Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes
Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes
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DOI：
10.1128/mcb.00709-07
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发表时间：
2008-06-01
影响因子：
5.3
通讯作者：
Kristiansen, Karsten
中科院分区：
文献类型：
--
作者：
Petersen, Rasmus Koefoed;Madsen, Lise;Kristiansen, Karsten
环腺苷酸（cAMP）依赖性过程在脂肪细胞分化的早期阶段是关键的。我们表明，交换蛋白直接激活cAMP（Epac），其功能作为一个鸟嘌呤核苷酸交换因子的Ras样GTP酶Rap 1和Rap 2，需要cAMP依赖性刺激脂肪细胞分化。Epac通过Rap发挥作用，与cAMP依赖性蛋白激酶（蛋白激酶A [PKA]）协同作用，促进脂肪生成。PKA的主要作用是下调Rho和Rho激酶活性，而不是增强CREB磷酸化。Rho激酶的抑制损害了前脂肪形成胰岛素/胰岛素样生长因子1信号传导，该信号传导通过Epac的激活而恢复。PKA和Epac介导的过程之间的这种相互作用不仅提供了对脂肪细胞分化的启动和调节的新见解，而且还证明了cAMP信号传导的新机制，其中cAMP使用PKA和Epac两者来实现适当的细胞应答。
Cyclic AMP (cAMP)-dependent processes are pivotal during the early stages of adipocyte differentiation. We show that exchange protein directly activated by cAMP (Epac), which functions as a guanine nucleotide exchange factor for the Ras-like GTPases Rap1 and Rap2, was required for cAMP-dependent stimulation of adipocyte differentiation. Epac, working via Rap, acted synergistically with cAMP-dependent protein kinase (protein kinase A [PKA]) to promote adipogenesis. The major role of PKA was to down-regulate Rho and Rho-kinase activity, rather than to enhance CREB phosphorylation. Suppression of Rho-kinase impaired proadipogenic insulin/insulin-like growth factor 1 signaling, which was restored by activation of Epac. This interplay between PKA and Epac-mediated processes not only provides novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of cAMP signaling whereby cAMP uses both PKA and Epac to achieve an appropriate cellular response.