期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 30, 期 7, 页码 1660-1672出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00696-09
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资金
- Norwegian Functional Genomics Program
- Research Council of Norway
- Norwegian Cancer Society
- European Union [LSHB-CT-2006-037189-thera-cAMP]
- Medical Research Council (United Kingdom) [G0600765]
- Fondation Leducq [06CVD02]
- BBSRC [BBS/E/B/0000C236] Funding Source: UKRI
- MRC [G0600765] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C236] Funding Source: researchfish
- Medical Research Council [G0600765] Funding Source: researchfish
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.
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