Open AccessPhosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca 2+ release and apoptosis
Author(s) -
Tania Szado,
Veerle Vanderheyden,
Jan B. Parys,
Humbert De Smedt,
Katja Rietdorf,
Larissa Kotelevets,
Eric Chastre,
F. Nawaz Khan,
Ulf Landegren,
Ola Söderberg,
Martin D. Bootman,
H. Llewelyn Roderick
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0711324105
Subject(s) - protein kinase b , phosphorylation , microbiology and biotechnology , inositol , apoptosis , endoplasmic reticulum , biology , programmed cell death , signal transduction , kinase , inositol trisphosphate , mitochondrion , receptor , chemistry , biochemistry
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 (InsP3 R) intracellular channels as a prosurvival target of PKB. We demonstrated that in response to survival signals, PKB interacts with and phosphorylates InsP3 Rs, significantly reducing their Ca2+ release activity. Moreover, phosphorylation of InsP3 Rs 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 InsP3 R 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.