A Novel MEK-ERK-AMPK Signaling Axis Controls Chemokine Receptor CCR7-dependent Survival in Human Mature Dendritic Cells

López-Cotarelo, Pilar; Escribano-Díaz, Cristina; González-Bethencourt, Ivan Luis; Gómez-Moreira, Carolina; Deguiz, María Laura; Torres‐Bacete, Jesús; Gómez-Cabañas, Laura; Fernández-Barrera, Jaime; Delgado-Martín, Cristina; Mellado, Mario; Regueiro, José R.; Miranda-Carús, María-Eugenia; Rodrı́guez-Fernández, José Luis

doi:10.1074/jbc.m114.596551

Cited by 45 publications

(43 citation statements)

References 58 publications

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“…In murine macrophage-like RAW 264.7 cells, Park et al (12) showed that IKK␤ phosphorylates AMPK at Ser 485 in response to LPS treatment in mature dendritic cells. ERK1/2 was recently shown to phosphorylate AMPK on this serine residue (13), an effect that may be an important part of the mechanism by which CCR7 signaling promotes cell survival. Furthermore, protein kinase A (PKA) has been reported to act as an upstream kinase for AMPK Ser 485/491 in INS-1 cells in response to forskolin or GIP stimulation (14) and in human diploid fibroblasts in response to lysophosphatidic acid (15).…”

Section: Discussionmentioning

confidence: 99%

“…Also, in the hypothalamus, Dagon et al (4,5) showed that p70S6K phosphorylates AMPK␣2 Ser 491 to inhibit AMPK activity and decrease food intake. Others have shown that in murine macrophage-like RAW 264.7 cells, IKK␤ phosphorylates AMPK at Ser 485 in response to LPS treatment (12), while ERK1/2 can inhibit AMPK by this mechanism in mature dendritic cells in response to CCR7 signaling (13). Finally, protein kinase A (PKA) has been reported to phosphorylate this site in INS-1 cells in response to forskolin or GIP stimulation (14) and in human diploid fibroblasts in response to lysophosphatidic acid (15).…”

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confidence: 99%

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PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells

Coughlan

Valentine

Sudit

et al. 2016

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells

Coughlan

Valentine

Sudit

et al. 2016

Journal of Biological Chemistry

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“…Recombinant PKA (cAMP-dependent protein kinase) also phosphorylates AMPKα1 Ser487 in vitro , and cAMP-elevating agents have also been reported to stimulate AMPKα1 Ser487 phosphorylation in mouse embryonic fibroblasts and insulin-secreting cell lines [19,20]. Recently, inhibitors of the mitogen-activated protein kinase kinase (MEK1/2) extracellular signal-regulated kinase 1/2 (ERK1/2) and IKK (inhibitor of nuclear factor-κB kinase) pathways have also been reported to attenuate AMPKα1 Ser487 phosphorylation in human dendritic cells and a mouse macrophage cell line, implicating these pathways as regulators of AMPKα1 Ser487 [21,22]. …”

Section: Introductionmentioning

confidence: 99%

Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487

Heathcote

Mancini

Strembitska

et al. 2016

Biochemical Journal

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The key metabolic regulator, AMP-activated protein kinase (AMPK), is reported to be down-regulated in metabolic disorders, but the mechanisms are poorly characterised. Recent studies have identified phosphorylation of the AMPKα1/α2 catalytic subunit isoforms at Ser487/491, respectively, as an inhibitory regulation mechanism. Vascular endothelial growth factor (VEGF) stimulates AMPK and protein kinase B (Akt) in cultured human endothelial cells. As Akt has been demonstrated to be an AMPKα1 Ser487 kinase, the effect of VEGF on inhibitory AMPK phosphorylation in cultured primary human endothelial cells was examined. Stimulation of endothelial cells with VEGF rapidly increased AMPKα1 Ser487 phosphorylation in an Akt-independent manner, without altering AMPKα2 Ser491 phosphorylation. In contrast, VEGF-stimulated AMPKα1 Ser487 phosphorylation was sensitive to inhibitors of protein kinase C (PKC) and PKC activation using phorbol esters or overexpression of PKC-stimulated AMPKα1 Ser487 phosphorylation. Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues.

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“…Polymet’s ability to activate the AMPKα pathway while simultaneously inhibiting mTOR suggests its mechanism of synergy with CDDP. The AMPK pathway is known to intersect with the congogenic Ras/Phosphatidylinositol 3-kinase (PI3K)/mTOR and extra cellular signal regulated kinase (ERK) pathways at multiple points [38,39]. Collectively, it is known that AMPK responds to a decrease in cellular ATP by phosphorylating effectors that inhibit mTOR activity.…”

Section: Resultsmentioning

confidence: 99%

Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer

Xiong

Zhao

Miao

et al. 2016

Journal of Controlled Release

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Clinically, combined therapy of cisplatin (CDDP) and metformin is an effective treatment for non-small cell lung cancer (NSCLC). The success is attributed to synergistic effects between the two drugs. Therefore, we hypothesize that co-encapsulation of CDDP and metformin will avoid the prominent toxicity of CDDP while maintaining the synergy between the regimens. CDDP was first conjugated to polyglutamic acid (PGA) to form anionic PGA-CDDP which was electrostatically complexed with the cationic polymeric metformin (polymet). The nano-sized complex was then stabilized with cationic liposomes composed of DOTAP (2, 3-Dioleoyloxy-propyl)-trimethylammonium/Cholesterol/DSPE-PEG-anisamide aminoethyl. Both in vitro and in vivo experiments confirmed the synergy between polymet and CDDP. CDDP delivered with nanoparticles (NPs) exhibited significantly increased tumor accumulation over free CDDP and suppressed tumor growth through apoptosis in NSCLC H460 tumor-bearing mice without nephrotoxicity. The synergistic effect of polymet alongside CDDP demonstrates that polymet-CDDP NPs can activate the AMP-activated protein kinase α (AMPKα) pathway and inhibit mammalian target rapamycin (mTOR) activity to enhance growth suppression. In all, this platform is the first to successfully co-load polymet, a polymeric metformin, and CDDP into the same nanoparticle for successful treatment of NSCLC.

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A Novel MEK-ERK-AMPK Signaling Axis Controls Chemokine Receptor CCR7-dependent Survival in Human Mature Dendritic Cells

Cited by 45 publications

References 58 publications

PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells

PKD1 Inhibits AMPKα2 through Phosphorylation of Serine 491 and Impairs Insulin Signaling in Skeletal Muscle Cells

Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487

Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer

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