Direct effects of caffeine and theophylline on p110δ and other phosphoinositide 3-kinases -: Differential effects on lipid kinase and protein kinase activities

被引:126
作者
Foukas, LC
Daniele, N
Ktori, C
Anderson, KE
Jensen, J
Shepherd, PR
机构
[1] UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England
[2] Monash Univ, Dept Med, Melbourne, Vic 3128, Australia
[3] Natl Inst Occupat Hlth, Dept Physiol, N-0033 Oslo, Norway
关键词
D O I
10.1074/jbc.M202101200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (IC(50) = 75 muM for p110delta, 400 muM for p110alpha and p110beta, and 1 mM for p110gamma), and theophylline has similar effects (IC(50) = 75 muM for p110delta, 300 muM for p110alpha, and 800 muM for p110beta and p110gamma) and also inhibits the alpha isoform. of class II PI3K (PI3K-C2alpha) (IC(50) approximate to 400 muM). 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 P110delta (IC(50) < 10 mu M). 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 (IC(50) approximate to 10 mM for p110 alpha, 3 mM for p110 beta, 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 IC(50). 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 p110 delta lipid kinase. Finally, we conclude that inhibition of PI3K (p110 delta in particular) is likely explain some of the physiological and pharmacological properties of caffeine and theophylline.
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页码:37124 / 37130
页数:7
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