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Beta-catenin control of FOXO4 signalling

By D. Hoogeboom

Abstract

The goal of this thesis was to gain a better understanding as to how beta-catenin controls FOXO4 signalling. Although beta-catenin was initially recognised for its role in cell proliferation upon Wnt signalling it is now beginning to be appreciated for its regulatory role in other pathways as well. Depending on the signal received beta-catenin can divert its interaction between different binding partners. Important for this mechanism to be relevant is the fact that only a limited pool of free beta-catenin is present. As there is basically no excess of free beta-catenin, shifting of beta-catenin between binding partners becomes an efficient mechanism to rapidly adapt to diverse and possible opposing stimuli. In this way beta -catenin activates specific genes to appropriately respond to the needs of the cell. As beta-catenin interacts with a diverse range of proteins we discuss in this thesis how changes in the oxidative state of the cell diverts beta-catenin between its interaction partners. When cells encounter stress such as hypoxia or abnormal changes in ROS they need to respond in a proper way to ensure cell survival or, in case of severe non-repairable damage, apoptosis. Thus, the cellular response towards stress requires an intricate and balanced adaptive response to ensure that the proper choice of cell fate will be made. Our lab has studied in particular the role of FOXO in the cellular stress response. Recently beta-catenin was identified as an important regulator of the FOXO-mediated stress control. Upon an increase in cellular ROS levels, FOXO interacts with beta-catenin whereby FOXO activity is enhanced. Our main focus was to understand how beta-catenin shifts interaction between different binding partners. ROS signalling overrules Wnt signalling preventing cell proliferation under unfavourable conditions. We revealed the necessity in changes of PTMs on FOXO4 for the interaction with beta-catenin to occur. We describe FOXO4-S258 dephosphorylation by PP2A as an initial step in clearing the road for FOXO4 and beta-catenin to interact. Methylation within the consensus PKB motif of FOXO4 by PRMT1 prevents PKB to rephosphorylate FOXO4 thereby enhancing beta-catenin to interact. Finally, we describe PRMT6 to be a new regulator of FOXO4 and TCF activity through inhibiting beta-catenin interaction. For cells to function properly it is important that the interaction between the proteins described above is tightly balanced. Through modulation of PTMs in reponse to growth factors or ROS protein-protein interactions can be regulated. Furthermore the interaction of one protein can influence the binding of other proteins to the same substrate. All these interactions and PTMs play a role in shifting the activation or inactivation of downstream pathways. It will be a challenge to understand in full and in detail the many aspects that play a role in balancing the outcome of these pathways

Publisher: Utrecht University
Year: 2011
OAI identifier: oai:dspace.library.uu.nl:1874/196852
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