IRIBHM, Université Libre de Bruxelles, Belgium.
GIGA-Neurosciences Research Center, Université de Liège, Belgium.
FEBS J. 2019 Mar;286(6):1120-1135. doi: 10.1111/febs.14769. Epub 2019 Feb 16.
Cell migration is an important process that occurs during development and has also been linked to the motility of cancer cells. Cytoskeleton reorganization takes place in the migration process leading to lamellipodia formation. Understanding the molecular underpinnings of cell migration is particularly important in studies of glioblastoma, a highly invasive and aggressive cancer type. Two members of the phosphoinositide 5-phosphatase family, SKIP and SHIP2, have been associated with cell migration in glioblastoma; however, the precise role these enzymes play in the process-and whether they work in concert-remains unclear. Here, we compared phosphoinositide 5-phosphatases expression in glioblastoma primary cells and cell lines and showed that SHIP2 and SKIP expression greatly varies between different cell types, while OCRL, another phosphoinositide 5-phosphatase, is constitutively expressed. Upon adhesion of U-251 MG cells to fibronectin, SHIP2, SKIP, and PI(4,5)P2 colocalized in membrane ruffles. Upregulation of PI(4,5)P2 was observed in SKIP-depleted U-251 MG cells compared to control cells, but only when cells were adhered to fibronectin. Both PTEN-deficient (U-251) and PTEN-containing (LN229) glioblastoma cells showed a decrease in cell migration velocity in response to SKIP downregulation. Moreover, a SHIP2 catalytic inhibitor lowered cell migration velocity in the U-251 MG cell line. We conclude that integrin activation in U-251 cells leads to colocalization of both SKIP and SHIP2 in ruffles, where they act as potential drivers of cell migration. Depending on their expression levels in glioblastoma, phosphoinositide 5-phosphatases could cooperate and synergize in the regulation of cell migration and adhesion.
细胞迁移是一个重要的过程，它发生在发育过程中，也与癌细胞的运动有关。细胞骨架重排在迁移过程中发生，导致片状伪足的形成。了解细胞迁移的分子基础在神经胶质瘤的研究中尤为重要，神经胶质瘤是一种高度侵袭性和侵袭性的癌症类型。磷酸肌醇 5-磷酸酶家族的两个成员，SKIP 和 SHIP2，与神经胶质瘤中的细胞迁移有关；然而，这些酶在该过程中的确切作用，以及它们是否协同作用，仍然不清楚。在这里，我们比较了神经胶质瘤原代细胞和细胞系中磷酸肌醇 5-磷酸酶的表达，结果表明 SHIP2 和 SKIP 的表达在不同细胞类型之间差异很大，而另一种磷酸肌醇 5-磷酸酶 OCRL 则持续表达。当 U-251 MG 细胞黏附到纤维连接蛋白上时，SHIP2、SKIP 和 PI(4,5)P2 共定位于膜皱褶中。与对照细胞相比，在 SKIP 耗尽的 U-251 MG 细胞中观察到 PI(4,5)P2 的上调，但仅在细胞黏附到纤维连接蛋白时观察到。PTEN 缺陷型（U-251）和包含 PTEN 型（LN229）神经胶质瘤细胞在 SKIP 下调时表现出迁移速度的降低。此外，在 U-251 MG 细胞系中，SHIP2 催化抑制剂降低了细胞迁移速度。我们得出结论，U-251 细胞中整合素的激活导致 SKIP 和 SHIP2 在皱褶中的共定位，它们在那里作为细胞迁移的潜在驱动因素。根据其在神经胶质瘤中的表达水平，磷酸肌醇 5-磷酸酶可能在调节细胞迁移和黏附中合作和协同作用。
