Mutant KSR proteins are disclosed. The mutants include single amino acid substitutions, leading to either a loss of kinase activity or a loss of scaffolding activity. Also disclosed are methods of screening compounds for inhibitors of KSR kinase activity or KSR scaffolding activity. In some embodiments, the screening methods include protein complementation assays in which nucleic acids encoding fusion constructs comprising enzyme portions and kinase dimerization domains are expressed in cells. Inhibitors of dimerization can be indicated by loss of enzyme activity.