A Novel MEK-ERK-AMPK Signaling Axis Controls Chemokine Receptor CCR7-dependent Survival in Human Mature Dendritic Cells
A Novel MEK-ERK-AMPK Signaling Axis Controls Chemokine Receptor CCR7-dependent Survival in Human Mature Dendritic Cells
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DOI：
10.1074/jbc.m114.596551
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发表时间：
2015-01-09
影响因子：
4.8
通讯作者：
Luis Rodriguez-Fernandez, Jose
中科院分区：
文献类型：
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作者：
Lopez-Cotarelo, Pilar;Escribano-Diaz, Cristina;Luis Rodriguez-Fernandez, Jose
趋化因子受体CCR7将成熟的树突状细胞(MDCs)导向次级淋巴结，在那里这些细胞调节T细胞的激活。CCR7还促进MDCS的存活，据信这主要是通过Akt依赖的信号机制发生的。我们分析了AMP依赖的激酶(AMPK)在CCR7依赖的生存控制中的作用。AMPK的APRO-凋亡作用是通过发现药理激活剂诱导细胞凋亡，而用siRNA敲除AMPK延长了MDC的存活。AMPK的药理激活也可诱导淋巴结中MDCs的凋亡。刺激CCR7可通过G(I)/Gβ-γ介导的Ser-485磷酸化抑制AMPK，而不是通过Akt或S6K这两个在其他环境中控制AMPK磷酸化的激酶。使用选择性药物抑制剂，我们证明CCR7诱导的AMPK在Ser-485上的磷酸化是由MEK和ERK介导的。免疫共沉淀分析和邻近连接分析表明，AMPK与ERK结合，但不与MEK结合。这些结果表明，除了Akt依赖的信号机制外，CCR7还可以通过一个新的MEK1/2-ERK1/2-AMPK信号轴促进MDCS的存活。数据还表明，AMPK可能是调节MDC寿命和免疫反应的潜在靶点。
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.