Weak and Tunable Adhesion-Clutch Drives Rapid Cell Migration and Glioblastoma Invasion

To move forward, migrating cells must exert backward forces against the extracellular environment. Recent studies have highlighted the importance of integrin-independent forces for cell migration; but the molecular machinery that exerts forces remains unclear. Here, we show that the clutch-linker molecule shootin1 and the cell adhesion molecule L1 transmit the backward force of treadmilling actin filaments to the adhesive environment for rapid dendritic cell migration. Notably, shootin1 and L1 transmit weak traction forces, ~100 times weaker than integrin-based forces, by constituting an integrin-independent slippery adhesion-clutch. This adhesion-clutch system is tunable in response to the chemoattractant CCL19 and the adhesive ligand laminin and mediates chemotaxis through its polarized activation within cells. Furthermore, its aberrant activity enhances glioblastoma cell motility. Our results show that the weak adhesion-clutch is well-suited for rapid cell migration, without forming strong adhesions that impede cell motility, and provides a potential target for inhibiting abnormal cell motility.为实现向前迁移，迁移中的细胞需向细胞外环境施加向后的作用力。过往研究已阐明非整合素（integrin）依赖型作用力在细胞迁移中的重要性，但介导此类作用力的分子机制仍未明确。本研究证实，离合器接头分子shootin1与细胞黏附分子L1可将踏车运动型肌动蛋白丝（treadmilling actin filaments）的向后作用力传递至黏附环境，从而介导树突状细胞（dendritic cell）的快速迁移。值得注意的是，shootin1与L1通过构建非整合素依赖型滑动黏附离合器，传递的牵引力（traction forces）仅为基于整合素的作用力的约1/100，强度极弱。该黏附离合器系统可响应趋化因子（chemoattractant）CCL19与黏附配体层粘连蛋白（laminin）进行动态调控，并通过在细胞内的极化激活介导细胞趋化运动。此外，该系统的异常激活可增强胶质母细胞瘤（glioblastoma）细胞的运动能力。本研究结果表明，这种弱效黏附离合器无需形成阻碍细胞运动的强黏附结构，即可适配细胞的快速迁移，同时可为抑制异常细胞运动提供潜在干预靶点。