Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530
Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530
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DOI：
10.1074/jbc.m116.753202
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发表时间：
2017-02-03
影响因子：
4.8
通讯作者：
Yamaguchi, Naoto
中科院分区：
文献类型：
--
作者：
Morii, Mariko;Kubota, Sho;Yamaguchi, Naoto
Src家族酪氨酸激酶在多种细胞类型中广泛表达，并参与多种信号转导途径。尽管 Src 在抑制细胞凋亡中具有重要意义，但其机制仍知之甚少。在这里，我们证明 Src 作为 Ku70 依赖性细胞凋亡抑制的效应子。抑制内源性 Src 活性会促进紫外线诱导的细胞凋亡，而 Ku70 敲低会损害这种细胞凋亡。 Src 在 Tyr-530 位点磷酸化 Ku70，该位点接近参与促进细胞凋亡的可能乙酰化位点。 Src 介导的 Ku70 Tyr-530 磷酸化会降低 Ku70 的乙酰化，而 Src 抑制会增强 Ku70 的乙酰化。重要的是，使用稳定的 Ku70 敲低细胞进行的敲低拯救实验表明，Ku70 的不可磷酸化 Y530F 突变体降低了 Ku70 抑制细胞凋亡的能力，同时伴随着 Ku70 乙酰化的增强。我们的结果表明，Src 通过在 Tyr-530 位点磷酸化 Ku70 来降低细胞凋亡的易感性，从而对过度活跃的细胞凋亡发挥保护作用。
Src-family tyrosine kinases are widely expressed in many cell types and participate in a variety of signal transduction pathways. Despite the significance of Src in suppression of apoptosis, its mechanism remains poorly understood. Here we show that Src acts as an effector for Ku70-dependent suppression of apoptosis. Inhibition of endogenous Src activity promotes UV-induced apoptosis, which is impaired by Ku70 knockdown. Src phosphorylates Ku70 at Tyr-530, being close to the possible acetylation sites involved in promotion of apoptosis. Src-mediated phosphorylation of Ku70 at Tyr-530 decreases acetylation of Ku70, whereas Src inhibition augments acetylation of Ku70. Importantly, knockdown-rescue experiments with stable Ku70 knockdown cells show that the nonphosphorylatable Y530F mutant of Ku70 reduces the ability of Ku70 to suppress apoptosis accompanied by augmentation of Ku70 acetylation. Our results reveal that Src plays a protective role against hyperactive apoptotic cell death by reducing apoptotic susceptibility through phosphorylation of Ku70 at Tyr-530.