G protein-coupled chemokine receptors induce both survival and apoptotic signaling pathways
G protein-coupled chemokine receptors induce both survival and apoptotic signaling pathways
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DOI：
10.4049/jimmunol.169.10.5546
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发表时间：
2002-11-15
影响因子：
4.4
通讯作者：
Paya, CV
中科院分区：
文献类型：
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作者：
Vlahakis, SR;Villasis-Keever, A;Paya, CV
趋化因子受体对于触发对免疫细胞的趋化性是必不可少的;然而，当与非趋化因子配体接合时，它们中的一些也可以介导死亡。当趋化因子受体CXCR 4与基质细胞衍生因子（SDF 1）α结合时，它会触发细胞趋化，并在某些细胞类型中，如神经元，导致细胞死亡。为了阐明这种双重和相反的受体功能，我们研究了趋化因子SDF 1 α激活CXCR 4是否会导致抗凋亡和促凋亡信号通路的同时激活;这种平衡最终影响细胞存活。SDF 1 α激活CD 4 T细胞中的CXCR 4导致促生存第二信使Akt和细胞外信号调节蛋白激酶的激活。每个信号的选择性抑制表明，细胞外信号调节蛋白激酶是必不可少的介导SDF 1 α触发的趋化性，但不赋予抗凋亡状态。相比之下，通过SDF 1 α相互作用通过CXCR 4激活Akt是赋予细胞凋亡抗性所必需的。由SDF 1 α-CXCR 4相互作用触发的促凋亡信号通路涉及促凋亡MAPK（p38）的G（i α）蛋白非依赖性激活。此外，其他趋化因子和趋化因子受体也通过类似的途径发出趋化性和促凋亡作用的信号。因此，G（i α）蛋白偶联趋化因子受体可以作为死亡倾向受体发挥作用，并且上述信号传导途径之间的平衡将最终决定活化细胞的命运。
Chemokine receptors are essential for triggering chemotaxis to immune cells; however, a number of them can also mediate death when engaged by nonchemokine ligands. When the chemokine receptor CXCR4 is engaged by stromal cell-derived factor, (SDF1)alpha, it triggers cells to chemotax, and in some cell types such as neurons, causes cell death. To elucidate this dual and opposing receptor function, we have investigated whether CXCR4 activation by its chemokine SDF1alpha could lead to the simultaneous activation of both anti- and proapoptotic signaling pathways; the balance ultimately influencing cell survival. CXCR4 activation in CD4T cells by SDF1alpha led to the activation of the prosurvival second messengers, Akt and extracellular signal-regulated protein kinase. Selective inhibition of each signal demonstrated that extracellular signal-regulated protein kinase is essential for mediating SDF1alpha-triggered chemotaxis but does not confer an antiapoptotic state. In contrast, Akt activation through CXCR4 by SDF1alpha interactions is necessary to confer resistance to apoptosis. The proapoptotic signaling pathway triggered by SDF1alpha-CXCR4 interaction involves the G(ialpha) protein-independent activation of the proapoptotic MAPK (p38). Furthermore, other chemokines and chemokine receptors also signal chemotaxis and proapoptotic effects via similar pathways. Thus, G(ialpha) protein-coupled chemokine receptors can function as death prone receptors and the balance between the above signaling pathways will ultimately mandate the fate of the activated cell.