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

应激反应性MAPK通路被广泛的应激刺激如DNA损伤激活，并且在调节细胞应激反应（从存活到凋亡性细胞死亡）中起关键作用。这些关键信号系统的扰动涉及各种危及生命的疾病，包括癌症。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，MTK1参与下调细胞周期蛋白的表达。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。在应激反应中，Mip1被磷酸化并被MTK1激活，从而抑制应激诱导的细胞凋亡。有趣的是，我们证实了Mip1表达在人类癌症中受到异常调节。

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.