Lipid phosphatases SKIP and SHIP2 regulate fibronectin‐dependent cell migration in glioblastoma

• Published in: The FEBS journal Vol. 286; no. 6; pp. 1120 - 1135
• Main Authors: Ramos, Ana Raquel, Ghosh, Somadri, Dedobbeleer, Matthias, Robe, Pierre A., Rogister, Bernard, Erneux, Christophe
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2019
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adhesion; Cancer; Catalysis; Cell adhesion & migration; Cell migration; Cell Movement; Cytoskeleton; Fibronectin; Fibronectins - metabolism; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Humans; Inositol polyphosphate 5-phosphatase; Invasiveness; Lamellipodia; Lipids; Phosphatase; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - genetics; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - metabolism; phosphoinositides; Phosphoric Monoester Hydrolases - metabolism; PI(4,5)P2; Pseudopodia; PTEN protein; RNA, Small Interfering - genetics; SHIP2; Signal Transduction; SKIP; Synergism; Tumor Cells, Cultured; Velocity; SKIP; glioblastoma; SHIP2; phosphoinositides; PI(4,5)P2
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14769

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. Analysis of glioblastoma cell lines demonstrated that the phosphoinositide 5‐phosphatases SHIP2 and SKIP are colocalized in membrane ruffles. Upregulation of PI(4,5)P2 in SKIP‐depleted cells compared to control cells is only observed when cells (e.g. U‐251 cells) adhere to fibronectin. The colocalization of SKIP and SHIP2 in circular ruffles suggests that the formation of ruffles could be controlled by PI 5‐phosphatases acting in concert, potentially as drivers of cell migration.