TY - JOUR
T1 - A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling
AU - Patterson, Heide Christine
AU - Gerbeth, Carolin
AU - Thiru, Prathapan
AU - Vögtle, Nora F.
AU - Knoll, Marko
AU - Shahsafaei, Aliakbar
AU - Samocha, Kaitlin E.
AU - Huang, Cher X.
AU - Harden, Mark Michael
AU - Song, Rui
AU - Chen, Cynthia
AU - Kao, Jennifer
AU - Shi, Jiahai
AU - Salmon, Wendy
AU - Shaul, Yoav D.
AU - Stokes, Matthew P.
AU - Silva, Jeffrey C.
AU - Bell, George W.
AU - MacArthur, Daniel G.
AU - Ruland, Jürgen
AU - Meisinger, Chris
AU - Lodish, Harvey F.
PY - 2015/10/20
Y1 - 2015/10/20
N2 - 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 spacelocalized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.
AB - 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 spacelocalized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.
KW - Btk
KW - Dasatinib
KW - Fostamatinib
KW - PTPN6
KW - Rotenone
UR - http://www.scopus.com/inward/record.url?scp=84945566427&partnerID=8YFLogxK
U2 - 10.1073/pnas.1517932112
DO - 10.1073/pnas.1517932112
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C2 - 26438848
AN - SCOPUS:84945566427
SN - 0027-8424
VL - 112
SP - E5679-E5688
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 42
ER -