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Caffeine inhibits PI3K and mTORC2 in Dictyostelium and differentially affects multiple other cAMP chemoattractant signaling effectors

Tariqul Islam, A. F. M. and Scavello, Margarethakay and Lotfi, Pouya and Daniel, Dustin and Haldeman, Pearce and Charest, Pascale G. (2019) Caffeine inhibits PI3K and mTORC2 in Dictyostelium and differentially affects multiple other cAMP chemoattractant signaling effectors. Molecular and Cellular Biochemistry, 457 . pp. 157-168. ISSN 0300-8177. doi:10.1007/s11010-019-03520-z.

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Caffeine is commonly used in Dictyostelium to inhibit the synthesis of the chemoattractant cAMP and, therefore, its secretion and the autocrine stimulation of cells, in order to prevent its interference with the study of chemoattractant-induced responses. However, the mechanism through which caffeine inhibits cAMP synthesis in Dictyostelium has not been characterized. Here, we report the effects of caffeine on the cAMP chemoattractant signaling network. We found that caffeine inhibits phosphatidylinositol 3-kinase (PI3K) and mechanistic target of rapamycin complex 2 (mTORC2). Both PI3K and mTORC2 are essential for the chemoattractant-stimulated cAMP production, thereby providing a mechanism for the caffeine-mediated inhibition of cAMP synthesis. Our results also reveal that caffeine treatment of cells leads to an increase in cAMP-induced RasG and Rap1 activation, and inhibition of the PKA, cGMP, MyoII, and ERK1 responses. Finally, we observed that caffeine has opposite effects on F-actin and ERK2 depending on the assay and Dictyostelium strain used, respectively. Altogether, our findings reveal that caffeine considerably affects the cAMP-induced chemotactic signaling pathways in Dictyostelium, most likely acting through multiple targets that include PI3K and mTORC2.

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Charest, Pascale G.0000-0002-2395-5294
Additional Information:© 2019 Springer Science+Business Media, LLC, part of Springer Nature. Received 20 November 2018; Accepted 09 March 2019; First Online 16 March 2019. We are grateful to the Dicty Stock Center and its material depositors for providing cells and DNA constructs. This study was funded by a Research Scholar Grant 127940-RSG-15-024-01-CSM from the American Cancer Society to P.G.C. M.S. was supported by NIH T32 Grant GM008804 and P.L. was supported by a U.S. Public Health Service Grant GM037830. Compliance with ethical standards. The authors declare that they have no conflict of interest.
Funding AgencyGrant Number
American Cancer Society127940-RSG-15-024-01-CSM
Subject Keywords:Dictyostelium; Chemotaxis; cAMP; Caffeine; PI3K; mTORC2
Record Number:CaltechAUTHORS:20190325-140352599
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Official Citation:Tariqul Islam, A.F.M., Scavello, M., Lotfi, P. et al. Mol Cell Biochem (2019) 457: 157.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94126
Deposited By: Tony Diaz
Deposited On:25 Mar 2019 21:15
Last Modified:16 Nov 2021 17:03

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