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


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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    • "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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    ABSTRACT: We demonstrated that glyphosate possesses tumor promoting potential in mouse skin carcinogenesis and SOD 1, calcyclin (S100A6), and calgranulin B (S100A9) have been associated with this potential, although the mechanism is unclear. We aimed to clarify whether imbalance in between [Ca(2+)] i levels and oxidative stress is associated with glyphosate-induced proliferation in human keratinocytes HaCaT cells. The [Ca(2+)] i levels, ROS generation, and expressions of G1/S cyclins, IP3R1, S100A6, S100A9, and SOD 1, and apoptosis-related proteins were investigated upon glyphosate exposure in HaCaT cells. Glyphosate (0.1 mM) significantly induced proliferation, decreases [Ca(2+)] i , and increases ROS generation in HaCaT cells, whereas antioxidant N-acetyl-L-cysteine (NAC) pretreatment reverts these effects which directly indicated that glyphosate induced cell proliferation by lowering [Ca(2+)] i levels via ROS generation. Glyphosate also enhanced the expression of G1/S cyclins associated with a sharp decrease in G0/G1 and a corresponding increase in S-phases. Additionally, glyphosate also triggers S100A6/S100A9 expression and decreases IP3R1 and SOD 1 expressions in HaCaT cells. Notably, Ca(2+) suppression also prevented apoptotic related events including Bax/Bcl-2 ratio and caspases activation. This study highlights that glyphosate promotes proliferation in HaCaT cells probably by disrupting the balance in between [Ca(2+)] i levels and oxidative stress which in turn facilitated the downregulation of mitochondrial apoptotic signaling pathways.
    08/2013; 2013(1):825180. DOI:10.1155/2013/825180
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    • "Decreased PI3-K/AKT signaling in ADPKD would thereby lead to a profound remodeling with increased IICR and SOCE (Fig. 3). This results from activation of Ca2+ release via polycystin-2, but also from a higher IP3R activity resulting from the relieve of the brake imposed by AKT-mediated phosphorylation [169]. Increased IICR, particularly at the contact sites of the ER and mitochondria, constitutes a strong apoptotic signal [84, 170]. "
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