Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex
- PMID: 22173835
- DOI: 10.1002/jcb.24018
Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex
Retraction in
-
RETRACTION: Upregulation of mTORC2 Activation by the Selective Agonist of EPAC, 8-CPT-2Me-cAMP, in Prostate Cancer Cells: Assembly of a Multiprotein Signaling Complex.J Cell Biochem. 2025 Jul;126(7):e70048. doi: 10.1002/jcb.70048. J Cell Biochem. 2025. PMID: 40662287
Abstract
Ligation of cell surface-associated GRP78 by activated α(2) -macroglobulin triggers pro-proliferative cellular responses. In part, this results from activation of adenylyl cyclase leading to an increase in cAMP. We have previously employed the cAMP analog 8-CPT-2Me-cAMP to probe these responses. Here we show in 1-LN prostate cancer cells that 8-CPT-2Me-cAMP causes a dose-dependent increase in Epac1, p-Akt(T308) , p-Akt(S473) , but not p-CREB. By contrast, the PKA activator 6-Benz-cAMP caused a dose-dependent increase in p-CREB, but not Epac1. We measured mTORC2-dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells. 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt(S473) and Akt(S473) kinase activity in Rictor immunoprecipitates. By contrast, there was only a negligible effect on p-Akt(T308) in Rictor immunoprecipitates. Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of Akt at Ser(473) . These studies represent the first report that Epac1 mediates mTORC2-dependent phosphorylation of Akt(S473) . Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP-dependent p-Akt(S473) and p-Akt(S473) kinase activities, and both effects were rapamycin insensitive. This treatment caused a two to threefold increase in S6 Kinase and 4EBP1 phosphorylation, indices of mTORC1 activation. Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of S6 Kinase and 4EBP1. We further demonstrate that in 8-CPT-2Me-cAMP-treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1-induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a "scaffold" protein.
Copyright © 2011 Wiley Periodicals, Inc.
Similar articles
-
Receptor-recognized α₂-macroglobulin binds to cell surface-associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells.PLoS One. 2012;7(12):e51735. doi: 10.1371/journal.pone.0051735. Epub 2012 Dec 14. PLoS One. 2012. Retraction in: PLoS One. 2025 Jun 5;20(6):e0325675. doi: 10.1371/journal.pone.0325675. PMID: 23272152 Free PMC article. Retracted.
-
Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.PLoS One. 2013 Apr 30;8(4):e63150. doi: 10.1371/journal.pone.0063150. Print 2013. PLoS One. 2013. Retraction in: PLoS One. 2025 Jun 5;20(6):e0325680. doi: 10.1371/journal.pone.0325680. PMID: 23646189 Free PMC article. Retracted.
-
Epac1-induced cellular proliferation in prostate cancer cells is mediated by B-Raf/ERK and mTOR signaling cascades.J Cell Biochem. 2009 Nov 1;108(4):998-1011. doi: 10.1002/jcb.22333. J Cell Biochem. 2009. Retraction in: J Cell Biochem. 2025 Jul;126(7):e70046. doi: 10.1002/jcb.70046. PMID: 19725049 Free PMC article. Retracted.
-
The Black Book of Psychotropic Dosing and Monitoring.Psychopharmacol Bull. 2024 Jul 8;54(3):8-59. Psychopharmacol Bull. 2024. PMID: 38993656 Free PMC article. Review.
-
Rapamycin and rapalogs for tuberous sclerosis complex.Cochrane Database Syst Rev. 2016 Jul 13;7(7):CD011272. doi: 10.1002/14651858.CD011272.pub2. Cochrane Database Syst Rev. 2016. Update in: Cochrane Database Syst Rev. 2023 Jul 11;7:CD011272. doi: 10.1002/14651858.CD011272.pub3. PMID: 27409709 Free PMC article. Updated.
Cited by
-
Revisiting the roles of cAMP signalling in the progression of prostate cancer.Biochem J. 2023 Oct 31;480(20):1599-1614. doi: 10.1042/BCJ20230297. Biochem J. 2023. PMID: 37830741 Free PMC article.
-
The Role of Neuropeptide-Stimulated cAMP-EPACs Signalling in Cancer Cells.Molecules. 2022 Jan 5;27(1):311. doi: 10.3390/molecules27010311. Molecules. 2022. PMID: 35011543 Free PMC article. Review.
-
Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines.J Neuroinflammation. 2016 Jan 13;13:9. doi: 10.1186/s12974-015-0463-9. J Neuroinflammation. 2016. PMID: 26757726 Free PMC article.
-
Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention.Pharmaceutics. 2021 Aug 3;13(8):1195. doi: 10.3390/pharmaceutics13081195. Pharmaceutics. 2021. PMID: 34452154 Free PMC article. Review.
-
Activated α2-macroglobulin binding to cell surface GRP78 induces T-loop phosphorylation of Akt1 by PDK1 in association with Raptor.PLoS One. 2014 Feb 6;9(2):e88373. doi: 10.1371/journal.pone.0088373. eCollection 2014. PLoS One. 2014. Retraction in: PLoS One. 2025 Jun 5;20(6):e0325677. doi: 10.1371/journal.pone.0325677. PMID: 24516643 Free PMC article. Retracted.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous