In addition to its conventional role for cell proliferation and survival, the Raf/MEK/Extracellular signal-regulated kinase (ERK) pathway can also induce growth arrest and death responses, if aberrantly activated. Here, we determined a molecular basis of ERK1/2 signaling that underlies these growth inhibitory physiological outputs. We found that overexpression of ERK1 or ERK2 switches ΔRaf-1:ER-induced growth arrest responses to caspase-dependent apoptotic death responses in different cell types. These death responses, however, were reverted to growth arrest responses upon titration of cellular phospho-ERK1/2 levels by the MEK1/2 inhibitor AZD6244. These data suggest that a cellular threshold for active ERK1/2 levels exists and affects the cell fate between death and growth arrest. We also found that death-mediating ability of ERK2 is abolished by the catalytic site-disabling Lys52Arg replacement or significantly attenuated by the F-site recruitment site-disabling Tyr261Asn replacement, although unaffected by the mutations that disable the common docking groove or the dimerization interface. Therefore, ERK1/2 mediates death signaling dependently of kinase activity and specific physical interactions. Intriguingly, Tyr261Asn-replaced ERK2 could still mediate growth arrest signaling, further contrasting the molecular basis of ERK1/2-mediated growth arrest and death signaling. These data reveal a mechanism underlying the role of ERK1/2 as a focal point of Raf/MEK/ERK-mediated growth arrest and death signaling.

除了其在细胞增殖和存活中的常规作用外，Raf / MEK /细胞外信号调节激酶（ERK）途径如果被异常激活，还可以诱导生长停滞和死亡反应。在这里，我们确定了这些生长抑制生理输出基础的ERK1 / 2信号的分子基础。我们发现，在不同细胞类型中，ERK1或ERK2的过表达将ΔRaf-1：ER诱导的生长停滞反应切换为caspase依赖性凋亡死亡反应。但是，通过MEK1 / 2抑制剂AZD6244滴定细胞磷酸化ERK1 / 2的水平后，这些死亡反应恢复为生长停滞反应。这些数据表明存在有效ERK1 / 2水平的细胞阈值，并影响死亡和生长停滞之间的细胞命运。我们还发现，虽然催化位点丧失的Lys52Arg替代物消除了ERK2的介导死亡能力，或者丧失了F位募集位点的Tyr261Asn替代物使ERK2的介导死亡能力显着减弱，尽管不受禁用通用对接凹槽或二聚化界面的突变的影响。因此，ERK1 / 2介导的死亡信号依赖于激酶活性和特定的物理相互作用。有趣的是，Tyr261Asn取代的ERK2仍然可以介导生长停滞信号，进一步对比了ERK1 / 2介导的生长停滞和死亡信号的分子基础。这些数据揭示了ERK1 / 2作为Raf / MEK / ERK介导的生长停滞和死亡信号转导的焦点的潜在机制。