title: An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance.
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.
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536-0509, USA.
authors: Weikang
authors: W
authors: Cai
authors: Jennifer L
authors: JL
authors: Rudolph
authors: Susan M W
authors: SM
authors: Harrison
authors: Ling
authors: L
authors: Jin
authors: Aubrey L
authors: AL
authors: Frantz
authors: Douglas A
authors: DA
authors: Harrison
authors: Douglas A
authors: DA
authors: Andres
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D017124:Conserved Sequence; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D019143:Evolution, Molecular; D005347:Fibroblasts / Q000502:physiology; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016877:Oxidants; C102569:RIC protein, Drosophila; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C472865:Rit1 protein, mouse; D018631:ras Proteins