Post-translational Modification of Serine/Threonine Kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at Lysine Residue 97 Directly Inhibits Kinase Activity

Calamaras, Timothy D.; Lee, Charlie; Li, Fan; Ido, Yasuo; Siwik, Deborah A.; Colucci, Wilson S.

doi:10.1074/jbc.m112.385831

Cited by 25 publications

(22 citation statements)

References 39 publications

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“…Dolinsky et al first reported that HNE (40 μM) could conjugate with LKB1 and repress its activity, and inhibit its downstream substrate AMPK activity, and thus result in the activation of mTOR/p70S6 kinas pathway in isolated cardiomyocytes [95]. This finding was supported by other studies, which demonstrated that LKB1 was inhibited by HNE in various cell models, including primary mouse cardiomyocytes (20 μM) [96], HEK293T cells (1–40 μM) [97], and rat ventricular cardiomyocytes (10 μM) [98]. In these studies, HNE-LKB1 adducts were detected and total LKB1 decreased, and this was postulated as the mechanism of LKB1 inhibition.…”

Section: Aging-related Signaling Pathways Affected By Hnementioning

confidence: 80%

4-hydroxynonenal-mediated signaling and aging

Zhang

2017

Free Radical Biology and Medicine

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4-Hydroxy-2-nonenal (HNE), one of the major α, β-unsaturated aldehydes produced during lipid peroxidation, is a potent messenger in mediating signaling pathways. Lipid peroxidation and HNE production appear to increase with aging. Although the cause and effect relation remains arguable, aging is associated with significant changes in diverse signaling events, characterized by enhanced or diminished responses of specific signaling pathways. In this review we will discuss how HNE may contribute to aging-related alterations of signaling pathways.

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Section: Aging-related Signaling Pathways Affected By Hnementioning

confidence: 80%

4-hydroxynonenal-mediated signaling and aging

Zhang

2017

Free Radical Biology and Medicine

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“…LKB1 can phosphorylate downstream AMPK at threonine 172 (30)(31)(32). Metformin, phenformin and AICAR are activators of AMPK (4,(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

LKB1/AMPK pathway mediates resistin-induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

Liu

Cheng

et al. 2016

Biomedical Reports

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Abstract.Resistin has been previously demonstrated to induce cardiac hypertrophy, however, the underlying molecular mechanisms of resistin-induced cardiac hypertrophy remain unclear. Using H9c2 cells, the present study investigated the liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway for a potential role in mediating resistin-induced cardiomyocyte hypertrophy. Treatment of H9c2 cells with resistin increased cell surface area, protein synthesis, and expression of hypertrophic marker brain natriuretic peptide and β-myosin heavy chain. Treatment with metformine attenuated these effects of resistin. Furthermore, treatment with resistin decreased phosphorylation of LKB1 and AMPK, whereas pretreatment with metformin increased phosphorylation of LKB1 and AMPK that is reduced by resistin. These results suggest that resistin induces cardiac hypertrophy through the inactivation of the LKB1/AMPK cell signaling pathway.

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“…While prior studies have used HNE concentrations of 40 uM [21] and higher [27] in cardiac myocytes, our previous work has shown that an HNE concentration as low as 10 μM inhibits LKB1 activity through the formation of HNE-adducts [28]. Therefore, cultured adult rat ventricular cardiac myocytes (ARVMs) were treated with 10 μM HNE for 1 hour or Norepinephrine (NE) as a positive control, and the cells were incubated with [ 3 H]-leucine for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1–p70S6K–RPS6 signaling

Calamaras

Lee

et al. 2015

Free Radical Biology and Medicine

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Reactive oxygen species (ROS) are elevated in the heart in response to hemodynamic and metabolic stress, and promote hypertrophic signaling. ROS also mediate the formation of lipid peroxidation-derived aldehydes that may promote myocardial hypertrophy. One lipid peroxidation byproduct, 4-Hydroxy-trans-2-nonenal (HNE), is a reactive aldehyde that covalently modifies proteins thereby altering their function. HNE adducts directly inhibit the activity of LKB1, a serine/threonine kinase involved in regulating cellular growth in part through its interaction with the AMP-activated protein kinase (AMPK), but whether this drives myocardial growth is unclear. We tested the hypothesis that HNE promotes myocardial protein synthesis, and if this effect is associated with impaired LKB1-AMPK signaling. In adult rat ventricular cardiomyocytes exposure to HNE (10 μM for 1 hour) caused HNE-LKB1 adduct formation and inhibited LKB1 activity. HNE inhibited the downstream kinase AMPK, increased hypertrophic mTOR-P70S6K-RPS6 signaling, and stimulated protein synthesis by 27.1 ±3.5%. HNE also stimulated Erk1/2 signaling, which contributed to RPS6 activation but was not required for HNE-stimulated protein synthesis. HNE-stimulated RPS6 phosphorylation was completely blocked using the mTOR inhibitor rapamycin. To evaluate if LKB1 inhibition by itself could promote the hypertrophic signaling changes observed with HNE, LKB1 was depleted in ARVMs using siRNA. LKB1 knockdown did not replicate the effect of HNE on hypertrophic signaling or affect HNE-stimulated RPS6 phosphorylation. Thus, in adult cardiac myocytes HNE stimulates protein synthesis by activation of mTORC1-P70S6K-RPS6 signaling most likely mediated by direct inhibition of AMPK. Because HNE in the myocardium is commonly increased by stimuli that cause pathologic hypertrophy, these findings suggest that therapies that prevent activation of mTORC1-P70S6K-RPS6 signaling may be of therapeutic value.

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Post-translational Modification of Serine/Threonine Kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at Lysine Residue 97 Directly Inhibits Kinase Activity

Cited by 25 publications

References 39 publications

4-hydroxynonenal-mediated signaling and aging

4-hydroxynonenal-mediated signaling and aging

LKB1/AMPK pathway mediates resistin-induced cardiomyocyte hypertrophy in H9c2 embryonic rat cardiomyocytes

The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1–p70S6K–RPS6 signaling

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