Calcium and cAMP signals differentially regulate cAMP-responsive element-binding protein function via a Rap1-extracellular signal-regulated kinase pathway
Calcium and cAMP signals differentially regulate cAMP-responsive element-binding protein function via a Rap1-extracellular signal-regulated kinase pathway
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DOI：
10.1074/jbc.m004728200
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发表时间：
2000-11-03
影响因子：
4.8
通讯作者：
Stork, PJS
中科院分区：
文献类型：
--
作者：
Grewal, SS;Fass, DM;Stork, PJS
调节神经元功能的两个主要细胞内信号是钙和cAMP，在许多情况下，这两种第二信使的作用涉及基因表达的长期变化。钙和cAMP信号传导的一个充分研究的靶点是转录因子cAMP反应元件结合蛋白（CREB）。多种信号传导途径已被证明有助于CREB依赖性转录的调节，包括蛋白激酶A（PKA）和促分裂原活化蛋白（MAP）激酶/细胞外信号调节激酶（ERK）依赖性激酶级联。我们先前已经描述了cAMP和钙内流可以刺激神经元细胞中的ERK的机制，该途径涉及Ras相关的小G蛋白Rap 1的PKA依赖性活化，以及随后的神经元Raf同种型B-Raf的刺激。在这项研究中，我们检查了Rap 1-ERK途径对钙内流和cAMP控制基因转录的贡献，使用PC 12细胞模型系统，我们发现钙内流和cAMP刺激CREB依赖的转录通过Rap 1-ERK途径，但这种调节通过不同的机制发生。钙介导的CREB磷酸化通过PKA-Rap 1-ERK途径。cAMP通过PKA直接磷酸化CREB，但需要Rap 1-ERK通路激活CREB磷酸化下游的组分和CREB结合蛋白的募集。这些数据表明，Rap 1/B-Raf信号通路可能在CREB依赖性基因表达的调节中起重要作用。
Two major intracellular signals that regulate neuronal function are calcium and cAMP, In many cases, the actions of these two second messengers involve long term changes in gene expression. One well studied target of both calcium and cAMP signaling is the transcription factor cAMP-responsive element-binding protein (CREB), Multiple signaling pathways have been shown to contribute to the regulation of CREB-dependent transcription, including both protein kinase A (PKA)- and mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK)-dependent kinase cascades. We have previously described a mechanism by which cAMP and calcium influx may stimulate ERKs in neuronal cells, This pathway involves the PKA-dependent activation of the Ras-related small G-protein, Rap1, and subsequent stimulation of the neuronal Raf isoform, B-Raf, In this study, we examined the contribution of the Rap1-ERK pathway to the control of gene transcription by calcium influx and cAMP, Using the PC12 cell model system, we found that both calcium influx and cAMP stimulated CREB-dependent transcription via a Rap1-ERK pathway, but this regulation occurred through distinct mechanisms. Calcium-mediated phosphorylation of CREB through the PKA-Rap1-ERK pathway. In contrast, cAMP phosphorylated CREB via PKA directly but required a Rap1-ERK pathway to activate a component downstream of CREB phosphorylation and CREB-binding protein recruitment, These data suggest that the Rap 1/B-Raf signaling pathway may have an important role in the regulation of CREB-dependent gene expression.