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Szado, T. et al. Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc. Natl Acad. Sci. USA 105, 2427-2432

Laboratories of Molecular Signaling and Protein Technologies, The Babraham Institute, Cambridge CB2 3AT, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2008; 105(7):2427-32. DOI: 10.1073/pnas.0711324105
Source: PubMed

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 Ca(2+). PKB elicits its effects through the phosphorylation and inactivation of proapoptotic factors. Ca(2+) stimulates many prodeath pathways, among which is mitochondrial permeability transition. We identified Ca(2+) release through inositol 1,4,5-trisphosphate receptor (InsP(3)R) intracellular channels as a prosurvival target of PKB. We demonstrated that in response to survival signals, PKB interacts with and phosphorylates InsP(3)Rs, significantly reducing their Ca(2+) release activity. Moreover, phosphorylation of InsP(3)Rs by PKB reduced cellular sensitivity to apoptotic stimuli through a mechanism that involved diminished Ca(2+) flux from the endoplasmic reticulum to the mitochondria. In glioblastoma cells that exhibit hyperactive PKB, the same prosurvival effect of PKB on InsP(3)R was found to be responsible for the insensitivity of these cells to apoptotic stimuli. We propose that PKB-mediated abolition of InsP(3)-induced Ca(2+) release may afford tumor cells a survival advantage.

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    • "The former was also more sensitive to apoptotic stimuli like menadione and displayed higher mitochondrial Ca 2+ rises in response to these stimuli. Also, glioblastoma cells exhibiting Akt hyperactivity due to loss of PTEN showed reduced IICR, menadione-induced mitochondrial Ca 2+ uptake and apoptosis compared with glioblastoma cells re-expressing PTEN[152]. These results indicate that phosphorylation of IP 3 Rs by active PKB/Akt reduces Ca 2+ release from the ER and subsequent Ca 2+ transfer to the mitochondria, leading to the protection of cells from apoptotic stimuli (Fig. 3). "
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    No preview · Article · Jan 2016 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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    • "Some years later, another master regulator of tumor growth, the mitogenic kinase Akt, was linked to Ca 2+ homeostasis control. This protein was found to modulate the phosphorylation state of IP3R to inhibit its Ca 2+ channel activity and then reduce the transfer of Ca 2+ from the ER to the mitochondria [15] [16]. Conversely, the tumor suppressors PML and PTEN, in cooperation with protein phosphatase 2A (PP2A), support the Ca 2+ transfer between the ER and mitochondria by reducing the phosphorylation state of IP3R [17]. "
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    ABSTRACT: Intracellular calcium (Ca(2+)) is largely known as a second messenger that is able to drive effects ranging from vesicle formation to muscle contraction, energy production and much more. In spite of its physiological regulation, Ca(2+) is a strategic tool for regulating apoptosis, especially during transmission between the endoplasmic reticulum and the mitochondria. Contact sites between these organelles are well-defined as signaling platforms where oncogenes and oncosuppressors can exert anti/pro-apoptotic activities. Recent advances from in vivo investigations into these regions highlight the role of the master oncosuppressor p53 in regulating Ca(2+) transmission and apoptosis, and we propose that Ca(2+) signals are relevant targets when developing new therapeutic approaches. Copyright © 2015. Published by Elsevier Ltd.
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    • "It has been shown that less apoptosis occurs in cells in which IP3R1 expression was reduced or wholly silenced [61]. Similarly, in our case the decrease in the level of IP3R1 also observed upon glyphosate exposure in HaCaT cells thus prevented cell death [62]. Furthermore, in the cancer cells the amplified appearance of antiapoptotic members of the Bcl-2 family of proteins or reduced appearance of the proapoptotic proteins like Bax or Bak can shield these cells from apoptosis by controlling [Ca2+]i signals [63, 64]. "
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