Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca²⁺ release and apoptosis

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 (2008). Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca²⁺ release and apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 105(7) pp. 2427–2432.

DOI: https://doi.org/10.1073/pnas.0711324105

Abstract

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.

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About

• Item ORO ID
• 34871
• Item Type
• Journal Item
• ISSN
• 1091-6490
• Extra Information
• This article contains supporting information online at www.pnas.org/cgi/content/full/0711324105/DC1.
• Keywords
• signalling; cell death; cancer
• Academic Unit or School
• Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
  Faculty of Science, Technology, Engineering and Mathematics (STEM)
• Research Group
• Cancer Research Group
• Copyright Holders
• © 2008 by The National Academy of Sciences of the USA
• Depositing User
• Martin Bootman