Partnerships and phosphorylation of cyclic AMP phosphodiesterase-4A5

[摘要] Phosphodiesterase 4 enzymes hydrolyse the second messenger cyclic AMP and therefore are set to play an important role in cell signaling. In this thesis I investigate the phosphorylation and protein-protein interactions of the cAMP hydrolyzing phosphodiesterase isoform, PDE4A4/5. In the first of my studies I show that PDE4A4/5 can be phosphorylated by MAPKAPK2 (MK2) the downstream kinase of the p38 MAPK signalling pathway. This phosphorylation reaction attenuates the degree of activation of PDE4A5 elicited through phosphorylation by Protein Kinase A. I also show that MAPKAPK2 can bind directly to PDE4A4/5 and map the two binding sites required by peptide array technology. In the second of my studies I show that PDE4A4/5 interacts with the low affinity neurotrophin receptor, p75NTR.This interaction inhibits normal fibrin breakdown in an in vitro model. I also show that phosphorylation of PDE4A5 by MAPKAPK2 enhances the inhibition of fibrin breakdown and increases PDE4A5:p75NTR complex formation. In the final study described in this thesis I show that long form PDE4 isoforms contain a potential multi-functional docking site where several partner proteins are able to bind. In conclusion, the work described in this thesis provides a valuable insight into PDE4A4/5, its interacting proteins, phosphorylation status and the potential for exploitation of this novel information therapeutically.

[发布机构] University:University of Glasgow;Department:Institute of Molecular Cell and Systems Biology

[关键词] phosphodiesterase