| RRC ID |
67563
|
| 著者 |
Patterson HC, Gerbeth C, Thiru P, Vögtle NF, Knoll M, Shahsafaei A, Samocha KE, Huang CX, Harden MM, Song R, Chen C, Kao J, Shi J, Salmon W, Shaul YD, Stokes MP, Silva JC, Bell GW, MacArthur DG, Ruland J, Meisinger C, Lodish HF.
|
| タイトル |
A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.
|
| ジャーナル |
Proc Natl Acad Sci U S A
|
| Abstract |
Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.
|
| 巻・号 |
112(42)
|
| ページ |
E5679-88
|
| 公開日 |
2015-10-20
|
| DOI |
10.1073/pnas.1517932112
|
| PII |
1517932112
|
| PMID |
26438848
|
| PMC |
PMC4620870
|
| MeSH |
Animals
Cells, Cultured
Chickens
Electron Transport*
Enzyme Activation
Hydrogen Peroxide / metabolism*
Intracellular Signaling Peptides and Proteins / metabolism
Mice
Mitochondrial Membranes / metabolism*
Phosphorylation
Protein-Tyrosine Kinases / metabolism
Reactive Oxygen Species / metabolism
Signal Transduction*
Syk Kinase
Tyrosine / metabolism
|
| IF |
9.412
|
| リソース情報 |
| ヒト・動物細胞 |
DT40(RCB1464) |
