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, Roderick H Llewelyn
Laboratories of Molecular Signaling and Protein Technologies, The Babraham Institute, Cambridge CB2 3AT, United Kingdom.
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2427-32. doi: 10.1073/pnas.0711324105. Epub 2008 Feb 4.
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.
控制细胞存活与死亡的信号失衡会导致包括癌症和神经退行性变在内的多种病理状况。脂质激活的蛋白激酶B（PKB）/Akt和Ca(2+)控制着两条在细胞存活与细胞死亡之间建立平衡中不可或缺的途径。PKB通过使促凋亡因子磷酸化并使其失活来发挥作用。Ca(2+)刺激许多促死亡途径，其中包括线粒体通透性转换。我们发现通过肌醇1,4,5-三磷酸受体（InsP(3)R）细胞内通道释放Ca(2+)是PKB的一个促存活靶点。我们证明，在对存活信号作出反应时，PKB与InsP(3)R相互作用并使其磷酸化，显著降低其Ca(2+)释放活性。此外，PKB对InsP(3)R的磷酸化通过一种涉及从内质网到线粒体的Ca(2+)通量减少的机制降低了细胞对凋亡刺激的敏感性。在表现出PKB过度活跃的胶质母细胞瘤细胞中，发现PKB对InsP(3)R同样具有促存活作用，这导致这些细胞对凋亡刺激不敏感。我们提出，PKB介导的对InsP(3)诱导的Ca(2+)释放的消除可能为肿瘤细胞提供生存优势。
