NDR Kinase Is Activated by RASSF1A/MST1 in Response to Fas Receptor Stimulation and Promotes Apoptosis
NDR Kinase Is Activated by RASSF1A/MST1 in Response to Fas Receptor Stimulation and Promotes Apoptosis
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DOI：
10.1016/j.cub.2008.10.060
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发表时间：
2008-12-09
期刊：
影响因子：
9.2
通讯作者：
Hemmings, Brian A.
中科院分区：
文献类型：
--
作者：
Vichalkovski, Anton;Gresko, Ekaterina;Hemmings, Brian A.
人 NDR1 和 2 (NDR1/2) 是 AGC 激酶家族亚组中的丝氨酸-苏氨酸蛋白激酶 [1]。 NDR1/2 的生理激活机制及其功能仍然很大程度上未知。在这里，我们报道 Fas 和 TNF-α 受体刺激通过促进疏水基序 (Thr444/442) 的磷酸化来激活人 NDR1/2。此外，NDR1/2 对于 Fas 受体诱导的细胞凋亡至关重要，事实证明，NOR 敲除显着减少了细胞死亡，而 NDR1 激酶的过度表达则进一步增强了细胞凋亡。死亡受体刺激引起的 NDR1/2 激活是由肿瘤抑制因子 RASSF1A 介导的。此外，RASSF1A 诱导的细胞凋亡很大程度上取决于 NDR1/2 的存在。 Fas 受体刺激促进哺乳动物 STE20 样激酶 1 (MST1)（RASSF1A 的下游效应子）对 NDR1/2 的直接磷酸化和激活。同时，NDR1/2 共激活剂 MOB1 诱导 MST1-NDR-MOB1 复合物形成，这对于 MST1 诱导细胞凋亡时诱导 NDR1/2 磷酸化至关重要。我们的研究结果将 NDR1/2 确定为新型促凋亡激酶和 RASSF1A/MST1 信号级联的关键成员。
Human NDR1 and 2 (NDR1/2) are serine-threonine protein kinases in a subgroup of the AGC kinase family [1]. The mechanisms of physiological NDR1/2 activation and their function remain largely unknown. Here we report that Fas and TNF-alpha receptor stimulation activates human NDR1/2 by promoting phosphorylation at the hydrophobic motif (Thr444/442). Moreover, NDR1/2 are essential for Fas receptor-induced apoptosis as shown by the fact that NOR knockdown significantly reduced cell death whereas overexpression of the NDR1 kinase further potentiated apoptosis. Activation of NDR1/2 by death receptor stimulation is mediated by the tumor suppressor RASSF1A. Furthermore, RASSF1A-induced apoptosis largely depends on the presence of NDR1/2. Fas receptor stimulation promoted direct phosphorylation and activation of NDR1/2 by the mammalian STE20-like kinase 1 (MST1), a downstream effector of RASSF1A. Concurrently, the NDR1/2 coactivator MOB1 induced MST1-NDR-MOB1 complex formation, which is crucial for MST1-induced NDR1/2 phosphorylation upon induction of apoptosis. Our findings identify NDR1/2 as novel proapoptotic kinases and key members of the RASSF1A/MST1 signaling cascade.