Akt-phosphorylated Mitogen-activated Kinase-activating Death Domain Protein (MADD) Inhibits TRAIL-induced Apoptosis by Blocking Fas-associated Death Domain (FADD) Association with Death Receptor 4
Akt-phosphorylated Mitogen-activated Kinase-activating Death Domain Protein (MADD) Inhibits TRAIL-induced Apoptosis by Blocking Fas-associated Death Domain (FADD) Association with Death Receptor 4
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DOI：
10.1074/jbc.m110.105692
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发表时间：
2010-07-16
影响因子：
4.8
通讯作者：
Prabhakar, Bellur S.
中科院分区：
文献类型：
--
作者：
Li, Peifeng;Jayarama, Shankar;Prabhakar, Bellur S.
MADD在癌细胞存活中起重要作用。内源性MADD表达的消除导致显著的自发性细胞凋亡和对肿瘤坏死因子α相关凋亡诱导配体（TRAIL）诱导的细胞凋亡的敏感性增强。然而，MADD功能的调节在很大程度上是未知的。在这里，我们证明，内源性MADD是磷酸化的Akt在三个高度保守的网站，只有磷酸化的MADD可以直接与TRAIL受体DR4，从而防止Fas相关的死亡结构域招聘。然而，在对TRAIL处理敏感的细胞中，TRAIL诱导MADD磷酸化水平的降低，导致MADD从DR4解离以及Fas相关死亡结构域与DR4缔合，这允许死亡诱导信号复合物（DISC）形成，导致细胞凋亡。因此，MADD的促存活功能依赖于其被Akt磷酸化。因为Akt在大多数癌细胞中是活性的，并且磷酸化的MADD赋予对TRAIL诱导的细胞凋亡的抗性，所以共靶向AktMADD轴可能增加基于TRAIL的疗法的功效。
MADD plays an essential role in cancer cell survival. Abrogation of endogenous MADD expression results in significant spontaneous apoptosis and enhanced susceptibility to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. However, the regulation of MADD function is largely unknown. Here, we demonstrate that endogenous MADDis phosphorylated at three highly conserved sites by Akt, and only the phosphorylated MADD can directly interact with the TRAIL receptor DR4 thereby preventing Fas-associated death domain recruitment. However, in cells susceptible to TRAIL treatment, TRAIL induces a reduction in MADD phosphorylation levels resulting in MADD dissociation from, and Fas-associated death domain association with DR4, which allows death-inducing signaling complex (DISC) formation leading to apoptosis. Thus, the pro-survival function of MADD is dependent upon its phosphorylation by Akt. Because Akt is active in most cancer cells and phosphorylated MADD confers resistance to TRAIL-induced apoptosis, co-targeting AktMADD axis is likely to increase efficacy of TRAIL-based therapies.