JNK mediates insulin-like growth factor binding protein 2/integrin alpha5-dependent glioma cell migration.
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.
Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kanchana Natarajan
KN
Mendes
George K
GK
Wang
Gregory N
GN
Fuller
Wei
W
Zhang
D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D018971:Insulin-Like Growth Factor Binding Protein 2; D039564:Integrin alphaV; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases