α_v Integrin, p38 Mitogen-activated Protein Kinase, and Urokinase Plasminogen Activator Are Functionally Linked in Invasive Breast Cancer Cells

We reported previously that endogenous p38 MAPK activity is elevated in invasive breast cancer cells and that constitutive p38 MAPK activity is important for overproduction of uPA in these cells (Huang, S., New, L., Pan, Z., Han, J., and Nemerow, G. R. (2000) J. Biol. Chem. 275, 12266-12272). However, it is unclear how elevated endogenous p38 MAPK activity is maintained in invasive breast cancer cells. In the present study, we found that blocking α_v integrin functionality with a function-blocking monoclonal antibody or down-regulating α_v integrin expression with α_v-specific antisense oligonucleotides significantly decreased the levels of active p38 MAPK and inhibited cell-associated uPA expression in invasive breast cancer MDA-MB-231 cells. These results suggest a function link between α_v integrin, p38 MAPK activity, and uPA expression in invasive tumor cells. We also found that vitronectin/α_v integrin ligation specifically induced p38 MAPK activation and uPA up-regulation in invasive MDA-MB-231 cells but not in non-invasive MCF7 cells. Finally, using a panel of melanoma cells, we demonstrated that the cytoplasmic tail of α_v integrin subunit is required for α _v integrin ligation-induced p38 MAPK activation.