Macropinocytosis is decreased in diabetic mouse macrophages and is regulated by AMPK

Guest, Christopher B.; Chakour, Kenneth S.; Freund, Gregory G.

doi:10.1186/1471-2172-9-42

Cited by 15 publications

(12 citation statements)

References 45 publications

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“…AMPK-dependent signaling pathways that result in macropinocytosis are not defined. Several recent studies hint at possible links between AMPK activity and the formation of actin-mediated lamellipodium formation and macropinocytosis (38,39). Rac1, PI3K/Akt, protein kinase C, and myosin light chain kinase (MLCK), which have either been previously identified to be involved in EBOV entry and macropinocytosis and/or were identified in our CGA screen, are known to be phosphorylation targets downstream of AMPK activation (36,(78)(79)(80)(81)(82).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to a role in regulating metabolism, recent studies have implicated AMPK activity in actin polymerization and the induction of macropinocytosis and phagocytosis (36)(37)(38)(39)(40). For instance, macrophages from diabetic mice have reduced macropi-nocytosis, and leptin-enhanced AMPK activity increased macropinocytosis (38). Another recent study implicated Rac1 as a mediator of AMPK-dependent phagocytosis (36).…”

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confidence: 99%

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AMP-Activated Protein Kinase Is Required for the Macropinocytic Internalization of Ebolavirus

Kondratowicz

Hunt

Davey

et al. 2013

J Virol

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c Identification of host factors that are needed for Zaire Ebolavirus (EBOV) entry provides insights into the mechanism(s) of filovirus uptake, and these factors may serve as potential antiviral targets. In order to identify novel host genes and pathways involved in EBOV entry, gene array findings in the National Cancer Institute's NCI-60 panel of human tumor cell lines were correlated with permissivity for EBOV glycoprotein (GP)-mediated entry. We found that the gene encoding the ␥2 subunit of AMPactivated protein kinase (AMPK) strongly correlated with EBOV transduction in the tumor panel. The AMPK inhibitor compound C inhibited infectious EBOV replication in Vero cells and diminished EBOV GP-dependent, but not Lassa fever virus GPC-dependent, entry into a variety of cell lines in a dose-dependent manner. Compound C also prevented EBOV GP-mediated infection of primary human macrophages, a major target of filoviral replication in vivo. Consistent with a role for AMPK in filovirus entry, time-of-addition studies demonstrated that compound C abrogated infection when it was added at early time points but became progressively less effective when added later. Compound C prevented EBOV pseudovirion internalization at 37°C as cell-bound particles remained susceptible to trypsin digestion in the presence of the inhibitor but not in its absence. Mouse embryonic fibroblasts lacking the AMPK␣1 and AMPK␣2 catalytic subunits were significantly less permissive to EBOV GP-mediated infection than their wild-type counterparts, likely due to decreased macropinocytic uptake. In total, these findings implicate AMPK in macropinocytic events needed for EBOV GP-dependent entry and identify a novel cellular target for new filoviral antivirals.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

AMP-Activated Protein Kinase Is Required for the Macropinocytic Internalization of Ebolavirus

Kondratowicz

Hunt

Davey

et al. 2013

J Virol

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“…It is worth mentioning that the top pathway, macropinocytosis by growth factor, is selected exclusively by SEROP. Previous research (Guest et al ., ) has found evidence that this process is closely related to high‐calorie‐induced obesity in mice.…”

Section: Real Data Analysismentioning

confidence: 99%

Variable Selection via Additive Conditional Independence

Lee

Zhao

2016

Journal of the Royal Statistical Society Series B: Statistical Methodology

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We propose a non-parametric variable selection method which does not rely on any regression model or predictor distribution. The method is based on a new statistical relationship, called additive conditional independence, that has been introduced recently for graphical models. Unlike most existing variable selection methods, which target the mean of the response, the method proposed targets a set of attributes of the response, such as its mean, variance or entire distribution. In addition, the additive nature of this approach offers non-parametric flexibility without employing multi-dimensional kernels. As a result it retains high accuracy for high dimensional predictors. We establish estimation consistency, convergence rate and variable selection consistency of the method proposed. Through simulation comparisons we demonstrate that the method proposed performs better than existing methods when the predictor affects several attributes of the response, and it performs competently in the classical setting where the predictors affect the mean only. We apply the new method to a data set concerning how gene expression levels affect the weight of mice.

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“…142 Moreover, the reduction in neointimal formation observed in rats treated with ␤-lapachone, a potent antitumor agent that stimulates NAD(P)H:quinone oxidoreductase activity, was attributed to the LKB1-dependent activation of the AMPK. 143 The contribution of inflammatory cells to atherogenesis is well documented; however, although hypoxia stimulates the AMPK in activated monocytes, 144 and AMPK activation attenuates the lipopolysaccharide-induced expression of inducible NOS, 145 regulates macropinocytosis, 146 and reduces migration to stromal cell-derived factor, 147 surprisingly little is known about the control and consequences of AMPK activation in monocytes/macrophages. In a study not directed at atherosclerosis, it could be demonstrated that AMPK signaling is a potential potent counter regulator of inflammatory signaling pathways.…”

Section: Fisslthaler and Fleming Ampk In Endothelial Signaling 121mentioning

confidence: 99%

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

Fißlthaler

Fleming

2009

Circulation Research

276

283

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Abstract-The AMP-activated protein kinase (AMPK) was initially identified as the kinase that phosphorylates the 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. As the name suggests, the AMPK is activated by increased intracellular concentrations of AMP, and is generally described as a "metabolite-sensing kinase" and when activated initiates steps to conserve cellular energy. Although there is a strong link between the activity of the AMPK and metabolic control in muscle cells, the activity of the AMPK in endothelial cells can be regulated by stimuli that affect cellular ATP levels, such as hypoxia as well as by fluid shear stress, Ca 2ϩ -elevating agonists, and hormones such as adiponectin. To date the AMPK in endothelial cells has been implicated in the regulation of fatty acid oxidation, small G protein activity and nitric oxide production as well as inflammation and angiogenesis. Moreover, there is evidence indicating that the activation of the AMPK may help to prevent the vascular complications associated with the metabolic syndrome. Key Words: angiogenesis Ⅲ nitric oxide synthase Ⅲ atherosclerosis Ⅲ 3-hydroxy-3-methylglutaryl coenzyme A Ⅲ energy metabolism T he AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine protein kinase consisting of the catalytic subunit (␣) and 2 regulatory subunits (␤ and ␥) that exist as multiple isoforms and splice variants, resulting in the generation of 12 possible heterotrimeric combinations. As its name suggests, the AMPK is activated in many different cell types by increased intracellular concentrations of AMP and is generally referred to as a "metabolite-sensing kinase." Indeed, the AMPK is activated following heat shock, vigorous exercise, hypoxia/ischemia, and starvation and appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, skeletal muscle fatty acid oxidation, and protein synthesis (reviewed recently 1,2 ). Although the complex picture regarding the regulation of AMPK activity is far from complete, it seems safe to state that the AMPK determines whole body insulin sensitivity and may prevent insulin resistance, in part, by inhibiting pathways that antagonize insulin signaling. Through its effects on signaling, metabolism, and gene expression, the AMPK enhances insulin sensitivity and may reduce the risk of type 2 diabetes. 3 The 2 previous review articles in this series have focused on the role of the AMPK in metabolic control and insulin signaling 4 and in the heart. 5 This review focuses on the role of the AMPK in vascular cells and the data implicating defects in AMPK signaling in the development of vascular disease. Activation of the AMPKEach subunit within the heterotrimeric AMPK complex has a distinct structure and function and their interaction is necessary for the modulation of kinase activity. The ␣ subunits Ori...

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Macropinocytosis is decreased in diabetic mouse macrophages and is regulated by AMPK

Cited by 15 publications

References 45 publications

AMP-Activated Protein Kinase Is Required for the Macropinocytic Internalization of Ebolavirus

AMP-Activated Protein Kinase Is Required for the Macropinocytic Internalization of Ebolavirus

Variable Selection via Additive Conditional Independence

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

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