A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE

Treatment of cells with a variety of growth factors triggers a phospho rylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, o r ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectiv ely inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), witho ut significant inhibitory activity of MAPK itself. Inhibition of MEK b y PD 098059 prevented activation of MAPK and subsequent phosphorylatio n of MAPK substrates both in vitro and in intact cells. Moreover, PD 0 98059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. Th ese results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is a n invaluable tool that will help elucidate the role of the MAPK cascad e in a variety of biological settings.