KINASE SUPPRESSOR OF RAS INHIBITS THE ACTIVATION OF EXTRACELLULAR LIGAND-REGULATED (ERK) MITOGEN-ACTIVATED PROTEIN (MAP) KINASE BY GROWTH-FACTORS, ACTIVATED RAS, AND RAS EFFECTORS

Kinase suppressor of Ras (KSR) is a loss-of-function allele that suppr esses the rough eye phenotype of activated Ras in Drosophila and the m ultivulval phenotype of activated Ras in Caenorhabditis elegans. Genet ic and biochemical studies suggest that KSR is a positive regulator of Ras signaling that functions between Ras and, Raf or in a pathway par allel to Raf. We examined the effect of mammalian KSR expression on th e activation of extracellular ligand-regulated (ERR) mitogen-activated protein (MAP) kinase in fibroblasts, Ectopic expression of HSR inhibi ted the activation of ERK MAP kinase by insulin, phorbol ester, or act ivated alleles of Ras, Raf, and mitogen and extracellular-regulated ki nase, Expression of deletion mutants of HSR demonstrated that the KSR kinase domain was necessary and sufficient for the inhibitory effect o f KSR on ERR MAP kinase activity, KSR inhibited cell transformation by activated Ras(Val-12) but had no effect on the ability of Ras(Val-12) to induce membrane ruffling, These data indicate that KSR is a potent modulator of a signaling pathway essential to normal and oncogenic ce ll growth and development.