Spatial Regulation of Cyclic AMP-Epac1 Signaling in Cell Adhesion by ERM Proteins
Spatial Regulation of Cyclic AMP-Epac1 Signaling in Cell Adhesion by ERM Proteins
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DOI：
10.1128/mcb.00463-10
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发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Bos, Johannes L.
中科院分区：
文献类型：
--
作者：
Gloerich, Martijn;Ponsioen, Bas;Bos, Johannes L.
Epac 1是小G蛋白Rap的鸟嘌呤核苷酸交换因子，并参与膜定位过程，如整合素介导的细胞粘附和细胞间连接形成。环磷酸腺苷（cAMP）通过释放自抑制直接激活Epac 1，并诱导其转运到质膜。在这里，我们显示了一个额外的机制Epac 1招聘，介导的激活ezrin-radixin-moesin（ERM）蛋白。Epac 1直接结合其N-末端49个氨基酸的ERM蛋白在其开放构象。受体诱导的ERM蛋白激活导致Epac 1结合增加，从而使Epac 1在质膜上聚集定位。Epac 1的N末端的缺失，以及由干扰radixin突变体或小干扰RNA（siRNA）介导的ERM蛋白的耗尽引起的Epac 1-ERM相互作用的破坏，损害Epac 1介导的细胞粘附。我们的结论是，ERM蛋白参与Epac 1的空间调控，并与cAMP和RAP介导的信号调节粘附到细胞外基质。
Epac1 is a guanine nucleotide exchange factor for the small G protein Rap and is involved in membrane-localized processes such as integrin-mediated cell adhesion and cell-cell junction formation. Cyclic AMP (cAMP) directly activates Epac1 by release of autoinhibition and in addition induces its translocation to the plasma membrane. Here, we show an additional mechanism of Epac1 recruitment, mediated by activated ezrin-radixin-moesin (ERM) proteins. Epac1 directly binds with its N-terminal 49 amino acids to ERM proteins in their open conformation. Receptor-induced activation of ERM proteins results in increased binding of Epac1 and consequently the clustered localization of Epac1 at the plasma membrane. Deletion of the N terminus of Epac1, as well as disruption of the Epac1-ERM interaction by an interfering radixin mutant or small interfering RNA (siRNA)-mediated depletion of the ERM proteins, impairs Epac1-mediated cell adhesion. We conclude that ERM proteins are involved in the spatial regulation of Epac1 and cooperate with cAMP- and Rap-mediated signaling to regulate adhesion to the extracellular matrix.