Ho S, Timmerman L, Northrop J, Crabtree G R
Department of Pathology, Howard Hughes Medical Institute, Stanford University School of Medicine, CA 94305-5428.
Adv Exp Med Biol. 1994;365:167-73. doi: 10.1007/978-1-4899-0987-9_17.
Present evidence indicates a pathway of signal transmission in T cells that is outlined in figure 1. The elevation in intracellular calcium that is induced by interactions at the antigen receptor leads to the activation of the calcium-dependent phosphatase calcineurin. This in turn leads to the nuclear association of the cytosolic component of NF-ATc. The activation of calcineurin and the nuclear import of NF-ATc can both be blocked by cyclosporin A or FK506 in complex with their respective immunophilins. Once in the nucleus, NF-ATc interacts with NF-ATn to form an active transcriptional complex. NF-ATn is a ubiquitous protein, can be synthesized in response to PMA, and has many similarities to AP-1. The mechanism by which NF-ATc enters the nucleus is unknown, and although it appears to require calcineurin, NF-ATc has not yet been shown to be an in vivo substrate of calcineurin. Alternative mechanisms include the possibility that NF-ATc operates on some cytoplasmic anchor or that other proteins that are controlled by calcineurin carry out the nuclear import of NF-ATc. Although NF-ATp copurifies with NF-ATc, there is as yet no understanding of how NF-ATp is functioning in vivo. Now that these proteins are purified and cloned, the major goals will be to understand their role and the roles of other family members in thymic development.
现有证据表明T细胞中的信号转导途径如图1所示。抗原受体处的相互作用诱导细胞内钙升高，导致钙依赖性磷酸酶钙调神经磷酸酶激活。这进而导致NF-ATc的胞质成分与细胞核结合。钙调神经磷酸酶的激活以及NF-ATc的核输入都可被环孢菌素A或FK506与其各自的亲免蛋白形成的复合物所阻断。一旦进入细胞核，NF-ATc就与NF-ATn相互作用形成活性转录复合物。NF-ATn是一种普遍存在的蛋白质，可响应佛波酯（PMA）合成，与AP-1有许多相似之处。NF-ATc进入细胞核的机制尚不清楚，尽管似乎需要钙调神经磷酸酶，但NF-ATc尚未被证明是钙调神经磷酸酶在体内的底物。其他机制包括NF-ATc作用于某些细胞质锚定物的可能性，或者由钙调神经磷酸酶控制的其他蛋白质执行NF-ATc的核输入。尽管NF-ATp与NF-ATc共纯化，但目前尚不清楚NF-ATp在体内是如何发挥作用的。既然这些蛋白质已被纯化和克隆，主要目标将是了解它们以及其他家族成员在胸腺发育中的作用。
