Department of Biomedical Engineering, Yale University, New Haven, United States.
Yale Systems Biology Institute, Yale University, West Haven, United States.
Elife. 2022 Feb 24;11:e66869. doi: 10.7554/eLife.66869.
Kinase activity in signaling networks frequently depends on regulatory subunits that can both inhibit activity by interacting with the catalytic subunits and target the kinase to distinct molecular partners and subcellular compartments. Here, using a new synthetic molecular interaction system, we show that translocation of a regulatory subunit of the protein kinase A (PKA-R) to the plasma membrane has a paradoxical effect on the membrane kinase activity. It can both enhance it at lower translocation levels, even in the absence of signaling inputs, and inhibit it at higher translocation levels, suggesting its role as a linker that can both couple and decouple signaling processes in a concentration-dependent manner. We further demonstrate that superposition of gradients of PKA-R abundance across single cells can control the directionality of cell migration, reversing it at high enough input levels. Thus, complex in vivo patterns of PKA-R localization can drive complex phenotypes, including cell migration.
信号转导网络中的激酶活性通常依赖于调节亚基，这些亚基可以通过与催化亚基相互作用来抑制活性，并且将激酶靶向到不同的分子伴侣和亚细胞隔室。在这里，我们使用一种新的合成分子相互作用系统，表明蛋白激酶 A（PKA-R）的调节亚基向质膜的易位对膜激酶活性具有矛盾的影响。即使在没有信号输入的情况下，较低的易位水平也可以增强其活性，而较高的易位水平则可以抑制其活性，这表明它作为一种连接物，可以以浓度依赖的方式偶联和去偶联信号转导过程。我们进一步证明，单个细胞中 PKA-R 丰度梯度的叠加可以控制细胞迁移的方向，在足够高的输入水平下可以逆转它。因此，PKA-R 定位的复杂体内模式可以驱动复杂的表型，包括细胞迁移。
