Prostaglandin-induced VASP phosphorylation controls αII-spectrin breakdown in apoptotic cells
Prostaglandin-induced VASP phosphorylation controls αII-spectrin breakdown in apoptotic cells
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DOI：
10.1016/j.intimp.2007.10.004
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发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Renne, Thomas
中科院分区：
文献类型：
--
作者：
Benz, Peter M.;Feller, Stephan M.;Renne, Thomas
在病理条件下，炎症介质前列腺素E_2(PGE(2))已被证明通过cAMP依赖的途径诱导细胞凋亡。然而，潜在的机制仍然是虚幻的。不管细胞凋亡是由内在途径还是外在途径诱导的，半胱氨酸蛋白酶caspase-3被激活，并裂解包括血影蛋白在内的许多关键蛋白。质膜相关光谱蛋白的裂解导致细胞萎缩、膜起泡、凋亡小体的形成和不可逆转的细胞死亡。最近，我们发现了一种新的αII-Spectrin与血管扩张剂刺激的磷酸蛋白(Vasp)之间的相互作用，这种作用被cAMP依赖的蛋白激酶(PKA)介导的Vasp磷酸化所阻断。在本研究中，我们研究了VASP与(A-Spectrin)的结合是否影响PGE(2)诱导的细胞凋亡中的Spectrin的分解。PGE(2)呈剂量和时间依赖性地触发Vasp的磷酸化。在诱导细胞凋亡后，野生型细胞中caspase-3介导的αII-血影蛋白降解和膜起泡明显延迟于Vasp缺陷内皮细胞。这表明Vasp与全影蛋白结合减弱了凋亡细胞中全影蛋白的切割，PGE(2)诱导的Vasp磷酸化调节了这一过程。因此，我们的发现可能为PGE(2)在病理事件中诱导细胞凋亡提供分子基础。(C)2007 Elsevier B.V.保留所有权利。
In pathological conditions, the inflammatory mediator prostaglandin E2 (PGE(2)) has been shown to induce apoptosis through a cAMP-dependent pathway. However, underlying mechanisms have remained illusive. Irrespective whether apoptosis is induced by the intrinsic or extrinsic pathway, the cysteine protease caspase-3 becomes activated and cleaves many key proteins including spectrins. Cleavage of the plasma membrane-associated spectrins leads to cell shrinkage, membrane blebbing, the formation of apoptotic bodies, and irreversible cell death. Recently, we identified a novel interaction between alpha II-spectrin and vasodilator-stimulated phosphoprotein (VASP), which is abrogated by the cAMP-dependent protein kinase (PKA)-mediated phosphorylation of VASP. In the present study we investigated whether VASP binding to (A-spectrin affects spectrin breakdown in PGE(2)-induced apoptosis. PGE(2) dose- and time-dependently triggered VASP phosphorylation. Following induction of apoptosis, caspase-3-mediated alpha II-spectrin breakdown and membrane blebbing were markedly delayed in wild-type as compared to VASP-deficient endothelial cells. This suggests that VASP binding to all-spectrin attenuates all-spectrin cleavage in apoptotic cells and that PGE(2)-induced VASP phosphorylation regulates this process. Our findings may therefore provide the molecular basis for PGE(2)-induced apoptosis in pathological events. (c) 2007 Elsevier B.V. All rights reserved.