National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
J Biol Chem. 2010 Feb 26;285(9):6259-64. doi: 10.1074/jbc.M109.038570. Epub 2009 Dec 22.
Protein kinases play an important role in the maintenance of homeostasis between cell survival and apoptosis. Deregulation of these kinases leads to various pathological manifestations, such as cancer and neurodegenerative diseases. The MST1 encodes a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn phosphorylates its downstream targets, Histone H2B and FOXO. However, the upstream regulators of MST1 kinase have been poorly studied. In this study, we report that JNK (c-Jun N-terminal kinase) phosphorylates MST1 at serine 82, which leads to the enhancement of MST1 activation. Accordingly, the activation of MST1 phosphorylates FOXO3 at serine 207 and promotes cell death. The inhibition of JNK kinase per se attenuates MST1 activity and nuclear translocation as well as MST1-induced apoptosis. We also find the S82A (serine mutated to alanine) diminishes MST1 activation and its effect on the FOXO transcription activity. Collectively, these findings define the novel feedback regulation of MST1 kinase activation by its putative substrate, JNK, with implication for our understanding of the signaling mechanism during cell death.
蛋白激酶在维持细胞存活和凋亡之间的内稳态中发挥着重要作用。这些激酶的失调导致了各种病理表现，如癌症和神经退行性疾病。MST1 编码一种丝氨酸/苏氨酸激酶，在凋亡刺激下被激活，进而磷酸化其下游靶标组蛋白 H2B 和 FOXO。然而，MST1 激酶的上游调节因子研究甚少。在这项研究中，我们报告 JNK（c-Jun N-末端激酶）在丝氨酸 82 位点磷酸化 MST1，从而增强 MST1 的激活。因此，MST1 的激活使 FOXO3 在丝氨酸 207 位点磷酸化，并促进细胞死亡。JNK 激酶的抑制本身会减弱 MST1 的活性和核转位以及 MST1 诱导的细胞凋亡。我们还发现 S82A（丝氨酸突变为丙氨酸）会降低 MST1 的激活及其对 FOXO 转录活性的影响。总之，这些发现定义了 MST1 激酶激活的新的反馈调节，由其假定的底物 JNK 介导，这对我们理解细胞死亡过程中的信号机制具有重要意义。
