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| Content Provider | Journal of Biological Chemistry (JBC) |
|---|---|
| Author | Foukas, Lazaros C. Daniele, Nathalie Ktori, Chariklia Anderson, Karen E. Jensen, Jørgen Shepherd, Peter R. |
| Abstract | We investigated the effects of methylxanthines on enzymatic activity of phosphoinositide 3-kinases (PI3Ks). We found that caffeine inhibits the in vitro lipid kinase of class I PI3Ks (IC50 = 75 μm for p110δ, 400 μm for p110α and p110β, and 1 mm for p110γ), and theophylline has similar effects (IC50 = 75 μm for p110δ, 300 μm for p110α, and 800 μm for p110β and p110γ) and also inhibits the α isoform of class II PI3K (PI3K-C2α) (IC50 ≈ 400 μm). However, four other xanthine derivatives tested (3-isobutyl-1-methylxanthine, 3-propylxanthine, alloxazine, and PD116948 (8-cyclopentyl-1,3-dipropylxanthine)) were an order of magnitude less effective. Surprisingly the triazoloquinazoline CGS15943 (9-chloro-2-(2-furyl)(1,2,d)triazolo(1,5-c)quinazolin-5-amine) also selectively inhibits p110δ (IC50 < 10 μm). Caffeine and theophylline also inhibit the intrinsic protein kinase activity of the class IA PI3Ks and DNA-dependent protein kinase, although with a much lower potency than that for the lipid kinase (IC50 ≈ 10 mm for p110α , 3 mm for p110β, and 10 mm for DNA-dependent protein kinase). In CHO-IR cells and rat soleus muscle, theophylline and caffeine block the ability of insulin to stimulate protein kinase B with IC50 values similar to those for inhibition of PI3K activity, whereas insulin stimulation of ERK1 or ERK2 was not inhibited at concentrations up to 10 mm. Theophylline and caffeine also blocked insulin stimulation of glucose transport in CHO-IR cells. These results demonstrate that these methylxanthines are direct inhibitors of PI3K lipid kinase activity but are distinctly less effective against serine kinase activity and thus could be of potential use in dissecting these two distinct kinase activities. Theophylline, caffeine, and CGS15943 may be of particular use in dissecting the specific role of the p110δ lipid kinase. Finally, we conclude that inhibition of PI3K (p110δ in particular) is likely explain some of the physiological and pharmacological properties of caffeine and theophylline. |
| Related Links | http://www.jbc.org/content/277/40/37124.abstract |
| Ending Page | 37130 |
| Starting Page | 37124 |
| Page Count | 7 |
| File Format | HTM / HTML PDF |
| ISSN | 00219258 |
| Journal | Journal of Biological Chemistry (JBC) |
| Issue Number | 40 |
| Volume Number | 277 |
| DOI | 10.1074/jbc.M202101200 |
| e-ISSN | 1083351X |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology |
| Publisher Date | 2002-10-04 |
| Access Restriction | Open |
| Subject Keyword | Phosphoinositide 3-kinase (PI3K) DNA-dependent protein kinase (DNA-PK) Protein kinase B (PKB) Extracellular signal-regulated kinase (ERK) Ataxia telangiectasia mutated (ATM) Mitogen-activated protein kinase (MAPK) MECHANISMS OF SIGNAL TRANSDUCTION |
| Alternative Title | Direct Effects of Caffeine and Theophylline on p110δ and Other Phosphoinositide 3-Kinases |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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