Within mTOR Complex 1 and the Modulating Effect of Leucine on Muscle Protein Synthesis
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Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKCζ
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Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells
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The Calcium/CaMKKalpha/beta and the cAMP/PKA Pathways Are Essential Upstream Regulators of AMPK Activity in Boar Spermatozoa1
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Therapeutic potential of panduratin A, LKB1‐dependent AMP‐activated protein kinase stimulator, with activation of PPAR α / δ for the treatment of obesity
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Metformin: the updated protective property in kidney disease
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Hydrogen sulfide mitigates hyperglycemic remodeling via liver kinase B1-adenosine monophosphate-activated protein kinase signaling
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SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells
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Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metforminenhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation 117: 952–962
Xie, Z., Dong, P. Y., Rol, P., Neumann, D., & Zou, M. (2008)
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The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism
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Phosphorylation of Serine 399 in LKB1 Protein Short Form by Protein Kinase Cζ Is Required for Its Nucleocytoplasmic Transport and Consequent AMP-activated Protein Kinase (AMPK) Activation
Zhu, H., Moriasi, C. M., Zhang, M., Zhao, Y. C., & Zou, M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.443580 · Cited by 29 · see citing works
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Further Evidence for AMP Deaminase as the target of Metformin Action in L6 Skeletal Muscle Cells
Parakhia, R. A., & Ochs, R. S. (2011) · The FASEB Journal · doi:10.1096/fasebj.25.1_supplement.917.4
Metformin Activates AMP-Activated Protein Kinase by Promoting Formation of the αβγ Heterotrimeric Complex
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Authors: Xie, Z., Dong, Y., Scholz, R., Neumann, D., & Zou, M.-H.
Affiliations: ETH Zurich (CH)
ORCID: Dong, Yunzhou
Neumann, Dietbert
Zou, Ming-Hui
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2008-02-19
Volume: 117
Issue: 7
Pages: 952-962
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.107.744490
PMC: PMC2862466
OpenAlex: W2021020436
Cited by: 273
References: 55
Citations by year: 2026: 9 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 11 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 10 · 2017: 13 · 2016: 16 · 2015: 13 · 2014: 18 · 2013: 20 · 2012: 26
FWCI: 11.10
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL105157, HL 079584, R01HL079584, HL-080499, HL074399, R01HL074399, R01HL080499, R01HL110488, R01HL089920, R01HL096032)
National Center for Research Resources (P20RR024215)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: LKB1, protein kinase C zeta, metformin, AMPK, AMPK activation, endothelial cells, upstream kinases
MeSH terms: AMP-Activated Protein Kinase Kinases, Protein Kinase C zeta, Acetyl-CoA Carboxylase, Animals, Cattle, Cells, Cultured, Codon, Cytosol, Enzyme Activation, HeLa Cells, Humans, Hypoglycemic Agents, Metformin, Multienzyme Complexes, Phosphorylation, Phosphoserine, Protein Kinase C, Protein Processing, Post-Translational, Transduction, Genetic, Protein Serine-Threonine Kinases, Point Mutation, Active Transport, Cell Nucleus, Endothelial Cells, AMP-Activated Protein Kinases

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Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells

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