Hoeflich K P, Yeh W C, Yao Z, Mak T W, Woodgett J R
Department of Medical Biophysics, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Oncogene. 1999 Oct 14;18(42):5814-20. doi: 10.1038/sj.onc.1202975.
Tumor necrosis factor-alpha (TNF), a major inflammatory cytokine, generates a wide variety of cellular responses via key cytoplasmic adaptor molecules named TNF receptor-associated factors (TRAFs). We report that TRAF2, TRAF5 and TRAF6 associate with apoptosis signal-regulating kinase 1 (ASK1), and a catalytically-inactive ASK1 mutant blocks stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) activation by these TRAFs. A truncated derivative of TRAF2, which inhibits SAPK activation by TNF, blocks TNF-induced ASK1 activation. Furthermore, protection from TNF-induced cell death conferred by an ASK1 mutant is dependent upon TRAF2. Hence, ASK1 is a common mediator of TRAF-regulated SAPK and apoptosis signaling, and the TRAF2 - ASK1 connection completes the signaling cascade from TNF to SAPK/JNK activation.
肿瘤坏死因子-α（TNF）是一种主要的炎性细胞因子，它通过名为TNF受体相关因子（TRAFs）的关键胞质衔接分子产生多种细胞反应。我们报告称，TRAF2、TRAF5和TRAF6与凋亡信号调节激酶1（ASK1）相关联，并且一种催化失活的ASK1突变体可阻断这些TRAFs介导的应激激活蛋白激酶（SAPK）/Jun氨基末端激酶（JNK）的激活。一种抑制TNF诱导的SAPK激活的TRAF2截短衍生物可阻断TNF诱导的ASK1激活。此外，ASK1突变体对TNF诱导的细胞死亡的保护作用依赖于TRAF2。因此，ASK1是TRAF调节的SAPK和凋亡信号传导的共同介质，并且TRAF2-ASK1连接完成了从TNF到SAPK/JNK激活的信号级联反应。
