Department of Biology, Stanford University, Stanford, California 94305-5020.
Cold Spring Harb Perspect Biol. 2020 Mar 2;12(3):a035436. doi: 10.1101/cshperspect.a035436.
Biological processes are dynamically regulated by signaling networks composed of protein kinases and phosphatases. Calcineurin, or PP3, is a conserved phosphoserine/phosphothreonine-specific protein phosphatase and member of the PPP family of phosphatases. Calcineurin is unique, however, in its activation by Ca and calmodulin. This ubiquitously expressed phosphatase controls Ca-dependent processes in all human tissues, but is best known for driving the adaptive immune response by dephosphorylating the nuclear factor of the activated T-cells (NFAT) family of transcription factors. Therefore, calcineurin inhibitors, FK506 (tacrolimus), and cyclosporin A serve as immunosuppressants. We describe some of the adverse effects associated with calcineurin inhibitors that result from inhibition of calcineurin in nonimmune tissues, illustrating the many functions of this enzyme that have yet to be elucidated. In fact, calcineurin has essential roles beyond the immune system, from yeast to humans, but since its discovery more than 30 years ago, only a small number of direct calcineurin substrates have been shown (∼75 proteins). This is because of limitations in current methods for identification of phosphatase substrates. Here we discuss recent insights into mechanisms of calcineurin activation and substrate recognition that have been critical in the development of novel approaches for identifying its targets systematically. Rather than comprehensively reviewing known functions of calcineurin, we highlight new approaches to substrate identification for this critical regulator that may reveal molecular mechanisms underlying toxicities caused by calcineurin inhibitor-based immunosuppression.
生物过程是由由蛋白激酶和磷酸酶组成的信号网络动态调节的。钙调神经磷酸酶（或 PP3）是一种保守的磷酸丝氨酸/磷酸苏氨酸特异性蛋白磷酸酶，是 PPP 家族磷酸酶的成员。然而，钙调神经磷酸酶的独特之处在于其被 Ca 和钙调蛋白激活。这种广泛表达的磷酸酶控制着所有人类组织中依赖 Ca 的过程，但它因去磷酸化活化 T 细胞核因子（NFAT）家族转录因子而驱动适应性免疫反应而最为人所知。因此，钙调神经磷酸酶抑制剂 FK506（他克莫司）和环孢素 A 用作免疫抑制剂。我们描述了与钙调神经磷酸酶抑制剂相关的一些不良反应，这些不良反应是由于非免疫组织中钙调神经磷酸酶的抑制引起的，说明了该酶尚未阐明的许多功能。事实上，钙调神经磷酸酶在从酵母到人类的免疫系统之外具有重要作用，但自 30 多年前发现以来，仅显示了少数直接的钙调神经磷酸酶底物（约 75 种蛋白质）。这是因为目前用于鉴定磷酸酶底物的方法存在局限性。在这里，我们讨论了钙调神经磷酸酶激活和底物识别机制的最新见解，这些见解对于开发系统地鉴定其靶标的新方法至关重要。我们没有全面回顾钙调神经磷酸酶的已知功能，而是强调了用于鉴定这种关键调节剂的底物的新方法，这可能揭示基于钙调神经磷酸酶抑制剂的免疫抑制引起毒性的分子机制。
