title: A novel MEK-ERK-AMPK signaling axis controls chemokine receptor CCR7-dependent survival in human mature dendritic cells.
abstract: Chemokine receptor CCR7 directs mature dendritic cells (mDCs) to secondary lymph nodes 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 signaling mechanisms. We have analyzed 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 mDC survival. Pharmacological activation of AMPK also induces apoptosis of mDCs in the lymph nodes. Stimulation of CCR7 leads to inhibition of AMPK, through phosphorylation of Ser-485, which was mediated by G(i)/Gβγ, but not by Akt or S6K, two kinases that control the phosphorylation of AMPK on Ser-485 in other settings. Using selective pharmacological inhibitors, we show that CCR7-induced phosphorylation of AMPK on Ser-485 is mediated by MEK and ERK. Coimmunoprecipitation analysis and proximity ligation assays indicate that AMPK associates with ERK, but not with MEK. These results suggest that in addition to Akt-dependent signaling mechanisms, CCR7 can also promote survival of mDCs through a novel MEK1/2-ERK1/2-AMPK signaling axis. The data also suggest that AMPK may be a potential target to modulate mDC lifespan and the immune response.
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Pilar
authors.initials: P
authors.lastname: López-Cotarelo
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Cristina
authors.initials: C
authors.lastname: Escribano-Díaz
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Ivan Luis
authors.initials: IL
authors.lastname: González-Bethencourt
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gómez-Moreira
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Deguiz
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Bacete
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Laura
authors.initials: L
authors.lastname: Gómez-Cabañas
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Jaime
authors.initials: J
authors.lastname: Fernández-Barrera
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid.
authors.forename: Cristina
authors.initials: C
authors.lastname: Delgado-Martín
authors.affiliation: the CNB/CSIC (Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas,) 28049 Madrid.
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
authors.affiliation: the School of Medicine, Universidad Complutense, 28040 Madrid, and.
authors.forename: José Ramón
authors.initials: JR
authors.lastname: Regueiro
authors.affiliation: the Department of Rheumatology, Hospital La Paz, 28046 Madrid, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Miranda-Carús
authors.affiliation: From the CIB/CSIC (Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas), 28040 Madrid, rodrifer@cib.csic.es.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rodríguez-Fernández
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics; D010766:Phosphorylation; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: C515370:CCR7 protein, human; D054400:Receptors, CCR7; C482128:MAP2K2 protein, human; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: AMP-activated Kinase (AMPK); Apoptosis; Chemokine; Dendritic Cell; Extracellular Signal-regulated Kinase (ERK); Human