Activation of the Drosophila MLK by ceramide reveals TNF-α and ceramide as agonists of mammalian MLK3
Activation of the Drosophila MLK by ceramide reveals TNF-α and ceramide as agonists of mammalian MLK3
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DOI：
10.1016/s1097-2765(02)00734-7
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发表时间：
2002-12-01
期刊：
影响因子：
16
通讯作者：
Rana, A
中科院分区：
文献类型：
--
作者：
Sathyanarayana, P;Barthwal, MK;Rana, A
混合谱系激酶（mlk）是MAPKKK成员，可激活JNK，据报道可导致细胞死亡。然而，调节MLK活性的激动剂仍然未知。在这里，我们证明神经酰胺是果蝇MLK （dMLK）的激活剂，并鉴定神经酰胺和tnf - α是哺乳动物MLK3的激动剂。dMLK和MLK3在体内被神经酰胺类似物和细菌鞘磷脂酶激活，而低纳摩尔浓度的天然神经酰胺在体外激活它们。在体内特异性抑制dMLK和MLK3可显著减弱神经酰胺对JNK的激活，而不影响神经酰胺诱导的p38或ERK的激活。此外，tnf - α还能激活MLK3，并在体内明显激活JNK。因此，神经酰胺作为dMLK和MLK3的共同激动剂，MLK3有助于tnf - α诱导的JNK活化。
Mixed lineage kinases (MLKs) are MAPKKK members that activate JNK and reportedly lead to cell death. However, the agonist(s) that regulate MLK activity remain unknown. Here, we demonstrate ceramide as the activator of Drosophila MLK (dMLK) and identify ceramide and TNF-alpha as agonists of mammalian MLK3. dMLK and MLK3 are activated by a ceramide analog and bacterial sphingomyelinase in vivo, whereas a low nanomolar concentration of natural ceramide activates them in vitro. Specific inhibition of dMLK and MLK3 significantly attenuates activation of JNK by ceramide in vivo without affecting ceramide-induced p38 or ERK activation. In addition, TNF-alpha also activates MLK3 and evidently leads to JNK activation in vivo. Thus, the ceramide serves as a common agonist of dMLK and MLK3, and MLK3 contributes to JNK activation induced by TNF-alpha.