ROS and ROS-Mediated Cellular Signaling

Abstract

It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell-signaling proteins (NF-κB, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca(2+) and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System.

Figure 1

Homeostasis of intracellular reactive oxygen species. NOX, NADPH oxidases; TNF-α, tumor necrosis factor-α; EGF, epidermal growth factor; IL-1β, Interleukin-1β; SOD, superoxide dismutase; GPx, glutathione peroxidase; GST-pi, glutathione S-transferase pi; MT3, metallothionein-3; FHC, ferritin heavy chain; DDH1, dihydrodiol dehydrogenase; TNFR, tumor necrosis factor receptor; TRADD, TNFRSF1A-associated via death domain; MyD88, myeloid differentiation factor 88; TLR, Toll-like receptor; cPLA2, cytosolic phospholipases A2.

Figure 2

Cross talk between ROS and NF-κB signaling pathway. MEKK1, mitogen-activated protein kinase kinase kinase 1; PKC, protein kinase C; NIK, NF-κB inducing kinase; NEDD8, neural precursor cell expressed developmentally downregulated 8.

Figure 3

Cross talk between ROS and MAPKs signaling pathway. MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinases; JNK, c-Jun N-terminal kinases; p38, p38 kinase; BMK1/ERK5, big MAP kinase 1; MAPKKK, MAP kinase kinase kinase; MAPKK, MAP kinase kinase; MAPK, MAP kinase; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol.

Figure 4

Cross talk between ROS and Keap1-Nrf2-ARE signaling pathway. Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response elements; Cul3, cullin-3 E3-ubiquitin ligase; GSK3β, glycogen synthase kinase 3; Ubc, E2-ubiquitin conjugating enzyme.

Figure 5

Cross talk between ROS and PI3K-Akt signaling pathway. PI3K, phosphoinositide-3-kinase; Akt, protein kinase B; PTEN, phosphatase and tensin homolog; FOXO, forkhead box protein O; mTOR1, mechanistic target of rapamycin 1.

Figure 6

Cross talk between ROS and Ca²⁺. IP3R, inositol 1,4,5-trisphosphate receptor; RyR, the ryanodine receptor; VDCC, voltage-dependent Ca²⁺ channels; SOC, store-operated Ca²⁺ channel; SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase; PMCA, plasma membrane Ca²⁺ ATPase; MCU, mitochondrial Ca²⁺ uniporter; TCA cycle, tricarboxylic acid cycle; NCX, Na⁺/ Ca²⁺ exchanger.

Figure 7

Cross talk between ROS and mPTP. VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocator; Cyp-D, cyclophilin-D.

Figure 8

Cross talk between ROS and protein kinase. CaMKII, calcium/calmodulin-dependent protein kinase II; RyR, the ryanodine receptor.

Figure 9

Regulation of Ubiquitination/Proteasome System by ROS. Ubc, E2-ubiquitin conjugating enzyme.