Actuation of single downstream nodes in growth factor network steers immune cell migration.
Actuation of single downstream nodes in growth factor network steers immune cell migration.
复制标题
生长因子网络中单个下游节点的激活可引导免疫细胞迁移。
DOI：
10.1016/j.devcel.2023.04.019
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发表时间：
2023
影响因子：
11.8
通讯作者：
Devreotes,PeterN
中科院分区：
文献类型：
--
作者：
Pal,DhimanSankar;Banerjee,Tatsat;Lin,Yiyan;deTrogoff,Félix;Borleis,Jane;Iglesias,PabloA;Devreotes,PeterN
Ras信号通常与细胞生长有关，但不直接调节运动或极性。通过光遗传学靶向分化的人HL-60中性粒细胞中Ras/PI3K/Akt网络的不同节点，我们突然改变了突起活性，绕过了化学引诱剂受体/ g蛋白网络。首先，活跃的KRas4B/HRas异构体或RasGEF， RasGRP4的全球募集立即增加了扩散和随机运动。其次，激活细胞后部的Ras产生新的突起，逆转先前存在的极性，并引导中性粒细胞或小鼠RAW 264.7巨噬细胞的持续迁移。第三，将RasGAP RASAL3募集到细胞前沿，使突起消失，改变迁移方向。值得注意的是，稳定锋面持续的RASAL3募集消除了三种不同化学引诱剂梯度下的定向迁移。第四，中性粒细胞或dictyosteliumamoebae中Ras-mTORC2效应物Akt的局部募集产生新的突起，并重新排列原有的极性。总的来说，这些光遗传效应依赖于mtorc2，但相对独立于PI3K。因此，与受体无关的经典生长控制途径的局部激活直接控制肌动蛋白组装、细胞形状和迁移模式。
Ras signaling is typically associated with cell growth, but not direct regulation of motility or polarity. By optogenetically targeting different nodes in the Ras/PI3K/Akt network in differentiated human HL-60 neutrophils, we abruptly altered protrusive activity, bypassing the chemoattractant receptor/G-protein network. First, global recruitment of active KRas4B/HRas isoforms or a RasGEF, RasGRP4, immediately increased spreading and random motility. Second, activating Ras at the cell rear generated new protrusions, reversed pre-existing polarity, and steered sustained migration in neutrophils or murine RAW 264.7 macrophages. Third, recruiting a RasGAP, RASAL3, to cell fronts extinguished protrusions and changed migration direction. Remarkably, persistent RASAL3 recruitment at stable fronts abrogated directed migration in three different chemoattractant gradients. Fourth, local recruitment of the Ras-mTORC2 effector, Akt, in neutrophils orDictyosteliumamoebae generated new protrusions and rearranged pre-existing polarity. Overall, these optogenetic effects were mTORC2-dependent but relatively independent of PI3K. Thus, receptor-independent, local activations of classical growth-control pathways directly control actin assembly, cell shape, and migration modes.