Qvit Nir, Mochly-Rosen Daria
*Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305-5174, U.S.A.
Biochem Soc Trans. 2014 Dec;42(6):1529-33. doi: 10.1042/BST20140189.
A large number of protein substrates are phosphorylated by each protein kinase under physiological and pathological conditions. However, it remains a challenge to determine which of these phosphorylated substrates of a given kinase is critical for each cellular response. Genetics enabled the generation of separation-of-function mutations that selectively cause a loss of one molecular event without affecting others, thus providing some tools to assess the importance of that one event for the measured physiological response. However, the genetic approach is laborious and not adaptable to all systems. Furthermore, pharmacological tools of the catalytic site are not optimal due to their non-selective nature. In the present brief review, we discuss some of the challenges in drug development that will regulate the multifunctional protein kinase Cδ (PKCδ).
在生理和病理条件下，每种蛋白激酶都会使大量蛋白质底物发生磷酸化。然而，确定给定激酶的这些磷酸化底物中哪一种对每种细胞反应至关重要，仍然是一项挑战。遗传学能够产生功能分离突变，这些突变选择性地导致一种分子事件的丧失而不影响其他事件，从而提供了一些工具来评估该事件对所测量的生理反应的重要性。然而，遗传方法既费力又不适用于所有系统。此外，催化位点的药理学工具由于其非选择性性质而并非最佳选择。在本简要综述中，我们讨论了在药物开发中调节多功能蛋白激酶Cδ（PKCδ）所面临的一些挑战。
