JNK mediates insulin-like growth factor binding protein 2/integrin alpha 5-dependent glioma cell migration

We have previously shown that a molecular interaction between insulin-like growth factor binding protein 2 (IGFBP2) and integrin alpha 5 is necessary for the enhancement of cell migration in IGFBP2-overexpressing gliomas. In the present study, we examined the mechanism through which the IGFBP2/integrin alpha 5 interaction mediates enhanced glioma cell migration. Although both ERK and JNK MAP kinases were activated, JNK was specifically involved in IGFBP2-mediated migration as shown by inhibitor analysis of IGFBP2-overexpressing cells. Because gliomas are solid tumors that require contact with a surface (e.g., other cells, extracellular matrix) for migration, we used the extracellular matrix (ECM) protein fibronectin, which is the sole ligand of the alpha 5 beta i integrin receptor, to show that integrin alpha 5 is an important mediator of JNK activation. In addition, we found the IGFBP2/integrin alpha 5 pathway to be activated in a significantly shorter interval in cells seeded onto fibronectin-coated surfaces compared to cells seeded onto plastic alone. The activation of JNK was downstream of the IGFBP2/integrin alpha 5 interaction, as shown by alpha 5 knockdown experiments using IGFBP2-overexpressing cells. Based on these data we propose that the interaction between IGFBP2 and integrin alpha 5 accelerates cell adhesion, and this, in turn, enhances JNK-mediated glioma cell migration.