Vichalkovski Anton, Gresko Ekaterina, Cornils Hauke, Hergovich Alexander, Schmitz Debora, Hemmings Brian A
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Curr Biol. 2008 Dec 9;18(23):1889-95. doi: 10.1016/j.cub.2008.10.060.
Human NDR1 and 2 (NDR1/2) are serine-threonine protein kinases in a subgroup of the AGC kinase family. 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 NDR 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.
人类NDR1和NDR2（NDR1/2）是AGC激酶家族一个亚组中的丝氨酸-苏氨酸蛋白激酶。NDR1/2生理性激活的机制及其功能在很大程度上仍不清楚。在此我们报告，Fas和肿瘤坏死因子-α受体刺激通过促进疏水基序（Thr444/442）处的磷酸化来激活人类NDR1/2。此外，NDR1/2对于Fas受体诱导的细胞凋亡至关重要，这一点可通过以下事实证明：NDR基因敲低显著降低细胞死亡，而NDR1激酶的过表达进一步增强细胞凋亡。死亡受体刺激对NDR1/2的激活由肿瘤抑制因子RASSF1A介导。此外，RASSF1A诱导的细胞凋亡在很大程度上依赖于NDR1/2的存在。Fas受体刺激促进了哺乳动物STE20样激酶1（MST1，RASSF1A的下游效应物）对NDR1/2的直接磷酸化和激活。同时，NDR1/2共激活因子MOB1诱导形成MST1-NDR-MOB1复合物，这对于凋亡诱导时MST1诱导的NDR1/2磷酸化至关重要。我们的研究结果确定NDR1/2为新型促凋亡激酶以及RASSF1A/MST1信号级联反应的关键成员。
