Szado, Tania; Vanderheyden, Veerle; Parys, Jan B.; De Smedt, Humbert; Rietdorf, Katja; Kotelevets, Larissa; Chastre, Eric; Khan, Farid; Landegren, Ulf; Söderberg, Ola; Bootman, Martin D. and Roderick, H. Llewelyn
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|DOI (Digital Object Identifier) Link:||http://dx.doi.org/10.1073/pnas.0711324105|
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Imbalance of signals that control cell survival and death results in pathologies, including cancer and neurodegeneration. Two pathways that are integral to setting the balance between cell survival and cell death are controlled by lipid-activated protein kinase B (PKB)/Akt and Ca2+. PKB elicits its effects through the phosphorylation and inactivation of proapoptotic factors. Ca2+ stimulates many prodeath pathways, among which is mitochondrial permeability transition. We identified Ca2+ release through inositol 1,4,5-trisphosphate receptor (InsP3R) intracellular channels as a prosurvival target of PKB. We demonstrated that in response to survival signals, PKB interacts with and phosphorylates InsP3Rs, significantly reducing their Ca2+ release activity. Moreover, phosphorylation of InsP3Rs by PKB reduced cellular sensitivity to apoptotic stimuli through a mechanism that involved diminished Ca2+ flux from the endoplasmic reticulum to the mitochondria. In glioblastoma cells that exhibit hyperactive PKB, the same prosurvival effect of PKB on InsP3R was found to be responsible for the insensitivity of these cells to apoptotic stimuli. We propose that PKB-mediated abolition of InsP3-induced Ca2+ release may afford tumor cells a survival advantage.
|Item Type:||Journal Article|
|Copyright Holders:||2008 by The National Academy of Sciences of the USA|
|Extra Information:||This article contains supporting information online at www.pnas.org/cgi/content/full/0711324105/DC1.
|Keywords:||signalling; cell death; cancer|
|Academic Unit/Department:||Science > Life, Health and Chemical Sciences|
|Interdisciplinary Research Centre:||Biomedical Research Network (BRN)|
|Depositing User:||Martin Bootman|
|Date Deposited:||24 Oct 2012 12:55|
|Last Modified:||07 Mar 2014 13:59|
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