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

J Biol Chem. 2015 Jan 9;290(2):827-40. doi: 10.1074/jbc.M114.596551. Epub 2014 Nov 25.


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.

Keywords: AMP-activated Kinase (AMPK); Apoptosis; Chemokine; Dendritic Cell; Extracellular Signal-regulated Kinase (ERK); Human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Apoptosis / genetics
  • Cell Survival
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Humans
  • Immunity, Innate / genetics*
  • MAP Kinase Kinase 1 / genetics*
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase 2 / genetics*
  • MAP Kinase Kinase 2 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Phosphorylation
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / metabolism*
  • Signal Transduction / genetics
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • CCR7 protein, human
  • Receptors, CCR7
  • MAP2K2 protein, human
  • Mitogen-Activated Protein Kinase 3
  • AMP-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human