Regulation of cell death and proliferation by the MTK1 SAPKKK and its failure in cancer

应激反应MAPK通路被DNA损伤等一系列应激刺激激活，在细胞应激反应的调节中发挥关键作用，从细胞存活到细胞死亡。这些关键信号系统的扰动与包括癌症在内的各种危及生命的疾病有关。在这项研究中，我们研究了应激反应MAPKKK，MTK1的生理功能。我们发现，在应激条件下，MTK1参与了细胞周期蛋白表达的下调。此外，我们筛选了与MTK1相互作用的分子，并确定了一种蛋白激酶(称为Mip1)作为MTK1的新底物。作为对应激的响应，Mip1被MTK1磷酸化并激活，从而抑制应激诱导的细胞凋亡。有趣的是，我们证实Mip1在人类癌症中的表达是异常调节的。

Stress-responsive MAPK pathways are activated by a wide array of stress stimuli such as DNA-damage, and play pivotal roles in the regulation of cellular stress responses, ranging from survival to apoptotic cell death. Perturbation of these critical signaling systems is involved in a variety of life-threatening disorders including cancer. In this study, we investigated physiological functions of a stress-responsive MAPKKK, MTK1. We found that, under stress conditions, MTK1 participated in down-regulation of cyclin expression. Furthermore, we screened for molecules that interact with MTK1, and identified a protein kinase(termed Mip1) as a novel substrate of MTK1. In response to stress, Mip1 was phosphorylated and activated by MTK1, thereby inhibiting stress-induced apoptosis. Interestingly, we confirmed that Mip1 expression was aberrantly regulated in human cancer.