ArticleAmerican journal of physiology. Gastrointestinal and liver physiology2009
cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 beta/alpha in rat hepatocytes.
Article in American journal of physiology. Gastrointestinal and liver physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- Hepatotoxic Mechanisms of Polyethylene Terephthalate Microplastics Revealed by Network Toxicology, Molecular Docking, and In Vivo Validation.International journal of molecular sciences · 2026Article
- Study of mechanism of drug-induced liver injury caused by pyrethroid insecticides based on network toxicology and mendelian randomization.Toxicology research · 2025Article
- Article
- Elevated cAMP Protects against Diclofenac-Induced Toxicity in Primary Rat Hepatocytes: A Protective Effect Mediated by the Exchange Protein Directly Activated by cAMP/cAMP-Regulated Guanine Nucleotide Exchange Factors.Molecular pharmacology · 2021Article
- Effect of cAMP Signaling Regulation in Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells.Cells · 2020Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma.Hepatic oncology · 2018Review
- Hydrophobic bile acid apoptosis is regulated by sphingosine-1-phosphate receptor 2 in rat hepatocytes and human hepatocellular carcinoma cells.American journal of physiology. Gastrointestinal and liver physiology · 2016Article
- Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters.Pflugers Archiv : European journal of physiology · 2014Review
- Activation of a cyclic amp-guanine exchange factor in hepatocytes decreases nitric oxide synthase expression.Shock (Augusta, Ga.) · 2013Article
- Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger.Acta physiologica (Oxford, England) · 2012Review
- INTRACELLULAR SIGNALING BY BILE ACIDS.Journal of bio-science · 2012Article
- cAMP-guanine exchange factor protection from bile acid-induced hepatocyte apoptosis involves glycogen synthase kinase regulation of c-Jun NH2-terminal kinase.American journal of physiology. Gastrointestinal and liver physiology · 2011Article
- Ultrastructural analysis reveals cAMP-dependent enhancement of microvascular endothelial barrier functions via Rac1-mediated reorganization of intercellular junctions.The American journal of pathology · 2011Article
- Article
- Phosphatidylinositol-3-kinase p110γ contributes to bile salt-induced apoptosis in primary rat hepatocytes and human hepatoma cells.Journal of hepatology · 2010Article
- Cyclic AMP-guanine exchange factor activation inhibits JNK-dependent lipopolysaccharide-induced apoptosis in rat hepatocytes.Hepatic medicine : evidence and research · 2010Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
Cyclic AMP protects against hepatocyte apoptosis by a protein kinase A-independent cAMP-GEF/phosphoinositide-3-kinase (PI3K)/Akt signaling pathway. However, the signaling pathway coupling cAMP-GEF with PI3K is unknown. The aim of this study was to investigate the role of Src tyrosine kinases (Src-TYK) and PI3K-p110 isoforms in this pathway. Studies were done in rat hepatocytes using the hydrophobic bile acid glycochenodeoxycholic acid (GCDC) to induce apoptosis. cAMP-binding guanine nucleotide exchange factors (cAMP-GEFs) were selectively activated by using 4-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate (CPT-2-Me-cAMP), which sequentially phosphorylated Src-TYK (within 1 min) followed by Akt (within 5 min). The Src inhibitors PP2 and SU6656 inhibited basal and CPT-2-Me-cAMP-mediated Src and Akt phosphorylation. These inhibitors had no effect on CPT-2-Me-cAMP-mediated activation of Rap GTPases. CPT-2-Me-cAMP induced transient Src dependent autophosphorylation of the epidermal growth factor receptor (EGFR). Inhibition of the EGFR with AG 1478 partially inhibited the ability of CPT-2-Me to phosphorylate Akt. Whereas PP2 completely abolished the protective effect of CPT-2-Me-cAMP in GCDC induced apoptosis, AG 1478 partially inhibited the cytoprotective effect. CPT-2-Me-cAMP treatment resulted in Src-dependent activation of the p110 beta and alpha subunits of PI3K, but only the latter was sensitive to inhibition with AG 1478. In conclusion, activation of cAMP-GEFs results in phosphorylation of Src-TYK and Akt and activation of the p110 beta/alpha subunits of PI3K. Maximal cAMP-GEF-mediated Akt phosphorylation as well as protection from bile acid-induced apoptosis requires activation of Src-TYK and the EGFR. These studies support the existence of two pathways: cAMP-GEF/Rap/Src/PI3Kbeta/Akt and cAMP-GEF/Rap/Src/EGFR/PI3Kalpha/Akt, both of which are necessary for maximal cytoprotective effect of cAMP-GEFs in hepatocytes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.