Accumulation of lipid peroxides in the cell are associated with diseases and cellular stress. In the current issue of Proceedings of the National Academy of Sciences, researchers at Helmholtz Zentrum München and the Swedish medical university Karolinska Institutet show that lipid peroxides also play an important, yet-unrecognized role in the regulation of receptor tyrosine kinases.
Neurodegenerative Diseases (DZNE) and a research group at Karolinska Institutet in Stockholm, Sweden, researchers have now discovered that lipid peroxides play a specific physiological role in the cell. Prior to this study, scientists had already established that accumulation of lipid peroxides indicate cell stress. Lipid peroxides have further been shown to be very potent inducers of cell death.
The results of this study now demonstrate that chemically modified (oxidized) lipids temporarily inactivate protein tyrosine phosphatases. These in turn regulate the cellular communication of receptor tyrosine kinases (RTK). This finding is of central importance because aberrant activation of the receptor tyrosine kinases contributes to many diseases, including cancer. Until now, only hydrogen peroxide was known to oxidize and inactivate protein tyrosine phosphatases and thus to have a regulating effect on kinases.
"We were able to show that lipid peroxides are 100-1000 times more effective than hydrogen peroxide," said Dr. Marcus Conrad, lead authors of the publication, who has since moved from Helmholtz Zentrum München to the German Center for Neurodegenerative Disease. Dr. Arne Östman and Åsa Sandin from the Karolinska Institutet added: "It will be very interesting to see if lipid peroxides contribute to the activation of tyrosine kinases in cancer and other diseases, e.g. diabetes and Alzheimer's disease."
Lipid peroxides are chemically modified lipids or fatty acids, which, among other things, indicate cellular stress. In high concentrations they can trigger cell death. Elevated concentrations of lipid peroxides are often found in patients with common diseases such as atherosclerosis, diabetes, cancer or neurodegenerative diseases including Parkinson's and Alzheimer's disease.
Receptor tyrosine kinases (RTK) and protein tyrosine phosphatases have an important function in the regulation of cell growth and division. Over-active receptor tyrosine kinases play a key role in the etiology of cancer. A frequent cause of breast cancer, for instance, is a malfunction of the receptor tyrosine kinase HER-2 (human epidermal growth factor receptor 2). In healthy tissues and cells receptor tyrosine kinases are precisely regulated by protein tyrosine phosphatases.
The above story is based on materials provided by Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health. Note: Materials may be edited for content and length.
- M. Conrad, A. Sandin, H. Forster, A. Seiler, J. Frijhoff, M. Dagnell, G. W. Bornkamm, O. Radmark, R. Hooft van Huijsduijnen, P. Aspenstrom, F. Bohmer, A. Ostman. 12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1007909107
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