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
Elisa Bjørgo,Silje A. Solheim,Hilde Abrahamsen,George S. Baillie,Kim M. Brown,Torunn Berge,Klaus Okkenhaug,Miles D. Houslay,Kjetil Taskén +8 more
TLDR
It is demonstrated that stimulation of CD28 leads to recruitment to lipid rafts of a β-arrestin/phosphodiesterase 4 (PDE4) complex that serves to degrade cAMP locally, thereby allowing full T-cell activation to proceed.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.read more
Citations
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Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions
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Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling.
TL;DR: Biophysical studies aimed at understanding multiple active conformations of the 7TMRs and the β-arrestins have begun to unravel the mechanistic basis for the diverse functional capabilities of β-Arrestins in cellular signaling.
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Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors.
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The Diverse Roles of Arrestin Scaffolds in G Protein-Coupled Receptor Signaling.
TL;DR: The structure–function relationships that enable arrestins to perform their diverse roles are examined, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners.
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Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function.
Selena Vigano,Dimitrios Alatzoglou,Melita Irving,Christine Ménétrier-Caux,Christophe Caux,Pedro Romero,George Coukos +6 more
TL;DR: The regulation of adenosine levels and mechanisms by which it promotes tumor growth and broadly suppresses protective immunity are reviewed, with extra focus on the attenuation of T cell function.
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