1] Program of Cancer Biology, Stanford University School of MedicineStanford California 94305 USA [2] Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA [3] Institute of Molecular Medicine, National Taiwan University College of MedicineTaipei 100 Taiwan.
Department of Chemical and Systems Biology, Stanford University School of MedicineStanford California 94305 USA.
Nat Cell Biol. 2014 Feb;16(2):133-44. doi: 10.1038/ncb2906. Epub 2014 Jan 26.
Ca(2+) signals control cell migration by regulating forward movement and cell adhesion. However, it is not well understood how Ca(2+)-regulatory proteins and second messengers are spatially organized in migrating cells. Here we show that receptor tyrosine kinase and phospholipase C signalling are restricted to the front of migrating endothelial leader cells, triggering local Ca(2+) pulses, local depletion of Ca(2+) in the endoplasmic reticulum and local activation of STIM1, supporting pulsatile front retraction and adhesion. At the same time, the mediator of store-operated Ca(2+) influx, STIM1, is transported by microtubule plus ends to the front. Furthermore, higher Ca(2+) pump rates in the front relative to the back of the plasma membrane enable effective local Ca(2+) signalling by locally decreasing basal Ca(2+). Finally, polarized phospholipase C signalling generates a diacylglycerol gradient towards the front that promotes persistent forward migration. Thus, cells employ an integrated Ca(2+) control system with polarized Ca(2+) signalling proteins and second messengers to synergistically promote directed cell migration.
钙离子信号通过调节向前运动和细胞黏附来控制细胞迁移。然而，人们对于钙离子调节蛋白和第二信使在迁移细胞中的空间组织方式还不太了解。在这里，我们发现受体酪氨酸激酶和磷脂酶 C 信号局限于迁移的内皮先导细胞的前端，触发局部钙离子脉冲、内质网钙离子局部耗竭以及 STIM1 的局部激活，从而支持脉冲式前缘回缩和黏附。与此同时，储存操作钙离子内流的介质 STIM1 通过微管正端被运送到前端。此外，质膜前端相对于后端的钙离子泵速率更高，从而通过局部降低基础钙离子浓度实现有效的局部钙离子信号转导。最后，极化的磷脂酶 C 信号产生朝向前端的二酰甘油梯度，促进持续的向前迁移。因此，细胞采用了一种集成的钙离子控制系统，其中包括极化的钙离子信号蛋白和第二信使，以协同促进定向细胞迁移。
