Dishevelled proteins lead to two signaling pathways - Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells

Dishevelled (Dsh/Dvl) proteins are known to mediate Wnt signaling by up-reg ulating beta-catenin levels and stimulating T cell factor (TCF)LEF-1-depend ent transcription. We have identified a new Dvl-mediated signaling pathway in that mouse Dvl proteins, when expressed in COS-7 cells, stimulate c-Jun- dependent transcription activity and the kinase activity of the c-Jun N-ter minal kinase (JNK), The DEP domain of Dvl1 is essential for JNK activation. By contrast, all three conserved domains of Dvl, including DIX, PDZ, and D EP, are required for up-regulation of beta-catenin and for stimulation of L EF-1-mediated transcription in mammalian cells. Thus, Dvl can lead to two d ifferent signaling pathways. Furthermore, the small G proteins of Cdc42 or Rad, which are involved in JNK activation by many stimuli, do not appear to play a major role in Dvl-mediated JNK activation, because the dominant neg ative mutants of Cdc42 and Rad could not inhibit Dv1-induced JNK activation . This suggests that Dvl may activate JNK via novel pathways.