Oxidation-dependent degradation as a novel principle for regulation of protein-tyrosine phosphatases - role of PTP DEP-1 oxidation for transformation in AML

• Antragsteller: Professor Dr. Frank-Dietmar Böhmer
• Fachliche Zuordnung: Zellbiologie
• Förderung: Förderung von 2000 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5289010

Cell surface receptors are important elements in cell-cell and cell-matrix communications as well as in the exchange of information through soluble factors. Several receptors elicit a signal transduction cascade through kinase function which is either part of the receptor molecule itself or gets recruited to the receptor. Initiation of signalling involves mutual tyrosine phosphorylation of at least two associated subunit molecules of the receptor. The interaction with its extracellularligand is thought to trigger this association (usually called dimerization). By the use of toxic agents we have discovered that dephosphorylation of these tyrosine kinases is a decisive process in the regulation. The toxic agents inactivate receptor tyrosine phosphatases by oxidizing (or reacting with) a cysteine in their active centers. As a result the balance between phosphorylation and dephosphorylation is shifted towards increased spontaneous (ligand-independent) kinase activity. These data suggest that a major part of the receptor dependent signalling is regulated by the activity of a closely associated tyrosine phosphatase. We speculate that the physiological regulation - like that by toxic agents - makes use of oxidation-reduction reactions. This project attempts to broaden the evidence for the significance of phosphatase regulation, to identify - by a trick to be described below - receptor substrate phosphatase pairs, and to explore how oxidation-reduction of protein tyrosine phosphatase is catalyzed.

• DFG-Verfahren: Sachbeihilfen