Résumé des résultats (Abstract)
(Anglais)
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Protein phosphorylation is a control mechanism that regulates most aspects of cell life. About one third of mammalian proteins contain covalently bound phosphate, and it now seems likely that protein kinases, protein phosphatases and their regulatory subunits will comprise several percent of all human gene products. Abnormal protein phosphorylation is a cause or consequence of major diseases, such as arthritis, Morbus Alzheimer, cancer, diabetes, hypertension and stroke, while defects in genes that encode particular protein kinases and phosphatases underlie a number of inherited disorders, including a variety of leukaemias, lymphomas and severe combined immunodeficiency syndromes. Here we focus on three different systems of sequentially regulated protein kinases designated as 'protein kinase cascades' or 'signalling cascades', which are involved in the development of cancer (the mitogen- activated protein kinase cascade - p42/44MAPK cascade), in inflammation (the p38 MAPK- or stress- activated protein kinase - SAPK - cascade) and in insulin signalling (the phosphoinositol-3 kinase/protein kinase B/Glycogen synthase kinase 3 - PI-3K/PKB/GSK3 - pathway). These signalling cascades contain different protein kinases as potential targets for therapeutic approaches. The aim of the proposal is to elucidate the role of the different protein kinases, to understand their molecular mechanisms of regulation and to identify their targets, which are responsible for the specific effects by using genetic, biochemical and chemical approaches in combination. As a result, therapeutic targets for the treatment of cancer, inflammatory diseases as well as diabetes will be defined and the suitability of these targets will be analysed in cell-based assays and model organisms.
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