Cross talk between phosphatidylinositol 3-kinase and cyclic AMP (cAMP)-protein kinase A signaling pathways at the level of a protein kinase B/β-Arrestin/cAMP phosphodiesterase 4 complex

Bjorgo, E., Solheim, S. A., Abrahamsen, H., Baillie, G. S. , Brown, K. M., Berge, T., Okkenhaug, K., Houslay, M. D. and Tasken, K. (2010) Cross talk between phosphatidylinositol 3-kinase and cyclic AMP (cAMP)-protein kinase A signaling pathways at the level of a protein kinase B/β-Arrestin/cAMP phosphodiesterase 4 complex. Molecular and Cellular Biology, 30(7), pp. 1660-1672. (doi:10.1128/MCB.00696-09)

Full text not currently available from Enlighten.

Publisher's URL: http://dx.doi.org/10.1128/MCB.00696-09

Abstract

Engagement of the T cell receptor (TCR) in human primary T cells activates a cAMP-protein kinase A (PKA)-Csk inhibitory pathway that prohibits full T cell activation in the absence of a co-receptor stimulus. Here, we demonstrate that stimulation of CD28 leads to recruitment of a {beta}-arrestin/phosphodiesterase-4 (PDE4) complex to lipid rafts that serves to degrade cAMP locally. Redistribution of the complex from the cytosol depends on Lck and PI3-kinase (PI3K) activity. Protein kinase B (PKB) interacts directly with β-arrestin to form part of the supramolecular complex together with sequestered PDE4. Translocation is mediated by the PKB plextrin homology (PH) domain, thus revealing a new role for PKB as an adaptor coupling PI3K- and cAMP signaling. Functionally, PI3K activation and PIP3 production leading to recruitment of the supramolecular PKB/β-arrestin/PDE4 complex to the membrane via the PKB PH domain results in degradation of the TCR-induced cAMP pool located in lipid rafts, thereby allowing full T cell activation to proceed.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Baillie, Professor George and Okkenhaug, Dr Klaus
Authors: Bjorgo, E., Solheim, S. A., Abrahamsen, H., Baillie, G. S., Brown, K. M., Berge, T., Okkenhaug, K., Houslay, M. D., and Tasken, K.
Subjects:Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Molecular and Cellular Biology
Publisher:American Society for Microbiology
ISSN:0270-7306
ISSN (Online):1098-5549
Published Online:19 January 2010
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

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
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute 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