蛋白激酶A对IAP的区室化磷酸化调节细胞保护作用。
Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection.
作者信息
Dohi Takehiko, Xia Fang, Altieri Dario C
机构信息
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
出版信息
Mol Cell. 2007 Jul 6;27(1):17-28. doi: 10.1016/j.molcel.2007.06.004.
Abstract
Cell death pathways are likely regulated in specialized subcellular microdomains, but how this occurs is not understood. Here, we show that cyclic AMP-dependent protein kinase A (PKA) phosphorylates the inhibitor of apoptosis (IAP) protein survivin on Ser20 in the cytosol, but not in mitochondria. This phosphorylation event disrupts the binding interface between survivin and its antiapoptotic cofactor, XIAP. Conversely, mitochondrial survivin or a non-PKA phosphorylatable survivin mutant binds XIAP avidly, enhances XIAP stability, synergistically inhibits apoptosis, and accelerates tumor growth, in vivo. Therefore, differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP.
摘要
细胞死亡途径可能在特殊的亚细胞微结构域中受到调控，但具体机制尚不清楚。在此，我们发现环磷酸腺苷依赖性蛋白激酶A（PKA）可使胞质溶胶中凋亡抑制蛋白（IAP）家族的生存素在丝氨酸20位点发生磷酸化，而在线粒体中则不会。这一磷酸化事件破坏了生存素与其抗凋亡辅因子X连锁凋亡抑制蛋白（XIAP）之间的结合界面。相反，线粒体生存素或非PKA可磷酸化的生存素突变体与XIAP紧密结合，增强XIAP的稳定性，协同抑制细胞凋亡，并在体内加速肿瘤生长。因此，PKA在亚细胞微结构域中对生存素的差异性磷酸化通过其与XIAP的相互作用来调节肿瘤细胞凋亡。
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