An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance.
An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance.
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DOI：
10.1091/mbc.e11-05-0400
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发表时间：
2011-09
影响因子：
3.3
通讯作者：
Andres DA
中科院分区：
文献类型：
--
作者：
Cai W;Rudolph JL;Harrison SM;Jin L;Frantz AL;Harrison DA;Andres DA
Rit knockout mice and D-Ric null Drosophila were used to identify the Rit/RIC subfamily of Ras-related GTPases as regulators of an evolutionarily conserved, p38-dependent signaling cascade that functions as a survival mechanism for cells in response to reactive oxygen species exposure. Ras-related small GTP-binding proteins control a wide range of cellular processes by regulating a variety of effector pathways, including prominent roles in the control of mitogen-activated protein kinase (MAPK) cascades. Although the regulatory role(s) for many Ras family GTPases are well established, the physiological function for the Rit/Rin subfamily has been lacking. Here, using both knockout mice and Drosophila models, we demonstrate an evolutionarily conserved role for Rit subfamily GTPases (mammalian Rit and Rin, and the Drosophila RIC homologue) in governing survival in response to oxidative stress. Primary embryonic fibroblasts derived from Rit knockout mice display increased apoptosis and selective disruption of MAPK signaling following reactive oxygen species (ROS) exposure but not in response to endoplasmic reticulum stress or DNA damage. These deficits include a reduction in ROS-mediated stimulation of a p38-MK2-HSP27 signaling cascade that controls Akt activation, directing Bad phosphorylation to promote cell survival. Furthermore, D-RIC null flies display increased susceptibility to environmental stresses and reduced stress-dependent p38 signaling, extending the Rit-p38 survival pathway to Drosophila. Together, our studies establish the Rit GTPases as critical regulators of an evolutionarily conserved, p38 MAPK–dependent signaling cascade that functions as an important survival mechanism for cells in response to oxidative stress.
