Cross talk between phosphatidylinositol 3-kinase and cyclic AMP (cAMP)-protein kinase a signaling pathways at the level of a protein kinase B/beta-arrestin/cAMP phosphodiesterase 4 complex
Authors: George S Baillie
Silje A Solheim
Kjetil Taskén
Klaus Okkenhaug
Hilde Abrahamsen
Torunn Berge
Elisa Bjørgo
Miles D Houslay
Kim M Brown
Journal: Molecular and cellular biology (2010)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: T-cell receptor; CD28; lipid rafts; beta-arrestin; phosphodiesterase 4
Affiliations: Biotechnology Centre of Oslo, University of Oslo, P.O. Box 1125, N-0317 Oslo, Norway., Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway, Neuroscience and Molecular Pharmacology, Wolfson Link and Davidson Buildings, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom, Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom

Abstract:  Engagement of the T-cell receptor (TCR) in human primary T cells activates a cyclic AMP (cAMP)-protein kinase A (PKA)-Csk inhibitory pathway that prevents full T-cell activation in the absence of a coreceptor stimulus. Here, we demonstrate that stimulation of CD28 leads to recruitment to lipid rafts of a beta-arrestin/phosphodiesterase 4 (PDE4) complex that serves to degrade cAMP locally. Redistribution of the complex from the cytosol depends on Lck and phosphatidylinositol 3-kinase (PI3K) activity. Protein kinase B (PKB) interacts directly with beta-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 phosphatidylinositol-(3,4,5)-triphosphate (PIP3) production, leading to recruitment of the supramolecular PKB/beta-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. 

Retracted: No

PubPeer comments:
 Figure 6A. https: imgur.com JE28AHI , 
 In response to this comment on PubPeer, the University of Glasgow contacted the MCB about the integrity of the left panel of Figure 6A of our paper (notably without first contacting the senior and corresponding author). The allegation was that as evident from the figure, the two bottom panels were spliced from two parts whereas the top part appeared (from the published image) not to be, indicating that the blots may have been treated differently. The Dean of the Medical Faculty, University of Oslo therefore asked the Research Integrity Commission of the Faculty, to instigate an investigation of possible fraud. We were able to provide the Commission with: i) the original laboratory journal describing the experiment; ii) the original films with exposures of the blots; iii) the untampered Corel Draw file that constituted Fig 6.; and iv) the original high-resolution TIF file that was uploaded on the MCB server on Dec 22, 2009 when the final revised version of the paper was submitted. The Commission found, examining the original data, that the left panel of Figure 6A was made by splicing lanes 1 and 3 of a Western blot, thus removing a miscellaneous lane 2 and that this was the case also for the top part of the panel originating from the same blot. Similarly, the Corel Draw file could be opened and deconstructed to show that all three blots in this panel had been spliced in the same way. Lastly, examination of the high-resolution TIF also showed a thin line in the top blot where the splicing occurred. The Commission concluded that the published Fig. 6A was authentic. The Commissionu2019s report has been accepted by the journal. In response to this, we have, as agreed with the Editor, published a corrected version of Figure 6A, left panel, in MCB acknowledging the splicing as well as an Author Contribution Statement indicating who did this experiment. See: https: journals.asm.org doi 10.1128 mcb.00556-21 ,