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A novel MEK-ERK-AMPK signalling axis controls chemokine receptor CCR7-dependent survival in human mature dendritic cells

AuthorsLópez-Cotarelo, Pilar; Escribano, Cristina; González-Bethencourt, Ivan Luis; Gómez-Moreira, Carolina; Deguiz, María Laura; Torres-Bacete, Jesús; Gómez-Cabañas, Laura; Fernández-Barrera, Jaime ; Delgado-Martín, Cristina ; Rodríguez-Fernández, José Luis
Dendritic Cells
Issue Date15-Jan-2015
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJ Biol Chem. 290(2):827-40 (2015)
AbstractChemokine receptor CCR7 directs mature dendritic cells (mDCs) to secondary lymph nodes (LNs) where these cells regulate the activation of T cells. CCR7 also promotes survival in mDCs, which is believed to take place largely through Akt-dependent signalling mechanisms. We have analysed the involvement of the AMP-dependent kinase (AMPK) in the control of CCR7-dependent survival. A pro-apoptotic role for AMPK is suggested by the finding that pharmacological activators induce apoptosis, whereas knocking-down of AMPK with siRNA extends mDCs survival. Pharmacological activation of AMPK also induces apoptosis of mDCs in the LNs. Stimulation of CCR7 leads to inhibition of AMPK, through phosphorylation of Ser485, which was mediated by Gi/Gbut not by Akt or S6K, two kinases that control the phosphorylation of AMPK on Ser485 in other settings. Using selective pharmacological inhibitors, we show that CCR7-induced phosphorylation of AMPK on Ser485 is mediated by MEK and ERK. Coimmunoprecipitation analysis and Proximity Ligation Assays (PLA) indicate that AMPK associates with ERK, but not with MEK. The results suggest that in addition to Akt-dependent signalling mechanisms, CCR7 can also promote survival of mDCs through a novel MEK1/2-ERK1/2-AMPK signalling axis. The data also suggest that AMPK may be a potential target to modulate mDC lifespan and the immune response.
Description14 p.-9 fig.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M114.596551
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