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

作者：Lopez Cotarelo Pilar; Escribano Diaz Cristina; Luis Gonzalez Bethencourt Ivan; Gomez Moreira Carolina; Laura Deguiz Maria; Torres Bacete Jesus; Gomez Cabanas Laura; Fernandez Barrera Jaime; Delgado Martin Cristina; Mellado Mario; Ramon Regueiro Jose; Eugenia Miranda Carus Maria; Luis Rodriguez Fernandez Jose

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290(2): 827-840.

DOI：10.1074/jbc.M114.596551

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. Apro-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)/G beta gamma, 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.

• 出版日期2015-1-9