Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 Cells
Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 Cells
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DOI：
10.1091/mbc.e05-05-0432
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发表时间：
2005-12-01
影响因子：
3.3
通讯作者：
Piiper, A
中科院分区：
文献类型：
--
作者：
Kiermayer, S;Biondi, RM;Piiper, A
细胞内cAMP浓度（[cAMP]（i））的升高调节代谢、细胞增殖和分化，并在记忆形成和肿瘤生长中起作用。cAMP主要通过激活蛋白激酶A（PKA）以及Epac 1和Epac 2（激活小GTP酶Rap 1和Rap 2的交换因子）来介导其作用。然而，cAMP如何利用这些效应物来诱导不同的生物反应是未知的。我们研究了PKA和Epac在神经内分泌PC 12细胞中的特殊作用。在这些细胞中，[cAMP]的升高（i）激活细胞外信号调节激酶（ERK）1/2并诱导低度神经突生长。目前的研究表明，PKA的特异性刺激触发ERK 1/2激活，这是相当多的比观察到的同时激活PKA和Epac的短暂。出乎意料的是，PKA特异性cAMP类似物诱导细胞增殖，而不是神经突生长。PKA特异性cAMP类似物激活的增殖信号通路涉及表皮生长因子受体和ERK 1/2的激活。Epac的激活似乎延长了PKA依赖性ERK 1/2激活的持续时间，并将cAMP从增殖信号转化为抗增殖、促进神经突生长的信号。因此，本研究表明cAMP信号传导的结果在很大程度上取决于激活的cAMP效应物的集合。
Elevation of the intracellular cAMP concentration ([cAMP](i)) regulates metabolism, cell proliferation, and differentiation and plays roles in memory formation and neoplastic growth. cAMP mediates its effects mainly through activation of protein kinase A (PKA) as well as Epac1 and Epac2, exchange factors activating the small GTPases Rap1 and Rap2. However, how cAMP utilizes these effectors to induce distinct biological responses is unknown. We here studied the specific roles of PKA and Epac in neuroendocrine PC12 cells. In these cells, elevation of [cAMP](i) activates extracellular signal-regulated kinase (ERK) 1/2 and induces low-degree neurite outgrowth. The present study showed that specific stimulation of PKA triggered ERK1/2 activation that was considerably more transient than that observed upon simultaneous activation of both PKA and Epac. Unexpectedly, the PKA-specific cAMP analog induced cell proliferation rather than neurite outgrowth. The proliferative signaling pathway activated by the PKA-specific cAMP analog involved activation of the epidermal growth factor receptor and ERK1/2. Activation of Epac appeared to extend the duration of PKA-dependent ERK1/2 activation and converted cAMP from a proliferative into an anti-proliferative, neurite outgrowth-promoting signal. Thus, the present study showed that the outcome of cAMP signaling can depend heavily on the set of cAMP effectors activated.