Cyclic AMP Phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a Vascular Endothelial Cadherin (VE-Cad)-based Signaling Complex and Controls cAMP-mediated Vascular Permeability

• DOI: 10.1074/jbc.m110.140004
• Publication Date: 2010-08-24T01:42:05Z
• Authors: Sarah N. Rampersad; Jeffrey D. Ovens; Elaine Huston; M. Bibiana Umana; Lindsay S. Wilson; Stuart J. Netherton; Martin J. Lynch; George S. Baillie; Miles D. Houslay; Donald H. Maurice
• Keywords: VE-cadherin; Vascular permeability

Vascular endothelial cell (VEC) permeability is largely dependent on the integrity of vascular cadherin (VE-cadherin or VE-Cad)-based intercellular adhesions. Activators protein kinase A (PKA) exchange activated by cAMP (EPAC) reduce VEC stabilizing VE-Cad-based Currently, little known concerning nature and composition signaling complexes that allow PKA EPAC to regulate structures through these actions control permeability. Using pharmacological, biochemical, biological approaches we identified determined functionality a complex coordinates cAMP-mediated adhesions Thus, report PKA, EPAC1, cyclic nucleotide phosphodiesterase 4D (PDE4D) enzymes integrate into in human arterial cells. Importantly, show protein-protein interactions between EPAC1 PDE4D serve foster their integration robust local regulation EPAC1-based stabilization Of potential translational importance, mapped peptide motif involved binding cell-permeable variant this antagonizes EPAC1-PDE4D directly alters Collectively, our data indicate regulates both activity subcellular localization identify novel mechanism for regulated