Abstract
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.
Document Type
Article
Publication Date
9-1-2011
Digital Object Identifier (DOI)
http://dx.doi.org/10.1091/mbc.E11-05-0400
Repository Citation
Cai, Weikang; Rudolph, Jennifer L.; Harrison, Susan M. W.; Jin, Ling; Frantz, Aubrey L.; Harrison, Douglas A.; and Andres, Douglas A., "An Evolutionarily Conserved Rit GTPase-p38 MAPK Signaling Pathway Mediates Oxidative Stress Resistance" (2011). Molecular and Cellular Biochemistry Faculty Publications. 62.
https://uknowledge.uky.edu/biochem_facpub/62
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Cell and Developmental Biology Commons
Notes/Citation Information
Published in Molecular Biology of the Cell, v. 22, no. 17, p. 3231-3241.
© 2011 Cai et al.
This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).