Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, United States.
Integrated Program in Biomedical Sciences, University of Tennessee Health Sciences Center, Memphis, United States.
Elife. 2018 Jan 23;7:e31678. doi: 10.7554/eLife.31678.
Hedgehog ligands activate an evolutionarily conserved signaling pathway that provides instructional cues during tissue morphogenesis, and when corrupted, contributes to developmental disorders and cancer. The transmembrane protein Dispatched is an essential component of the machinery that deploys Hedgehog family ligands from producing cells, and is absolutely required for signaling to long-range targets. Despite this crucial role, regulatory mechanisms controlling Dispatched activity remain largely undefined. Herein, we reveal vertebrate Dispatched is activated by proprotein convertase-mediated cleavage at a conserved processing site in its first extracellular loop. Dispatched processing occurs at the cell surface to instruct its membrane re-localization in polarized epithelial cells. Cleavage site mutation alters Dispatched membrane trafficking and reduces ligand release, leading to compromised pathway activity in vivo. As such, convertase-mediated cleavage is required for Dispatched maturation and functional competency in Hedgehog ligand-producing cells.
刺猬配体激活了一个进化上保守的信号通路，该通路在组织形态发生过程中提供指导线索，而当该通路发生异常时，则会导致发育障碍和癌症。跨膜蛋白Dispathced 是将刺猬家族配体从产生细胞中释放出来的机器的重要组成部分，对于向远程靶标发出信号是绝对必需的。尽管具有至关重要的作用，但控制 Dispatched 活性的调节机制在很大程度上仍未得到定义。本文中，我们揭示脊椎动物 Dispatched 是通过其第一细胞外环中的保守加工位点的蛋白原转化酶介导的切割而被激活的。Dispatched 的加工发生在细胞表面，以指示其在极化上皮细胞中的膜重新定位。切割位点突变改变了 Dispatched 的膜运输，并减少了配体的释放，从而导致体内信号通路活性受损。因此，蛋白原转化酶介导的切割对于 Hedgehog 配体产生细胞中 Dispatched 的成熟和功能至关重要。
