Program in Molecular and Systems Pharmacology of the Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA.
Oncogene. 2010 Feb 11;29(6):822-30. doi: 10.1038/onc.2009.382. Epub 2009 Nov 23.
Faithful and efficient transmission of biological signals through mitogen-activated protein kinase (MAPK) pathways requires engagement of highly regulated cellular machinery in response to diverse environmental cues. Here, we report a novel mechanism controlling signal relay between two MAP3Ks, apoptosis signal-regulating kinase (ASK) 1 and ASK2. We show that ASK2 specifically interacts with 14-3-3 proteins through phosphorylated S964. Although a 14-3-3-binding defective mutant of ASK1 (S967A) has no effect on the ASK2/14-3-3 interaction, both overexpression of the analogous ASK2 (S964A) mutant and knockdown of ASK2 dramatically reduced the amount of ASK1 complexed with 14-3-3. These data suggest a dominant role of ASK2 in 14-3-3 control of ASK1 function. Indeed, ASK2 S964A-induced dissociation of 14-3-3 from ASK1 correlated with enhanced phosphorylation of ASK1 at T838 and increased c-Jun N-terminal kinase phosphorylation, the two biological readouts of ASK1 activation. Our results suggest a model in which upstream signals couple ASK2 S964 phosphorylation to the ASK1 signalosome through dual engagement of 14-3-3.
通过丝裂原活化蛋白激酶 (MAPK) 途径忠实高效地传递生物信号需要细胞机制的高度调控，以响应各种环境线索。在这里，我们报告了一种控制两种 MAP3K（凋亡信号调节激酶 (ASK) 1 和 ASK2 之间信号传递的新机制。我们表明，ASK2 通过磷酸化 S964 特异性地与 14-3-3 蛋白相互作用。尽管 ASK1 的一个无 14-3-3 结合缺陷突变体 (S967A) 对 ASK2/14-3-3 相互作用没有影响，但类似的 ASK2 (S964A) 突变体的过表达和 ASK2 的敲低都显著减少了与 14-3-3 结合的 ASK1 量。这些数据表明 ASK2 在 14-3-3 控制 ASK1 功能中起主导作用。事实上，ASK2 S964A 诱导的 14-3-3 从 ASK1 解离与 ASK1 在 T838 处的磷酸化增强以及 c-Jun N 端激酶磷酸化增加相关，这是 ASK1 激活的两个生物学读出。我们的结果表明，上游信号通过双重结合 14-3-3，将 ASK2 S964 磷酸化与 ASK1 信号体偶联在一起的模型。
