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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Arrestins / genetics
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Arrestins / metabolism*
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CD28 Antigens / metabolism
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CD3 Complex / metabolism
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Cell Line
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Enzyme Activation
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Humans
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Lymphocyte Activation
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
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Membrane Microdomains / chemistry
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Membrane Microdomains / metabolism
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Molecular Sequence Data
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Multiprotein Complexes / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Antigen, T-Cell / metabolism
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Sequence Alignment
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Signal Transduction / physiology*
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T-Lymphocytes / metabolism
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beta-Arrestins
Substances
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Arrestins
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CD28 Antigens
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CD3 Complex
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Multiprotein Complexes
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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beta-Arrestins
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Phosphatidylinositol 3-Kinases
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Proto-Oncogene Proteins c-akt
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Cyclic AMP-Dependent Protein Kinases
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Cyclic Nucleotide Phosphodiesterases, Type 4