The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways
The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways
复制标题
DOI：
10.1038/nature03966
复制
发表时间：
2005-09-22
期刊：
影响因子：
64.8
通讯作者：
Scott, JD
中科院分区：
文献类型：
--
作者：
Dodge-Kafka, KL;Soughayer, J;Scott, JD
环腺苷3 '，5'-单磷酸（cAMP）是细胞内信号事件的普遍存在的介质。它主要通过刺激cAMP依赖性蛋白激酶（PKA）（1，2）发挥作用，但也激活某些离子通道和鸟嘌呤核苷酸交换因子（Epac）（3）。cAMP的代谢由磷酸二酯酶（PDE）催化（4，5）。在这里，我们确定了一个cAMP响应信号复合物维持的肌肉特异性A-激酶锚定蛋白（mAKAP），包括PKA，PDE 4D 3和Epac 1。这些分子间相互作用促进了不同cAMP信号通过每个效应蛋白的传播。锚定的PKA刺激PDE 4D 3以降低局部cAMP浓度，而mAKAP相关的ERK 5激酶模块抑制PDE 4D 3。PDE 4D 3还作为一种衔接蛋白发挥作用，其募集Epac 1（一种小GTdR ap 1的交换因子），以使ERK 5的cAMP依赖性衰减成为可能。mAKAP复合物的药理学和分子操作表明，锚定的ERK 5可以诱导心肌细胞肥大。因此，两个偶联的cAMP依赖性反馈环在mAKAP复合物的背景下协调，表明AKAP蛋白对cAMP信号传导的局部控制比以前认识到的更复杂。
Cyclic adenosine 3', 5'- monophosphate ( cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP- dependent protein kinases ( PKAs)(1,2) but also activates certain ion channels and guanine nucleotide exchange factors ( Epacs)(3). Metabolism of cAMP is catalysed by phosphodiesterases ( PDEs) (4,5). Here we identify a cAMP- responsive signalling complex maintained by the muscle-specific A- kinase anchoring protein ( mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP- associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP- dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP- dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.