We have previously shown that a molecular interaction between insulin-like growth factor binding protein 2 (IGFBP2) and integrin alpha5 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 alpha5 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 alpha5beta1 integrin receptor, to show that integrin alpha5 is an important mediator of JNK activation. In addition, we found the IGFBP2/integrin alpha5 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 alpha5 interaction, as shown by alpha5 knockdown experiments using IGFBP2-overexpressing cells. Based on these data we propose that the interaction between IGFBP2 and integrin alpha5 accelerates cell adhesion, and this, in turn, enhances JNK-mediated glioma cell migration.
