Rampersad, S. N., Ovens, J. D., Huston, E., Umana, M. B., Wilson, L. S., Netherton, S. J., Lynch, M. J., Baillie, G. S. , Houslay, M. D. and Maurice, D. H. (2010) Cyclic AMP Phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a Vascular Endothelial Cadherin (VE-Cad)-based Signaling Complex and Controls cAMP-mediated Vascular Permeability. Journal of Biological Chemistry, 285(44), pp. 33614-33622. (doi: 10.1074/jbc.M110.140004)
Full text not currently available from Enlighten.
Publisher's URL: http://dx.doi.org/10.1074/jbc.M110.140004
Abstract
Vascular endothelial cell (VEC) permeability is largely dependent on the integrity of VE-cadherin (VECAD)-based intercellular adhesions. Activators of protein kinase A (PKA) or of exchange protein activated by cAMP (EPAC) reduce VEC permeability largely by stabilizing VECAD-based intercellular adhesions. Currently, little is known concerning the nature and composition of the signaling complexes which allow PKA or EPAC to regulate VECAD-based structures and through these actions control permeability. Using pharmacological, biochemical and cell biological approaches we identify and determine the composition and functionality of a signaling complex that coordinate cAMP-mediated control of VECAD-based adhesions and VEC permeability. Thus, we report that PKA, EPAC1 and cyclic nucleotide phosphodiesterase 4D (PDE4D) enzymes integrate into VECAD-based signaling complexes in human arterial endothelial cells (HAECs). Importantly, we show that protein-protein interactions between EPAC1 and PDE4D serve to foster their integration into VECAD-based complexes and allow robust local regulation of EPAC1-based stabilization of VECAD-based adhesions. Of potential translational importance, we mapped the EPAC1 peptide motif involved in binding PDE4D and show that a cell-permeable variant of this peptide antagonizes EPAC1-PDE4D binding and directly alters VEC permeability. Collectively, our data indicate that PDE4D regulates both the activity and subcellular localization of EPAC1 and identify a novel mechanism for regulated EPAC1 signaling in these cells
Item Type: | Articles |
---|---|
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Houslay, Professor Miles and Baillie, Professor George and Huston, Dr Elaine and Lynch, Dr Martin |
Authors: | Rampersad, S. N., Ovens, J. D., Huston, E., Umana, M. B., Wilson, L. S., Netherton, S. J., Lynch, M. J., Baillie, G. S., Houslay, M. D., and Maurice, D. H. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
Journal Name: | Journal of Biological Chemistry |
Journal Abbr.: | J Biol Chem. |
Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN: | 0021-9258 |
ISSN (Online): | 1083-351X |
Published Online: | 23 August 2010 |
Related URLs: |
University Staff: Request a correction | Enlighten Editors: Update this record