The M-72 gene of C. elegans and the Notch gene of D. melanogaster encode structurally related transmembrane proteins that mediate Intercellular signaling. We show that truncated forms of these proteins consisting of only the intracellular domains cause cell fate transformations associated with constitutive activity in their respective organisms. This activity does not depend on endogenous gene function. Our results indicate that the intracellular domains of Lin-12 and Notch have intrinsic activity and that the principal role of the extracellular domains in the intact proteins is to regulate this activity. Our results also suggest that equivalent truncated forms of/in-WNotch family members in vertebrates, including known oncogenes, are similarly active.