Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, and Women's Health Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cell Rep. 2018 Apr 10;23(2):485-498. doi: 10.1016/j.celrep.2018.03.034.
Focal adhesions anchor cells to extracellular matrix (ECM) and direct assembly of a pre-stressed actin cytoskeleton. They act as a cellular sensor and regulator, linking ECM to the nucleus. Here, we identify proteolytic turnover of the anti-adhesive proteoglycan versican as a requirement for maintenance of smooth muscle cell (SMC) focal adhesions. Using conditional deletion in mice, we show that ADAMTS9, a secreted metalloprotease, is required for myometrial activation during late gestation and for parturition. Through knockdown of ADAMTS9 in uterine SMC, and manipulation of pericellular versican via knockdown or proteolysis, we demonstrate that regulated pericellular matrix dynamics is essential for focal adhesion maintenance. By influencing focal adhesion formation, pericellular versican acts upstream of cytoskeletal assembly and SMC differentiation. Thus, pericellular versican proteolysis by ADAMTS9 balances pro- and anti-adhesive forces to maintain an SMC phenotype, providing a concrete example of the dynamic reciprocity of cells and their ECM.
焦点黏附将细胞固定在细胞外基质（ECM）上，并指导预先存在的肌动蛋白细胞骨架的组装。焦点黏附作为细胞的传感器和调节剂，将 ECM 与细胞核连接起来。在这里，我们发现抗黏附蛋白聚糖 versican 的蛋白水解周转是维持平滑肌细胞（SMC）焦点黏附的必要条件。我们利用小鼠条件性缺失，表明分泌金属蛋白酶 ADAMTS9 在妊娠晚期和分娩时需要用于子宫肌层的激活。通过在子宫 SMC 中敲低 ADAMTS9，并通过敲低或蛋白水解来操纵细胞周 versican，我们证明了细胞周基质动力学的调节对于焦点黏附的维持是必不可少的。通过影响焦点黏附的形成，细胞周 versican 作用于细胞骨架组装和 SMC 分化的上游。因此，ADAMTS9 对细胞周 versican 的蛋白水解作用平衡了促进黏附和抗黏附的力量，以维持 SMC 表型，为细胞与其 ECM 的动态互惠提供了一个具体的例子。
