Taskén Kjetil, Aandahl Einar Martin
The Biotechnology Centre of Oslo, University of Oslo, Norway.
Physiol Rev. 2004 Jan;84(1):137-67. doi: 10.1152/physrev.00021.2003.
More than 20% of the human genome encodes proteins involved in transmembrane and intracellular signaling pathways. The cAMP-protein kinase A (PKA) pathway is one of the most common and versatile signal pathways in eukaryotic cells and is involved in regulation of cellular functions in almost all tissues in mammals. Various extracellular signals converge on this signal pathway through ligand binding to G protein-coupled receptors, and the cAMP-PKA pathway is therefore tightly regulated at several levels to maintain specificity in the multitude of signal inputs. Ligand-induced changes in cAMP concentration vary in duration, amplitude, and extension into the cell, and cAMP microdomains are shaped by adenylyl cyclases that form cAMP as well as phosphodiesterases that degrade cAMP. Different PKA isozymes with distinct biochemical properties and cell-specific expression contribute to cell and organ specificity. A kinase anchoring proteins (AKAPs) target PKA to specific substrates and distinct subcellular compartments providing spatial and temporal specificity for mediation of biological effects channeled through the cAMP-PKA pathway. AKAPs also serve as scaffolding proteins that assemble PKA together with signal terminators such as phosphatases and cAMP-specific phosphodiesterases as well as components of other signaling pathways into multiprotein signaling complexes that serve as crossroads for different paths of cell signaling. Targeting of PKA and integration of a wide repertoire of proteins involved in signal transduction into complex signal networks further increase the specificity required for the precise regulation of numerous cellular and physiological processes.
超过20%的人类基因组编码参与跨膜和细胞内信号通路的蛋白质。环磷酸腺苷-蛋白激酶A（PKA）通路是真核细胞中最常见且功能多样的信号通路之一，参与哺乳动物几乎所有组织的细胞功能调节。各种细胞外信号通过配体与G蛋白偶联受体结合汇聚到该信号通路，因此cAMP-PKA通路在多个层面受到严格调控，以在众多信号输入中保持特异性。配体诱导的cAMP浓度变化在持续时间、幅度和向细胞内的扩展方面各不相同，cAMP微区由形成cAMP的腺苷酸环化酶以及降解cAMP的磷酸二酯酶塑造。具有不同生化特性和细胞特异性表达的不同PKA同工酶有助于细胞和器官的特异性。一种激酶锚定蛋白（AKAPs）将PKA靶向特定底物和不同的亚细胞区室，为通过cAMP-PKA通路介导的生物学效应提供空间和时间特异性。AKAPs还作为支架蛋白，将PKA与信号终止剂（如磷酸酶和cAMP特异性磷酸二酯酶）以及其他信号通路的成分组装成多蛋白信号复合物，这些复合物充当细胞信号不同路径的交叉点。PKA的靶向以及将大量参与信号转导的蛋白质整合到复杂信号网络中，进一步提高了精确调节众多细胞和生理过程所需的特异性。
