Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP
Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP
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作者：
de Rooij, J;Zwartkruis, FJT;Bos, JL
Rap 1是一种小的Ras样GTP酶，其首先被鉴定为可以通过Ras抑制细胞的致癌转化的蛋白质，Rap 1被几种细胞外刺激物激活（2-7），并且可能参与细胞过程，例如细胞增殖（8）、细胞分化（4）、T细胞无反应性（2）和血小板活化（7）。至少三种不同的第二信使，即甘油二酯、钙和环AMP（5- 7，9），能够通过促进其释放鸟嘌呤核苷酸GDP及其与GTP的结合来激活Rap 1。在这里，我们报告，Rap 1的激活毛喉素和cAMP发生独立的蛋白激酶A（也称为cAMP-abivated蛋白激酶）。我们克隆了编码鸟嘌呤核苷酸交换因子（GEF）的基因，我们将其命名为Epac（cAMP直接激活的交换蛋白）。该蛋白含有一个cAMP结合位点和一个结构域，该结构域与已知的GEF对pas和Rap 1的结构域同源，Epac在体外与cAMP结合并表现出对Rap 1的体内和体外GEF活性，cAMP在体内和体外均强烈诱导Epac对Rap 1的GEF活性。我们的结论是，Epac是Rapl的GEF，直接由cAMP调节，并且Epac是cAMP的新靶蛋白。
Rap1 is a small, Ras-like GTPase that was first identified as a protein that could suppress the oncogenic transformation of cells by Ras', Rap1 is activated by several extracellular stimuli(2-7) and may be involved in cellular processes such as cell proliferations(8), cell differentiation(4), T-cell anergy(2) and platelet activation(7). At least three different second messengers, namely diacylglycerol, calcium and cyclic AMP(5-7,9), able to activate Rap1 by promoting its release of the guanine nucleotide GDP and its binding to GTP. Here we report that activation of Rap1 by forskolin and cAMP occurs independently of protein kinase A (also known as cAMP-abivated protein kinase). We have cloned the gene encoding a guanine-nucleotide-exchange factor (GEF) which we have named Epac (exchange protein directly activated by cAMP). This protein contains a cAMP-binding site and a domain that is homologous to domains of known GEFs for pas and Rap1, Epac binds cAMP in vitro and exhibits in vivo and in vitro GEF activity towards Rap1, cAMP strongly induces the GEF activity of Epac towards Rap1 both in vivo and in vitro. We conclude that Epac is a GEF for Rapl that is regulated directly by cAMP and that Epac is a new target protein for cAMP.