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

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)

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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
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology
421571thera-cAMP: identification of therapeutic molecules to target compartmentalised cAMP signalling networks in human diseaseMiles HouslayEuropean Commission (EC)UNSPECIFIEDInstitute of Neuroscience and Psychology
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute of Neuroscience and Psychology