Functional role of death-associated protein 3 (DAP3) in anoikis
Functional role of death-associated protein 3 (DAP3) in anoikis
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DOI：
10.1074/jbc.m408101200
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发表时间：
2004-10-22
影响因子：
4.8
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Miyazaki, T;Shen, M;Reed, JC
贴壁上皮细胞脱离细胞外基质诱导细胞凋亡，称为细胞凋亡。整合素刺激保护细胞免受损伤，但其机制尚不清楚。在这里，我们证明了一种促凋亡的gtp结合蛋白DAP3（死亡相关蛋白3）对诱导anoikis至关重要。通过反义寡核苷酸下调DAP3的表达可抑制疾病的发生。相反，DAP3的过表达增加了细胞脱离诱导的细胞死亡和caspase激活。此外，细胞脱离诱导DAP3与FADD的关联和caspase-8的激活。我们还发现，DAP3被激酶Akt （PKB）磷酸化，活性Akt可以抵消DAP3诱导的细胞凋亡。DAP3中一致Akt磷酸化位点的突变使其能够抵抗细胞中活性Akt的抑制。整合素连接刺激完整细胞中Akt的激活和DAP3的磷酸化，并抑制DAP3过表达增强anoikis的能力。DAP3参与anoikis信号传导，证明了这种gtp结合蛋白在细胞脱离诱导凋亡中的新作用。
Detachment of adherent epithelial cells from the extracellular matrix induces apoptosis, known as anoikis. Integrin stimulation protects cells from anoikis, but the responsible mechanisms are not well known. Here, we demonstrated that a pro-apoptotic GTP-binding protein, DAP3 (death-associated protein 3), is critical for induction of anoikis. Down-regulation of DAP3 expression by antisense oligonucleotides inhibited anoikis. Conversely, overexpression of DAP3 augmented cell death and caspase activation induced by cell detachment. Furthermore, the association of DAP3 with FADD and the activation of caspase-8 were induced by cell detachment. We also showed that DAP3 is phosphorylated by kinase Akt (PKB), and active Akt can nullify apoptosis induction by DAP3. Mutation of a consensus Akt phosphorylation site in DAP3 renders it resistant to suppression by active Akt in cells. Integrin ligation stimulates Akt activation and phosphorylation of DAP3 in intact cells, as well as suppresses the ability of DAP3 overexpression to augment anoikis. Involvement of DAP3 in anoikis signaling demonstrates a novel role for this GTP-binding protein in apoptosis induction caused by cell detachment.