Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, 3333 Burnet Ave., ML 7017, Cincinnati, OH, 45229, USA.
Division of Pain Management, Department of Anesthesia, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
Acta Neuropathol Commun. 2018 Nov 23;6(1):127. doi: 10.1186/s40478-018-0635-9.
Normal Schwann cells (SCs) are quiescent in adult nerves, when ATP is released from the nerve in an activity dependent manner. We find that suppressing nerve activity in adult nerves causes SC to enter the cell cycle. In vitro, ATP activates the SC G-protein coupled receptor (GPCR) P2Y2. Downstream of P2Y2, β-arrestin-mediated signaling results in PP2-mediated de-phosphorylation of AKT, and PP2 activity is required for SC growth suppression. NF1 deficient SC show reduced growth suppression by ATP, and are resistant to the effects of β-arrestin-mediated signaling, including PP2-mediated de-phosphorylation of AKT. In patients with the disorder Neurofibromatosis type 1, NF1 mutant SCs proliferate and form SC tumors called neurofibromas. Elevating ATP levels in vivo reduced neurofibroma cell proliferation. Thus, the low proliferation characteristic of differentiated adult peripheral nerve may require ongoing, nerve activity-dependent, ATP. Additionally, we identify a mechanism through which NF1 SCs may evade growth suppression in nerve tumors.
正常雪旺细胞（SCs）在成人神经中处于静止状态，当神经以活动依赖的方式释放 ATP 时。我们发现，抑制成人神经中的神经活动会导致 SC 进入细胞周期。在体外，ATP 激活 SC G 蛋白偶联受体（GPCR）P2Y2。P2Y2 的下游，β-arrestin 介导的信号导致 PP2 介导的 AKT 去磷酸化，并且 PP2 活性是 SC 生长抑制所必需的。NF1 缺陷的 SC 显示出对 ATP 的生长抑制作用降低，并且对β-arrestin 介导的信号的作用（包括 PP2 介导的 AKT 去磷酸化）具有抗性。在神经纤维瘤病 1 型（Neurofibromatosis type 1）患者中，NF1 突变的 SC 增殖并形成称为神经纤维瘤的 SC 肿瘤。体内升高 ATP 水平可减少神经纤维瘤细胞的增殖。因此，分化的成人周围神经的低增殖特性可能需要持续的、依赖神经活动的 ATP。此外，我们确定了一种机制，通过该机制 NF1 SC 可能逃避神经肿瘤中的生长抑制。
