Cai Weikang, Shi Geng-Xian, Andres Douglas A
Department of Molecular and Cellular Biochemistry; College of Medicine; University of Kentucky; Lexington, KY USA.
Commun Integr Biol. 2013 Jan 1;6(1):e22297. doi: 10.4161/cib.22297.
Cells mobilize diverse signaling pathways to protect against stress-mediated injury. Ras family GTPases play critical roles in this process, controlling the activation and integration of multiple regulatory cascades. p38 mitogen-activated protein kinase (MAPK) signaling serves as a critical fulcrum in this process, regulating networks that stimulate cellular apoptosis but also promote cell survival. However, this functional dichotomy is incompletely understood, particularly regulation of p38-dependent survival. Here, we discuss our recent evidence that the Rit GTPase associates with and is required for stress-mediated activation of a scaffolded p38-MK2-HSP27-Akt pro-survival signaling cascade. Drosophila lacking D-Ric, a Rit homologue, are susceptible to a variety of environmental stresses, while embryonic fibroblasts derived from Rit knockout mice display blunted stress-dependent signaling and decreased viability. Conversely, expression of constitutively active Rit triggers p38-Akt-dependent cell survival. Together, our studies establish Rit as the central regulator of an evolutionarily conserved, p38-dependent signaling cascade that functions as a critical survival mechanism in response to stress.
细胞动员多种信号通路来抵御应激介导的损伤。Ras家族GTP酶在这一过程中发挥关键作用，控制多个调节级联的激活和整合。p38丝裂原活化蛋白激酶（MAPK）信号在此过程中充当关键支点，调节刺激细胞凋亡但也促进细胞存活的网络。然而，这种功能二分法尚未完全被理解，尤其是对p38依赖性存活的调节。在此，我们讨论我们最近的证据，即Rit GTP酶与支架化的p38-MK2-HSP27-Akt促存活信号级联的应激介导激活相关联且是其必需的。缺乏Rit同源物D-Ric的果蝇易受多种环境应激的影响，而源自Rit基因敲除小鼠的胚胎成纤维细胞表现出减弱的应激依赖性信号传导和降低的活力。相反，组成型活性Rit的表达触发p38-Akt依赖性细胞存活。总之，我们的研究确立了Rit作为进化保守的、p38依赖性信号级联的核心调节因子，该级联在应激反应中作为关键的存活机制发挥作用。
