MEKK1 is required for inducible urokinase-type plasminogen activator expression.

Urokinase-type plasminogen activator (uPA) regulates the remodeling of extracellular matrix and controls reparative processes such as wound healing and liver regeneration. Here we show inducible uPA expression is controlled by MEKK1, a MAPK kinase kinase that regulates the ERK1/2 and JNK pathways. MEKK1 is activated in response to growth factors and cytoskeletal changes. We have found MEKK1 to be necessary for uPA up-regulation in response to treatment with phorbol 12-myristate 13-acetate or basic fibroblast growth factor. We demonstrate that growth factor-treated MEKK1-deficient fibroblasts display greatly reduced uPA expression and activity compared with control fibroblasts. Further, we show that growth factor-induced uPA expression requires MEKK1-dependent MKK1 and JNK activity and that transfection of MEKK1 into knockout cells restores inducible uPA expression and activity. Importantly, disrupted expression of MEKK2, a related MAPK kinase kinase, had no effect on uPA activity. Therefore, we conclude that MEKK1 expression is required for PMA- or FGF-2-induced signals to control uPA expression and function.