12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.
Protein tyrosine phosphatases (PTPs) are regulated through reversible oxidation of the active-site cysteine. Previous studies have implied soluble reactive oxygen species (ROS), like H(2)O(2), as the mediators of PTP oxidation. The potential role(s) of peroxidized lipids in PTP oxidation have not been described. This study demonstrates that increases in cellular lipid peroxides, induced by disruption of glutathione peroxidase 4, induce cellular PTP oxidation and reduce the activity of PDGF receptor targeting PTPs. These effects were accompanied by site-selective increased PDGF beta-receptor phosphorylation, sensitive to 12/15-lipoxygenase (12/15-LOX) inhibitors, and increased PDGF-induced cytoskeletal rearrangements. Importantly, the 12/15-LOX-derived 15-OOH-eicosatetraenoic acid lipid peroxide was much more effective than H(2)O(2) in induction of in vitro PTP oxidation. Our study thus establishes that lipid peroxides are previously unrecognized inducers of oxidation of PTPs. This identifies a pathway for control of receptor tyrosine kinase signaling, which might also be involved in the etiology of diseases associated with increased lipid peroxidation.
Conrad
Marcus
M
Helmholtz Center Munich, Institute of Clinical Molecular Biology and Tumor Genetics, Germany. marcus.conrad@helmholtz-muenchen.de
Sandin
Asa
A
Förster
Heidi
H
Seiler
Alexander
A
Frijhoff
Jeroen
J
Dagnell
Markus
M
Bornkamm
Georg W
GW
Rådmark
Olof
O
Hooft van Huijsduijnen
Rob
R
Aspenström
Pontus
P
Böhmer
Frank
F
Ostman
Arne
A
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D004789:Enzyme Activation; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction
C475064:12-15-lipoxygenase; D008054:Lipid Peroxides; D017382:Reactive Oxygen Species; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D017027:Protein Tyrosine Phosphatases
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