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Conrad, M. ; Sandin, A.* ; Förster, H. ; Seiler, A. ; Frijhoff, J.* ; Dagnell, M.* ; Bornkamm, G.W. ; Radmark, O.* ; van Huijsduijnen, R.H.* ; Aspenström, P.* ; Böhmer, F.* ; Östman, A.*

12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.

Proc. Natl. Acad. Sci. U.S.A. 107, 15774-15779 (2010)
DOI Order publishers version
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Phospholipid hydroperoxide glutathione peroxidase; PDGF; Redox regulation; Reversible oxidation
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Quellenangaben Volume: 107, Issue: 36, Pages: 15774-15779 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed