RAS SIGNALING IS ABNORMAL IN A C-RAF1 MEK1 DOUBLE MUTANT

A mutant rat cell clone that suppresses the transformation defects of RAS effector loop substitutions is heterozygous for mutations in c-raf 1 acid MEK1. The mutant cells can be transformed by many otherwise def ective RAS effector mutants, including RAS genes with the effector reg ions of distantly related GTPases, even though the encoded RAS protein s do not interact with either the mutant or wild-type RAF in Saccharom yces cerevisiae. While the significance of the c-raf1 mutation is uncl ear, the MEK1 mutation increases MEK1 activity and leads to activation of mitogen-activated protein kinase. The mutant MEK1 is coupled to th e epidermal growth factor pathway but exhibits decreased physical inte raction with RAF. When overexpressed, the MEK1 mutation is transformin g and causes hyperphosphorylation of RAF, Signalling from RAS to MEK1 may be mediated by something other than RAF alone, but signalling thro ugh MEK1 is probably sufficient for RAS transformation.