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

Abstract

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 β-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.phospholipid hydroperoxide glutathione peroxidase | PDGF | redox regulation | reversible oxidation S ignaling through receptor tyrosine kinases (RTKs), such as the PDGF β-receptor, is subjected to negative control by protein tyrosine phosphatases (PTPs) (1-3). Consequently, alterations in expression levels or the specific activity of PTPs will affect the cellular response to ligands of RTKs. With regard to the PDGF β-receptor, a series of PTPs, including T cell protein tyrosine phosphatase (TC-PTP), density enhanced phosphatase-1 (DEP-1), SHP-2, and PTP-1B, have been found to modulate receptor signaling (4-7). Detailed analyses of the consequences of deletion of individual PTPs have shown that individual PDGF receptorantagonizing PTPs preferentially dephosphorylate particular phospho-tyrosine residues of the receptor and thereby are able to modulate the signaling output (4,(8)(9)(10).Inhibitory and reversible oxidation of the active-site cysteine has emerged as a general mechanism for PTP regulation (11,12). As a consequence of the microenvironment of the conserved active site of PTPs, the catalytic cysteine of PTPs usually exists as thiolate anion, which is highly susceptible to oxidation. Studies in cellular models, as well as in vitro studies, indicate that PTPs display intrinsic differences in oxidation susceptibility (13-15). PTP oxidation has been shown after activation of reactive oxygen species (ROS)-inducing cell-surface

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

“…This concurs with reports showing 12/15-lipoxygenase-catalzed lipid peroxidation to modulate intracellular signaling, i.e. tyrosine phosphatase activity (45). Our data point to 15(S)-HETE being involved in proinflammatory macrophage activation, although a much lower efficacy was observed compared with IL-4 pretreatment.…”

Selenoproteins: Molecular Pathways and Physiological Roles

“…Due to reversible oxidation of the Cys residue in the active site of PTPs, H 2 O 2 has been shown to inhibit their function. A recent study demonstrated that, in addition to H 2 O 2 , PTPs are also subject to inactivation by lipid hydroperoxides (69). Therefore, similar to GPx1 and peroxiredoxin II (PrxII), which regulate PTPs by modulating levels of H 2 O 2 , GPx4 may participate in the control of PTP proteins by degrading lipid hydroperoxides.…”

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

“…As just mentioned, the GPX1 and 3 play important roles in reducing H 2 O 2 to water, and Se status in immune cells can directly affect the half-life of this ROS. In addition, GPX4 educes phospholipid hydroperoxides, and this activity has recently been shown to regulate protein tyrosine phosphatase (PTP) signaling, particularly through Gpx4-mediated reduction of 12/15-lipoxygenase (45). Txnrd1 may indirectly regulate the downstream effects of H 2 O 2 by reducing disulfide bonds generated by H 2 O 2 in signaling molecules.…”

“…Oxidation of this Cys by H 2 O 2 inactivates the PTP, and reduction by GSH or TXN reverts the catalytic domain back to its active state (37,272). In addition to H 2 O 2 , phospholipid hydroperoxides can also oxidize signaling molecules at their active-site Cys residues (45).…”